KE-4 4120 boger book

Lecture Notes Modern Organic Synthesis Dale L. Boger The Scripps Research Institute Coordinated by Robert M. Garbaccio Assembled by Conformational Analysis Steven L. Castle Kinetics and Thermodynamics Reaction Mechanisms and Conformational Effects Richard J. Lee Oxidation Reactions and Alcohol Oxidation Bryan M. Lewis Christopher W. Boyce Reduction Reactions and Hydroboration Reactions Clark A. Sehon Marc A. Labroli Enolate Chemistry and Metalation Reactions Jason Hongliu Wu Robert M. Garbaccio Key Ring Transformations Wenge Zhong Jiyong Hong Brian M. Aquila Mark W. Ledeboer Olefin Synthesis Gordon D. Wilkie Conjugate Additions Robert P. Schaum Synthetic Analysis and Design Robert M. Garbaccio Combinatorial Chemistry Joel A. Goldberg TSRI Press La Jolla, CA Copyright © 1999 TSRI Press. All rights reserved. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic tape, mechanical, photocopying, recording or otherwise, without permission in writing from the publisher. Print First Edition 1999 CD Version 1.0 (1999) CD Version 1.01 (2000) CD Version 1.02 (2001) ISBN Flexicover The CD versions of the Lecture Notes (Versions 1.01 and 1.02) contain corrections and updates to the science and will differ slightly from the printed text (First Edition, 1999). We anticipate that this will continue on an annual basis, as with any set of classroom lecture notes. Consequently, we would like to encourage you to inform us of mistakes you might find and we welcome suggestions for additions to the content. In fact, if we are provided ChemDraw files of science you would like to see included, the barriers to its incorporation are minimized. The text of the CD may be searched by Adobe Acrobat Reader and this may be used in lieu of an index. Printed and Bound in the U.S.A. by Rush Press, San Diego, California Introduction Dale L. Boger Preface The notes have been used as the introductory section of a course on Modern Organic Synthesis that composes 6 weeks or a little more than one-half of a quarter course at The Scripps Research Institute, Department of Chemistry. Consequently, an exhaustive treatment of the individual topics is beyond the scope of this portion of the course. The remaining 4 weeks of the quarter delve into more detail on various topics and introduce concepts in multistep organic synthesis (E. Sorensen). For our students, this is accompanied by a full quarter course in physical organic chemistry and is followed by a full quarter course on state of the art natural products total synthesis (K. C. Nicolaou, E. Sorensen) and a quarter elective course on transition metal chemistry. Complementary to these synthetic and mechanistic courses, two quarter courses on bioorganic chemsitry and an elective course on the principles of molecular biology and immunology are available to our students. Efforts have been made to not duplicate the content of these courses. For those who might examine or use the notes, I apologize for the inevitable oversight of seminal work, the misattribution of credit, and the missing citations to work presented. The original notes were not assembled with special attention to this detail, but rather for the basic content and the ‘nuts and bolts’ laboratory elements of organic synthesis. In addition, some efforts were made to highlight the chemistry and contributions of my group and those of my colleagues for the intrinsic interest and general appreciation of our students. I hope this is not mistaken for an effort to unduly attribute credit where this was not intended. We welcome any suggestions for content additions or corrections and we would be especially pleased to receive even minor corrections that you might find. – Dale L. Boger Heinrich Friedrich von Delius (1720–1791) is credited with introducing chemistry into the academic curriculum. Acknowledgments Significant elements of the material in the notes were obtained from the graduate level organic synthesis course notes of P. Fuchs (Purdue University) and were influenced by my own graduate level course taught by E. J. Corey (Harvard). They represent a set of course notes that continue to evolve as a consequence of the pleasure of introducing young colleagues to the essence and breadth of modern organic synthesis and I thank them for the opportunity, incentive, and stimulation that led to the assemblage of the notes. Those familiar with ChemDraw know the efforts that went into reducing my hand drafted notes and those maintained by Robert J. Mathvink (Purdue University) and Jiacheng Zhou (The Scripps Research Institute) to a ChemDraw representation. For this, I would like to thank Robert M. Garbaccio for initiating, coordinating, proofing and driving the efforts, and Steve, Richard, Chris, Bryan, Clark, Marc, Jason, Rob, Wenge, Jiyong, Brian, Mark, Gordon, Robert and Joel for reducing the painful task to a reality. Subsequent updates have been made by Steven L. Castle (Version 1.01) and Jiyong Hong (Version 1.02). i Modern Organic Chemistry The Scripps Research Institute It is a pleasure to dedicate this book and set of notes to Richard Lerner who is responsible for their appearance. His vision to create a chemistry program within Scripps, his energy and enthusiasm that brought it to fruition, his support for the graduate program and committment to its excellence, and his personal encouragement to this particular endeavour of developing a graduate level teaching tool for organic synthesis, which dates back to 1991, made this a reality. Antoine L. Lavoisier, universally regarded as the founder of modern chemistry, published in 1789 his Elementary Treatise on Chemistry that distinguished between elements and compounds, initiated the modern system of nomenclature, and established the oxygen theory of combustion. He and his colleagues founded Annales de Chemie in 1789, he earned his living as a tax official and his “chemical revolution” of 1789 coincided with the start of the violent French Revolution (1789−1799). He was executed by guillotine in 1794. Jons Jacob Berzelius (1779–1848), a Swedish chemist, discovered cerium, produced a precise table of experimentally determined atomic masses, introduced such laboratory equipment as test tubes, beakers, and wash bottles, and introduced (1813) a new set of elemental symbols based on the first letters of the element names as a substitute for the traditional graphic symbols. He also coined the term “organic compound” (1807) to define substances made by and isolated from living organisms which gave rise to the field of organic chemistry. ii Introduction Dale L. Boger Table of Contents I. Conformational Analysis A. Acyclic sp3–sp 3 Systems B. Cyclohexane and Substituted Cyclohexanes, A Values (∆G°) C. Cyclohexene D. Decalins E. Acyclic sp3–sp2 Systems F. Anomeric Effect G. Strain H. pKa of Common Organic Acids 1 1 2 7 7 8 12 14 16 II. Kinetics and Thermodynamics of Organic Reactions A. Free Energy Relationships B. Transition State Theory C. Intramolecular Versus Intermolecular Reactions D. Kinetic and Thermodynamic Control E. Hammond Postulate F. Principle of Microscopic Reversibility 17 17 18 18 20 21 22 III. Reaction Mechanisms and Conformational Effects on Reactivity A. Ester Hydrolysis B. Alcohol Oxidations C. SN2 Reactions D. Elimination Reactions E. Epoxidation by Intramolecular Closure of Halohydrins F. Epoxide Openings (SN2) G. Electrophilic Additions to Olefins H. Rearrangement Reactions I. Pericyclic Reactions J. Subtle Conformational and Stereoelectronic Effects on Reactivity K. Methods for the Synthesis of Optically Active Materials 23 23 25 25 26 29 29 30 31 33 36 39 IV. Oxidation Reactions A. Epoxidation Reactions B. Additional Methods for Epoxidation of Olefins C. Catalytic Asymmetric Epoxidation D. Stoichiometric Asymmetric Epoxidation E. Baeyer–Villiger and Related Reactions F. Beckmann Rearrangement and Related Reactions G. Olefin Dihydroxylation H. Catalytic and Stoichiometric Asymmetric Dihydroxylation I. Catalytic Asymmetric Aminohydroxylation J. Ozonolysis 41 41 51 56 67 67 70 74 81 84 86 V. Oxidation of Alcohols A. Chromium-based Oxidation Reagents 87 87 iii Modern Organic Chemistry The Scripps Research Institute B. Manganese-based Oxidation Reagents C. Other Oxidation Reagents D. Swern Oxidation and Related Oxidation Reactions 89 90 93 Reductions Reactions A. Conformational Effects on Carbonyl Reactivity B. Reactions of Carbonyl Groups C. Reversible Reduction Reactions: Stereochemistry D. Irreversible Reduction Reactions: Stereochemistry of Hydride Reduction Reactions and Other Nucleophilic Additions to Carbonyl Compounds E. Aluminum Hydride Reducing Agents F. Borohydride Reducing Agents G. Hydride Reductions of Functional Groups H. Characteristics of Hydride Reducing Agents I. Asymmetric Carbonyl Reductions J. Catalytic Hydrogenation K. Dissolving Metal Reductions L. Amalgam-derived Reducing Agents M. Other Reduction Methods 95 95 96 96 97 112 113 115 118 124 127 128 134 136 VII. Hydroboration–Oxidation A. Mechanism B. Regioselectivity C. Diastereoselectivity D. Metal-catalyzed Hydroboration E. Directed Hydroboration F. Asymmetric Hydroboration 139 139 140 140 143 144 144 VIII. Enolate Chemistry A. Acidic Methylene Compounds B. Enolate Structure C. Enolate Alkylations D. Enolate Generation E. Alkylation Reactions: Stereochemistry F. Asymmetric Alkylations G. Aldol Addition (Condensation) H. Aldol Equivalents I. Enolate-imine Addition Reactions J. Claisen Condensation K. Dieckmann Condensation L. Enolate Dianions M. Metalloimines, Enamines and Related Enolate Equivalents N. Alkylation of Extended Enolates 147 147 155 156 159 168 175 179 197 199 200 201 203 203 206 IX. Metalation Reactions A. Directed Metalation B. Organolithium Compounds by Metal–Halogen Exchnage C. Organolithium Compounds by Metal–Metal Exchange (Transmetalation) D. Organolithium Compounds from the Shapiro Reaction E. Key Organometallic Reactions Enlisting Metalation or Transmetalation Reactions 207 207 210 211 211 212 VI. iv Introduction Dale L. Boger X. Key Ring Forming Reactions A. Diels–Alder Reaction B. Robinson Annulation C. Birch Reduction D. Dieckmann Condensation E. Intramolecular Nucleophilic Alkylation F. Intramolecular Aldol Condensation G. Intramolecular Michael Reaction H. Cation–Olefin Cyclizations I. Free Radical Cyclizations J. Anionic Cyclizations K. 1,3-Dipolar Cycloadditions L. [1,3]-Sigmatropic Rearrangements M. Electrocyclic Reactions N. Nazarov Cyclization O. Divinylcyclopropane Rearrangement P. Carbene Cycloaddition to Alkenes Q. [2 + 3] Cycloadditions for 5-Membered Ring Formation R. Cyclopropenone Ketal Cycloaddition Reactions S. [2 + 2] Cycloadditions T. Arene–Olefin Photoadditions U. Intramolecular Ene Reaction V. Oxy–Ene Reaction: Conia Reaction W. Cyclopentenone Annulation Methodology X. Pauson–Khand Reaction Y. Carbonylation Cyclizations Z. Olefin Ring Closing Metathesis 213 213 271 287 287 287 288 288 289 301 321 322 326 328 328 330 331 336 339 343 346 347 349 350 353 355 356 XI. Olefin Synthesis A. Wittig Reaction B. Wadsworth–Horner–Emmons Reaction C. Peterson Olefination D. Tebbe Reaction and Related Titanium-stabilized Methylenations E. Other Methods for Terminal Methylene Formation F. Olefin Inversion Reactions G. [3,3]-Sigmatropic Rearrangements: Claisen and Cope Rearrangements H. [2,3]-Sigmatropic Rearrangements I. Olefin Synthesis Illustrated with Juvenile Hormone 359 359 365 367 370 371 372 374 378 381 XII. Conjugate Additions: Organocuprate 1,4-Additions 395 XIII. Synthetic Analysis and Design A. Classifications B. Retrosynthetic Analysis C. Strategic Bond Analysis D. Total Synthesis Exemplified with Longifolene 427 428 431 440 443 XIV. Combinatorial Chemistry 461 v Conformational Analysis Dale L. Boger I. Conformational Analysis A. Acyclic sp3–sp3 Systems: Ethane, Propane, Butane staggered eclipsed H 1. Ethane H H H H H 1.0 kcal H H 60° rotation HH H H H HH H H H E 3 rel. E 2 (kcal) 1 E 3.0 kcal S 0 H H H E 60 S 120 60° rotation 180 S 240 300 360 dihedral angle H H H - Two extreme conformations, barrier to rotation is 3.0 kcal/mol. eclipsed H 2. Propane H CH3 H H H H CH3 HH 1.3 kcal 60° rotation H HH H fully eclipsed (synperiplanar) E 3.3 kcal S S 60 120 180 S 240 300 360 dihedral angle H - Barrier to rotation is 3.3 kcal/mol. - Note: H/H (1.0 kcal) and Me/H (1.3 kcal) eclipsing interactions are comparable and this is important in our discussions of torsional strain. gauche (synclinal) H H3C CH3 E CH3 60° rotation 1.0 kcal each H3C E 0 H H 3. Butane 4 rel. E 3 (kcal) 2 1 staggered H H CH3 H H H eclipsed (anticlinal) H3C CH3 staggered (antiperiplanar) H3C H H H H H CH3 H H CH3 gauche interaction 4.0 kcal 1.3 kcal each 0.9 kcal H3C H3C CH3 CH3 H CH3 60° rotation H 60° rotation H CH3 60° rotation H H HH HH HH H H CH3 H H H CH3 H H H H H H H H 1.0 kcal each 6 5 4 rel. E (kcal) 3 2 1 1.0 kcal FE FE E E - Note: the gauche butane interaction and its magnitude (0.9 kcal) are very important and we will discuss it frequently. 6.0 kcal G 3.6 kcal 0.9 kcal 0 60 120 G S 180 240 300 360 dihedral angle 1 Modern Organic Chemistry The Scripps Research Institute 4. Substituted Ethanes - There are some exceptions to the lowest energy conformation. Sometimes, a gauche conformation is preferred over staggered if X,Y are electronegative substituents. cf: Kingsbury J. Chem. Ed. 1979, 56, 431. X H X Y H H H H Y X H H H H H H H Y gauche H X H H Y H staggered Egauche < Estaggered if X = OH, OAc and Y = Cl, F 5. Rotational Barriers H H H H H H H H H CH3 H H H H H 2.88 kcal/mol (3.0 kcal/mol 3.40 kcal/mol 3.3 kcal/mol H CH3 H3 C H H CH3 CH3 H CH3 3.90 kcal/mol 3.6 kcal/mol - Experimental - Simple prediction 4.70 kcal/mol 3.9 kcal/mol) - The rotational barrier increases with the number of CH3/H eclipsing interactions. H H H H H H H 2.88 kcal/mol (3.0 kcal/mol H H H H H N •• 1.98 kcal/mol 2.0 kcal/mol •• H H O •• H - Experimental - Simple prediction 1.07 kcal/mol 1.0 kcal/mol) - The rotational barrier increases with the number of H/H eclipsing interactions. B. Cyclohexane and Substituted Cyclohexanes, A Values (∆G°) 1. Cyclohexane 4 Hax 1 Heq 3 2 chair 5 6 4 6 5 3 Ea = 10 kcal Heq 1 Hax chair 2 4 atoms in plane H HH H H H H HH H H half chair (rel E = 10 kcal) 2 H H H H H H twist boat (rel E = 5.3 kcal) H HH HH H H half chair (rel E = 10 kcal) Conformational Analysis Dale L. Boger - Chair conformation (all bonds staggered) Hax Hax Hax Heq Heq Heq Heq Hax Hax Hax - Rapid interconversion at 25 °C (Ea = 10 kcal/mol, 20 kcal/mol available at 25 °C). - Hax and Heq are indistinguishable by 1H NMR at 25 °C. - At temperatures < –70 °C, Heq and Hax become distinct in 1H NMR. - Boat conformation 2.9 kcal flagpole interaction H Hax H Heq H H H H H Hax H Hax H Heq 1.0 kcal each (4x) - Rel E = 6.9 kcal, not local minimum on energy surface. - More stable boat can be obtained by twisting (relieves flagpole interaction somewhat). - Twist boat conformation (rel E = 5.3 kcal) does represent an energy minimum. - The boat conformation becomes realistic if flagpole interactions are removed, i.e. O X - Half chair conformation H HH D.H.R. Barton received the 1969 Nobel Prize in Chemistry for his contributions to conformational analysis, especially as it relates to steroids and six-membered rings. Barton Experientia 1950, 6, 316. H H HH H - Energy maximum (rel E = 10.0 kcal) 10 half chair half chair rel E (kcal) 5 10 kcal twist boat 5.3 kcal 0 chair chair 3 Modern Organic Chemistry The Scripps Research Institute 2. Substituted Cyclohexanes - Methylcyclohexane H H CH3 H ∆G° = –RT(ln K) –1.8 × 1000 1.99 × 298 = –ln K CH3 H 1.8 kcal more stable K = 21 - The gauche butane interaction is most often identifiable as 1,3-diaxial interactions. H H H H H H H CH3 H H H H H H CH3 H H 2 gauche butane interactions 2 × 0.9 kcal = 1.8 kcal (experimental 1.8 kcal) H H H 0 gauche butane interactions - A Value (–∆G°) = Free energy difference between equatorial and axial substituent on a cyclohexane ring. Typical A Values R F Cl Br I OH OCH3 OCOCH3 NH2 NR2 CO2H CO2Na CO2Et SO2Ph R A Value (kcal/mol) 0.25 0.52 0.5–0.6 0.46 0.7 (0.9) 0.75 0.71 1.8 (1.4) 2.1 1.2 (1.4) 2.3 1.1 2.5 CN C CH 0.2 Small, linear 0.41 groups ca. 0.5 kcal NO2 1.1 1.7 ca. 0.7 kcal (2nd atom effect very small) CH=CH2 CH3 CH2CH3 nC H 3 7 nC H 4 9 CH(CH3)2 C(CH3)3 C6H5 2.1 - Note on difference between iPr and tBu A values. H CH3 CH3 H3C H H CH3 CH3 H H 4 A Value (kcal/mol) iPr group can position H toward "inside," but tBu group cannot. Very serious interaction, 7.2 kcal. 1.8 2.1 2nd atom effect very 2.1 small 1.9 (1.8) >4.5 (ca. 5.4) 3.1 (2.9) Conformational Analysis Dale L. Boger - Determination of A value for tBu group. 0.9 kcal CH3 7.2 kcal H3C H H CH3 H H ∆G° = (9.0 kcal – 3.6 kcal) = 5.4 kcal H H CH3 H CH3 H CH3 0.9 kcal 7.2 kcal + (2 × 0.9 kcal) = 9.0 kcal 0.9 kcal each 4 × 0.9 kcal = 3.6 kcal - Note on interconversion between axial and equatorial positions. H Cl H Cl t1/2 = 22 years at –160 °C Even though Cl has a small A value (i.e., small ∆G° between rings with equatorial and axial Cl group), the Ea (energy of activation) is high (it must go through half chair conformation). trans-1,2-dimethylcyclohexane H H CH3 H H CH3 CH3 H H H CH3 H H H H CH3 4 × (gauche interaction) 4 × (0.9 kcal) = 3.6 kcal H H H H H H CH2 H CH3 ∆E = 0 kcal/mol H H CH3 H CH3 H H 1 × (gauche interaction) 1 × (0.9 kcal) = 0.9 kcal H CH3 H CH2 H H CH3 CH3 H CH2 H H 2.7 kcal/mol more stable H H H H H H CH3 H cis-1,2-dimethylcyclohexane H H 3 × (gauche interaction) 3 × (0.9 kcal) = 2.7 kcal H2/Pt CH3 H H H H H H H H CH2 CH3 H 3 × (gauche interaction) 3 × (0.9 kcal) = 2.7 kcal CH3 CH3 ∆G = 1.87 kcal/mol (exp) ∆G = 1.80 kcal/mol (calcd) 5 Modern Organic Chemistry The Scripps Research Institute trans-1,3-dimethylcyclohexane H H CH3 H CH3 CH3 H H CH3 H H cis-1,3-dimethylcyclohexane H CH3 H CH3 H H H CH3 H H CH3 H H H H CH3 H H CH3 CH3 H H H H H H H H H 2 × (gauche interaction) 2 × (0.9 kcal) = 1.8 kcal CH3 H CH3 CH3 CH3 H H 2 × (gauche interaction) 2 × (0.9 kcal) = 1.8 kcal CH3 H H H2/Pt H CH3 H H 2 × (gauche interaction) + 1 × (Me–Me 1,3 diaxial int) 2 × (0.9 kcal) + 3.7 kcal = 5.5 kcal H H H 0 × (gauche interaction) 0 × (0.9 kcal) = 0 kcal CH3 CH3 CH3 ∆G = 1.80 kcal/mol (exp and calcd) - Determination of energy value of Me–Me 1,3-diaxial interaction. CH3 CH3 CH3 H CH3 CH3 CH3 3 × Me–Me 1,3-diaxial interaction H CH3 H2/Pt CH3 H 2 × (gauche interaction) 2 × (0.9 kcal) = 1.8 kcal 500 °C CH3 H CH3 CH3 H H CH3 CH3 2 × (gauche interaction) + 1 × (Me–Me 1,3 diaxial int) = 2 × (0.9 kcal) + ? CH3 CH3 H 2 × (gauche interaction) + 1 × (Me–Me 1,3 diaxial int) = 2 x (0.9 kcal) + ? ∆G = 3.7 kcal/mol (exp) So, Me–Me 1,3-diaxial interaction = 3.7 kcal/mol. 1,3-diaxial interactions R/R OH/OH OAc/OAc OH/CH3 CH3/CH3 ∆G° 1.9 kcal 2.0 kcal 2.4 (1.6) kcal 3.7 kcal ∆G° of common interactions ax H ax OH eq OH eq CH3 ax OH ax CH3 eq OH 0.45* 1.9 0.35 0.35 0.9 1.6 0.35 0.9 0.0 0.35 0.35 0.35 *1/2 of A value 6 CH3 Conformational Analysis Dale L. Boger C. Cyclohexene One 1,3-diaxial interaction removed One 1,3-diaxial interaction reduced pseudoequatorial pseudoaxial - half-chair - Ea for ring interconversion = 5.3 kcal/mol - the preference for equatorial orientation of a methyl group in cyclohexene is less than in cyclohexane because of the ring distortion and the removal of one 1,3-diaxial interaction (1 kcal/mol) D. Decalins trans-decalin cis-decalin H HH H H H H H two conformations equivalent H H H H H H H H H H H H H H H H H H H H H H H H H H H H 3 gauche interactions 3 × 0.9 kcal = 2.7 kcal 0.0 kcal ∆E between cis- and trans-decalin = 2.7 kcal/mol trans-9-methyldecalin H H cis-9-methyldecalin CH3 H H H H H H H H CH3 H H CH3 H H H two conformations equivalent H H H H CH3 H H H H H H H H H H H H H H 4 gauche interactions 4 × 0.9 = 3.6 kcal H H H H H CH3 H H H 5 gauche interactions 5 × 0.9 = 4.5 kcal ∆E between cis- and trans-9-methyldecalin = 0.9 kcal/mol 7 Modern Organic Chemistry The Scripps Research Institute E. Acyclic sp3–sp2 Systems - Key references - Origin of destabilization for eclipsed conformations: Prog. Phys. Org. Chem. 1968, 6, 1. Lowe Pure Appl. Chem. 1971, 25, 563. Oosterhoff Wyn-Jones, Pethrick Top. Stereochem. 1970, 5, 205. Quat. Rev., Chem. Soc. 1969, 23, 301. J. Mol. Struct. 1970, 6, 23. Brier Science 1973, 179, 527. Lowe - Molecular orbital calculations: Repulsion of overlapping filled orbitals: Pitzer Acc. Chem. Res. 1983, 16, 207. - Propionaldehyde: Butcher, Wilson Allinger, Hickey Allinger J. Chem. Phys. 1964, 40, 1671. J. Mol. Struct. 1973, 17, 233. J. Am. Chem. Soc. 1969, 91, 337. - Propene: Allinger Herschbach J. Am. Chem. Soc. 1968, 90, 5773. J. Chem. Phys. 1958, 28, 728. - 1-Butene: Geise J. Am. Chem. Soc. 1980, 102, 2189. - Allylic 1,3-strain: Houk, Hoffmann Hoffmann J. Am. Chem. Soc. 1991, 113, 5006. Chem. Rev. 1989, 89, 1841. Jacobus van't Hoff studied with both Kekule and Wurtz and received the first Nobel Prize in Chemistry (1901) in recognition of his discovery of the laws of chemical kinetics and the laws governing the osmotic pressure of solutions. More than any other person, he created the formal structure of physical chemistry and he developed chemical stereochemistry which led chemists to picture molecules as objects with three dimensional shapes. He published his revolutionary ideas about chemistry in three dimensions just after his 22nd birthday in 1874, before he completed his Ph.D, in a 15 page pamphlet which included the models of organic molecules with atoms surrounding a carbon atom situated at the apexes of a tetrahedron. Independently and two months later, Joseph A. Le Bel, who also studied with Kekule at the same time as van't Hoff, described a similar theory to the Paris Chem. Soc. Kekule himself had tetrahedral models in the lab and historians concur that they must have influenced van't Hoff and Le Bel. Interestingly, these proposals which serve as the very basis of stereochemistry today were met with bitter criticism. 8 Conformational Analysis Dale L. Boger 1. Acetaldehyde O O H H 60° rotation H H HH 60° rotation H H eclipsed HO bisected H H H O H H 2 rel E (kcal) 1 B E HH B E 0 60 120 E 180 240 300 360 dihedral angle relative energies (kcal) Exp MM2 B 0.0 0.0 - Two extreme conformations. - Barrier to rotation is 1.0 kcal/mol. - H-eclipsed conformation more stable. 1.0 1.1–1.2 2. Propionaldehyde O 60° rotation Me H O H Me HH O 60° rotation H H bisected H O H H HH HO O H Me eclipsed Me H Me O H H H H Me H eclipsed 60° rotation bisected Me H H O H H H Me relative energies (kcal) Exp MM2 Ab initio 0.0 0.0 0.0 0.8, 0.9, 1.0 0.8, 0.9 0.4 1.25, 2.28 2.1 1.7 unknown 1.0, 2.3–1.7, 1.5 0.7 2 rel E (kcal) 1 B1 E2 B2 B1 E2 E1 0 E1 60 120 180 240 300 - J. Chem. Phys. 1964, 40, 1671. - J. Mol. Struct. 1973, 17, 233. - J. Am. Chem. Soc. 1969, 91, 337. 360 dihedral angle O tBu 120° rotation H HH alkyl eclipsed O H H H tBu H-eclipsed relative energies (kcal) Exp 2.5 0.0 - Alkyl eclipsed conformation more stable than H-eclipsed and exceptions occur only if alkyl group is very bulky (i.e., tBu). - Because E differences are quite low, it is difficult to relate ground state conformation to experimental results. All will be populated at room temperature. 9 Modern Organic Chemistry The Scripps Research Institute 3. Propene H C H H H H H 60° rotation H HH H C 60° rotation H H eclipsed HH C 2 bisected H H H H2C H H B 2 B rel E (kcal) 1 E E HH 0 60 120 E 180 240 0.0 0.0 Note: H O vs. H C Me H H 60° rotation H H Me HH C H H 60° rotation eclipsed C H H bisected H H2C H H C H 60° rotation H H H H bisected Me HH C 2 C Me eclipsed HH H H H H H Me H H H Me H MeH C 2 360 - Two extreme conformations - Barrier to rotation is 2.0 kcal/mol 2.0 2.1–2.2 4. 1-Butene H 300 dihedral angle relative energies (kcal) Exp MM2 B H H H2C H H H Me relative energies (kcal) Exp MM2 Ab initio 0.0, 0.2, 0.4, 0.5 0.5, 0.7 0.6 1.4–1.7 (2.6) - 0.0 0.0 0.0 1.4–1.8 (2.6) 2.0 3 B2 2 B1 rel E (kcal) 1 E1 E2 0 H tBu C H 120° rotation H HH relative energies (kcal) 10 C H H H H tBu eclipsed (E1) Exp 60 H B1, B2 > E1 >> E2 B1 eclipsed (E2) 120 E1 E2 180 240 300 360 dihedral angle - There is an additional destabilization of placing the alkyl group eclipsed with C=C. This is due to the larger steric size of olefinic CH compared to carbonyl C=O. - The eclipsed conformations (even with an α-tBu) are both more stable than the bisected conformations. Conformational Analysis Dale L. Boger 5. E-2-Pentene H C Me Me H H Me 60° rotation H HH C Me H 60° rotation Me H C Me H H H H H Me bisected H H Me C Me H H H 60° rotation H H H eclipsed Me C Me H Me eclipsed bisected Me H H C Me HH C H H C Me H H H H Me relative energies (kcal) Exp MM2 0.0 (0.0–0.4) 0.6 1.4–1.7 (2.6) 0.0 0.0 1.5–1.8 (2.6) 3 B1 rel E (kcal) 1 E1 0 B1 E2 60 Me 60° rotation Me H H Me HH C H Me 30° rotation H eclipsed 240 300 360 H 30° rotation H C H Me 60° rotation H Me Me C H H H H bisected H Me C H H Me Me H C H H H H H C Me eclipsed perpendicular HH H H Me Me Me C H H H Me H H bisected H C H Me H Me Me C H 180 dihedral angle H C E1 E2 120 6. Z-2-Pentene Me - Analogous to 1-butene. B2 2 H H H Me relative energies (kcal) MM2 3.9 0.6 0.0 4.9 5 E1 E1 H H H 4 H CH3 CH3 - Serious destabilizing interaction, often referred to as allylic 1,3-strain (A 1,3-strain). H 2 1 E2 B2 E2 P1 0 60 P1 120 180 240 300 360 H H CH3 H - The analogous H/CH3 eclipsing interaction in the bisected conformation is often referred to as allylic 1,2-strain (A 1,2-strain). H3C 3 rel E (kcal) 0.5 B1 B1 dihedral angle 11 Modern Organic Chemistry The Scripps Research Institute 7. 3-Methyl-1-butene H H C Me Me H H bisected Me H C HH H 60° rotation C Me H 60° rotation H H Me MeH C 2 H Me relative energies (kcal) H Me 60° rotation C H H H H Me Me eclipsed Me HH C 2 H Me 2.60–2.94 B2 B2 B1 H H 0.73–1.19 3 H 2 H 2.4–3.0 C Me bisected Me H C H Me eclipsed Me 2 Ab initio H 0.0 B1 2 rel E (kcal) 1 E1 - J. Am. Chem. Soc. 1991, 113, 5006. - Chem. Rev. 1989, 89, 1841. E1 E2 0 60 120 180 240 dihedral angle 300 360 8. 4-Methyl-2-pentene Me H Me H Me H Me H C C C C Me H 60° rotation 60° rotation 60° rotation Me Me H Me H H H H H Me Me H Me Me eclipsed eclipsed bisected bisected Me Me Me Me Me Me Me Me Me H H Me C H C H C H C H H H H H Me H H Me relative energies (kcal) Ab initio 3.4–4.3 - 4.9–5.9 6 4 0.0 B2 B2 B1 B1 E1? E1? - Only H-eclipsed conformation is reasonable. rel E (kcal) 2 E2 60 0 120 180 240 dihedral angle 300 360 F. Anomeric Effect 1. Tetrahydropyrans (e.g., Carbohydrates) C C H X Dipoles opposed → preferred 12 R H O OR' R R'O H C C O X X = OR' H Dipoles aligned → destabilizing R = H, preferred conformation. ∆G° = 0.85 kcal/mol - generally 0–2 kcal/mol, depends on C2/C3 substituents - effect greater in non-polar solvent Conformational Analysis Dale L. Boger Comprehensive Org. Chem. Vol. 5, 693. Comprehensive Het. Chem. Vol. 3, 629. Review: Tetrahedron 1992, 48, 5019. 1. A value for R group will be smaller, less preference for equatorial vs axial C3 or C5 substituent since one 1,3-diaxial interaction is with a lone pair versus C–H bond. 2. Polar, electronegative group (e.g., OR and Cl) adjacent to oxygen prefers axial position. 3. Alkyl group adjacent to oxygen prefers equatorial position. 4. Electropositive group (such as +NR3, NO2, SOCH3) adjacent to oxygen strongly prefers equatorial position. ⇒ Reverse Anomeric Effect - Explanations Advanced: 1. Dipole stabilization C opposing dipoles, stabilizing C H C C OR OR dipoles aligned, destabilizing H 2. Electrostatic repulsion minimizes electrostatic repulsion between lone pairs and the electronegative substituent C C H C C OR maximizes destabilizing electrostatic interaction between electronegative centers (charge repulsion) OR H 3. Electronic stabilization n–σ* orbital stabilizing interaction C n electron delocalization into σ* orbital H C C C OR no stabilization possible H 4. Gauche interaction involving lone pairs is large (i.e., steric) 1 lone pair / OR gauche interaction + 1 C/OR gauche interaction (0.35 kcal/mol) C C H OR C C 2 lone pair / OR gauche interactions, but would require that they be ~1.2 kcal/mol OR H 2. Anomeric Effect and 1,3-Dioxanes H O O R OO H R lone pair / R interaction 1. Polar, electronegative C2/C4 substituents prefer axial orientation. 2. The lone pair on oxygen has a smaller steric requirement than a C–H bond. ∆G° is much lower, lower preference between axial and equatorial C5 substituent 3. Polar electropositive groups C2 equatorial position preferred: C5 axial position may be preferred for F, NO2, SOCH3, +NMe3. tBu CH3 O O preferred conformation CH3 H H O O tBu Eliel J. Am. Chem. Soc. 1968, 90, 3444. 13 Modern Organic Chemistry The Scripps Research Institute A Value (kcal/mol) for Substituents on Tetrahydropyran and 1,3-Dioxane versus Cyclohexane Group Cyclohexane Tetrahydropyran C2 1,3-Dioxane C2 1,3-Dioxane C5 CH3 Et iPr t Bu 1.8 1.8 2.1 >4.5 2.9 4.0 4.0 4.2 0.8 0.7 1.0 1.4 3. Exo Anomeric Effect preferred orientation 55° O R H H H R O O O R O R α-axial-glycosides 1 R/OR gauche 1 R/R gauche 1 R/OR gauche 1 R/R gauche Rel. E = 0.35 kcal/mol 0.9 kcal/mol 1.25 kcal/mol 55° R O H H O H2C H H R O H H H H O H R R Kishi J. Org. Chem. 1991, 56, 6412. G. Strain Cyclic Hydrocarbon, Heats of Combustion/Methylene Group (gas phase) Ring Size strain free 3 4 5 6 7 8 9 –∆Hc (kcal/mol) 166.3 163.9 158.7 157.4 158.3 158.6 158.8 Ring Size 10 11 12 13 14 15 16 –∆Hc (kcal/mol) 158.6 158.4 157.8 157.7 157.4 157.5 157.5 largely strain free 1. Small rings (3- and 4-membered rings): small angle strain For cyclopropane, reduction of bond angle from ideal 109.5° to 60° 27.5 kcal/mol of strain energy. For cyclopropene, reduction of bond angle from ideal 120° to 60° 52.6 kcal/mol of strain energy. To form a small ring in synthetic sequences, must overcome the energy barrier implicated in forming a strained high energy product. 2. Common rings (5-, 6-, and 7-membered rings): - largely unstrained and the strain that is present is largely torsional strain (Pitzer strain). 14 Conformational Analysis Dale L. Boger 3. Medium rings (8- to 11-membered rings): a. large angle strain - bond angles enlarged from ideal 109.5° to 115–120°. - bond angles enlarged to reduce transannular interactions. b. steric (transannular) interactions - analogous to 1,3-diaxial interactions in cyclohexanes, but can be 1,3-, 1,4-, or 1,5- ... c. torsional strain (Pitzer strain) in cyclohexanes 60° H H H H H H in medium rings - deviation from ideal φ of 60° and approach an eclipsing interaction. H C C H just like gauche butane. (CH2)n 40° 4. Large rings (12-membered and up): - little or no strain. 5. Some highly strained molecules: Buckminsterfullerene (C60) has a strain energy of 480 kcal/mol and is one of the highest strain energies ever computed. However, since there are 60 atoms, this averages to ca. 8 kcal/mol per carbon atom - not particularly unusual. First isolated in 1990: Kroto, Heath, O'Brian, Curl, and Smalley Nature 1985, 318, 162. [1.1.1] propellane Robert Curl, Harold Kroto, and Richard Smalley shared the 1996 Nobel Prize in Chemistry for the discovery of fullerenes. Wiberg J. Am. Chem. Soc. 1982, 104, 5239. strain energy = 98 kcal/mol note: the higher homologs are not stable at 25 °C. Wiberg J. Am. Chem. Soc. 1983, 105, 1227. Eaton J. Am. Chem. Soc. 1964, 86, 3157. cubane strain energy = 155 kcal/mol note: kinetically very stable, may be prepared in kg quantities. cyclopropabenzene Vogel Tetrahedron Lett. 1965, 3625. strain energy = 68 kcal/mol note: even traces of this substance provides an intolerable smell and efforts to establish its properties had to be cancelled at the Univ. of Heidelberg. 15 Modern Organic Chemistry The Scripps Research Institute H. pKa of Common Organic Acids Acid cyclohexane ethane benzene ethylene Et2NH NH3 (ammonia) toluene, propene (C6H5)3CH DMSO (CH3S(O)CH3) C6H5NH2 HC CH CH3CN CH3CO2Et CH3SO2CH3 CH3CONMe2 aliphatic ketones (CH3)3CCOCH(CH3)2 (CH3)3CCOCH3 CH3COCH3 CH3COC6H5 (CH3)3COH C6H5C CH XH H+ + X− Acid (CH3)2CHOH CH3CH2OH cyclic ketones e.g. cyclohexanone CH3OH CH3CONHCH3 PhCH2COPh H2O cyclopentadiene CH2(CO2Et)2 CH2(CN)2 CH3COCH2CO2Et CH3NO2 phenol R3NH+Cl− HCN CH3CH2NO2 CH3COCH2COCH3 CH2(CN)CO2Et CH3CO2H py•HCl C6H5NH3+Cl− pKa 45 42 37 36 36 35 35 28−33 31 27 25 25 25 23−27 25 20−23 23 21 20 19 19 19 pKa 18 17 17 17 16 (16−18) 16−17 16 16 15 13 11 11 10 10 10 9 9 9 9 5 5 5 Ka = [H+][X−] [HX] pKa = −logKa = −log[H+] Increase in pKa means decrease in [H+] and acidity Decrease in pKa means increase in [H+] and acidity For more extensive lists, see: The Chemist's Companion, p 58–63. Familiarity with these pKa's will allow prediction/estimation of acidities of other compounds. This is important, since many organic reactions have a pKa basis (i.e., enolate alkylations). Alfred Werner, who received the 1913 Nobel Prize in Chemistry for his studies of stereochemistry and inorganic complexes, is also responsible for the redefinition of (acids and) bases as compounds that have varying degrees of ability to attack hydrogen ions in water resulting in an increase in hydroxide ion. The most acidic natural product is the mycotoxin monliformin also known as semisquaric acid, pKa = 0.88 O O Springer, Clardy J. Am. Chem. Soc. 1974, 96, 2267. OH Compare the strength of the following neutral bases: tBu DBU Me3N N N pKb = 4.1 pKb = 24.3 Schwesinger Liebigs Ann. 1996, 1055. 16 N R R R R=N R P N P N P N P R R N R R R P R pKb = 46.9 R Kinetics and Thermodynamics of Organic Reactions Dale L. Boger II. Kinetics and Thermodynamics of Organic Reactions A. Free Energy Relationships ∆G = ∆H − T∆S The equilibrium for the reaction can be described by ln Keq = − ∆G RT To achieve a high ratio of two products (desired product and undesired product) in a thermodynamically controlled reaction run under reversible conditions, one needs the following ∆G's: K (25 °C) ∆G (kcal/mol) (67:33) 2 (83:17) 5 (90:10) 9 (95:5) 20 (99:1) 99 (99.9:0.1) 999 0.41 0.95 1.30 1.74 2.73 4.09 K (0 °C) 2.1 5.7 10.9 27.5 ∆G (kcal/mol) (68:32) (85:15) (92:18) (96:4) 0.41 0.95 1.30 1.80 Hydrogenation reaction: H2C CH2 + C C H H 2.9 11.6 28.5 103.3 ∆G (kcal/mol) (75:25) (92:8) (97:3) (99:1) 0.41 0.95 1.30 1.80 H H H2C CH2 H2 bonds broken 1 1 K (−78 °C) bonds formed 163 kcal/mol 104 kcal/mol 1 2 267 kcal/mol C C C H 88 kcal/mol 2 × 98 kcal/mol 284 kcal/mol -Overall reaction is exothermic -> ∆G = −17 kcal/mol, so reaction is favorable, spontaneous. -To calculate equilibrium constant: ln Keq = − ∆G RT 2.303 log Keq log Keq Keq = 17 kcal × 1000 cal/mol / (298 K) × 1.99 = 12.45 = 2.8 × 1012 - But experimentally this reaction is very slow. - Molecule rate (experimentally) = 1012 molecules/sec 6.023 × 1023 molecules/mol mole rate = = 2 × 104 years 12 (10 molecules/sec) × (60 sec/min) × (60 min/hour) × (24 hour/day) × (365 day/year) i.e., 2 × 104 years to hydrogenate one mole of ethylene (without catalyst). 17 Modern Organic Chemistry The Scripps Research Institute E Transition State: A transition state (TS) possesses a defined geometry and charge delocalization but has no finite existence. At TS, energy usually higher and although many reactant bonds are broken or partially broken, the product bonds are not yet completely formed. ∆G‡uncat. = 33.87 kcal ∆G‡cat. = 20 kcal ∆G° = –17 kcal H2C=CH2 reaction coordinate H3C–CH3 uncatalyzed reaction catalyzed reaction Svante Arrhenius received the 1903 Nobel Prize in Chemistry in recognition of his theory of electrolytic dissociation where he introduced the idea that many substances dissociate into positive and negative ions (NaCl Na+ + Cl–) in water including the partial dissociation of weak acids like HOAc, where the equilibrium amount depends on the concentration. His qualitative ideas on the exponential increase in the rate of reactions when temperature is increased are retained in modern theories that relate kinetic rate constants to temperature by means of an energy of activation. B. Transition State Theory ∆G‡ = ∆H‡ – T∆S‡ Ahmed Zewail was awarded the 1999 Nobel Prize in Chemistry for his studies of the transition states of chemical reactions using femtosecond spectroscopy. - Free Energy of Activation (∆G‡) - Enthalpy of Activation (∆H‡): Difference in bond energy between reactants and the transition state. - Entropy of Activation (–T∆S‡): ∆S‡ usually negative, making the change more endothermic. From ∆G‡ = ∆H‡ – T∆S‡ , ∆G‡ = – RT ln K‡ for uncatalyzed H2 reaction catalyzed H2 reaction ∆G‡ = 33.9 kcal/mol ∆G‡ = 20 kcal/mol and for the rate for uncatalyzed H2 reaction catalyzed H2 reaction k = 1.0 × 1012 mol/sec k = 1.0 × 1022 mol/sec C. Intramolecular Versus Intermolecular Reactions CH3OH + O CH3 C OH O OH OH H+ k1 H+ O CH3 C OCH3 ∆S‡1 O k2 O ∆S‡2 O ∆S‡3 O O OH OH H+ k3 k3 > k2 > k1 –T∆S‡1 > –T∆S‡2 > –T∆S‡3 > 0 ∆S‡1 < ∆S‡2 < ∆S‡3 < 0 ∆G‡3 < ∆G‡2 < ∆G‡1 18 Kinetics and Thermodynamics of Organic Reactions Dale L. Boger - Intramolecular versus intermolecular reactions benefit from a far more favorable entropy of activation (∆S‡). - In forming small rings, ring strain developing in the product decelerates the rate of reaction (large ∆H‡) and that can offset the favorable ∆S‡ rate acceleration. O OH H+ OH very slow Examples: Br O O O H2O (CH2)n NH2 (CH2)n Ring size Rel. Rate 3 4 5 6 7 70 1.0 10000 1000 2 aq DMSO O n NH 25 °C O Br Ring size Rel. Rate 3 4 5 6 7 8 9 10 21.7 5.4 × 103 1.5 × 106 1.7 × 104 97.3 1.00 1.12 3.35 O n 50 °C Ring size Rel. Rate 11 12 13 14 15 16 17 18 8.51 10.6 32.2 41.9 45.1 52.0 51.2 60.4 - gem dimethyl effect Rel. Rate HO HO HO aq. NaOH Cl O 1.0 18 °C O 325 Cl O Cl 39000 Compare to relative rates of intermolecular SN2 displacement where the more substituted alkoxide reacts slowest: CH3OH + CH3Cl OH + CH3Cl OH OH + CH3Cl + CH3Cl k1 O k2 O k3 O k4 O k1 > k2 > k3 > k4 DeTar J. Am. Chem. Soc. 1980, 102, 4505. Winnik Chem. Rev. 1981, 81, 491. Mandolini J. Am. Chem. Soc. 1978, 100, 550. Illuminati J. Am. Chem. Soc. 1977, 99, 2591. Mandolini, Illuminati Acc. Chem. Res. 1981, 14, 95. For the intramolecular case: The reactive conformation is more favorable and populated to a greater extent in the more substituted case ⇒ One must consider both the length of the chain (i.e., ring size being formed) and the nature of the atoms in the chain (i.e., conformation, hybridization). 19 Modern Organic Chemistry The Scripps Research Institute D. Kinetic and Thermodynamic Control – For competitive reactions: transition state: possesses a defined geometry, charge delocalization, but has no finite existence E ∆∆G‡ ∆Gc‡ ∆GB‡ ∆GB Free E of Activation ∆Gc ∆∆G kinetic product thermodynamic product C A B reaction coordinate If this is an irreversible reaction, most of the reaction product will be B (kinetic product). If this is a reversible reaction, most of the product will be C (more stable, thermodynamic product). OLi O Me thermodynamic product more favorable ∆G LDA OLi Me LDA Me kinetic product more favorable ∆G‡ A beautiful example of this was observed in the kinetic versus thermodynamic asymmetric Dieckmann-like condensation illustrated below. The most stable product (lower ∆G) was observed upon conducting the reaction under equilibrating conditions for the reversible reaction while the alternative kinetic product (lower ∆G‡) was observed when the reaction was conducted under lower temperature and nonequilibrating conditions (kinetic conditions). 20 Kinetics and Thermodynamics of Organic Reactions Dale L. Boger epi-(+)-Duocarmycin A (+)-Duocarmycin A Thermodynamic control: single TBDMSO diastereomer Kinetic control: 5 – 7:1 diastereomers TBDMSO TBDMSO HN HN Me NBOC LDA N THF O 81% O –78 to –40 °C O XcOC N BOC OBn NBOC NC Me NBOC XcOC LDA N BOC OBn THF Me N 58% BOC OBn –78 °C, 30 min TBDMSO Thermodynamic control: single diastereomer Divergent Control of C6-Stereochemistry Kinetic control: 5 – 7:1 diastereomers TBDMSO HN Me TBDMSO HN NBOC NC Me LDA N THF O 58% O –78 °C O 30 min XcOC N BOC OBn NBOC NBOC XcOC LDA THF Me N 81% BOC OBn –78 to –40 °C N BOC OBn CO2tBu > CHO epi-(+)-Duocarmycin A (+)-Duocarmycin A anti-carbonyls Chelated Z-enolate Me N N N O iPr N Me N O Li O O O iPr R Me NH Li O N R N O iPr N R O iPr O O N O NH Me O N R ∆E = 0.76 kcal/mol Boger J. Am. Chem. Soc. 1997, 119, 311. E. Hammond Postulate The geometry of the transition state for a step most closely resembles the side (i.e., reactant or product) to which it is closer in energy. Transition state can not be studied experimentally – has zero lifetime (transient species) → information obtained indirectly ⇒ Hammond postulate Examples: 1) Thermoneutral reactions: CH3–1I + 2– I CH3–2I + 1– I 21 Modern Organic Chemistry The Scripps Research Institute 2I– H H + 1I 1I H H 2I H H symmetrical T.S. E Thermoneutral reaction – transition state resembles both starting material and product equally p s 2) For reactions which proceed through an intermediate: solvolysis of tertiary alcohol [X] A B X: discrete intermediate R R C OH R R HCl T.S. E R C R R R C R Cl Cl– G. A. Olah received the 1994 Nobel Prize in Chemistry for his contributions to carbocation chemistry. T.S. I s p Resemble the geometry of the carbocation intermediate and not that of the reactant (alcohol) or product (alkyl chloride). Intermediate (for this reaction it will be C+ so T.S. ⇒ I ) Notes a. 20 kcal/mol energy available at 25 °C for free energy of activation. b. Increase reaction temperature, increase the rate of reaction. c. Decrease reaction temperature, decrease the rate of reaction, but increase the selectivity of the reaction. Hammond J. Am. Chem. Soc. 1955, 77, 334. Farcasiu J. Chem. Ed. 1975, 52, 76. F. Principle of Microscopic Reversibility The forward or reverse reactions, run under identical conditions, must proceed by the same mechanism i.e., if forward reaction proceeds via intermediate X A [X] B [X] A then reverse reaction also goes through X. B 22 Reaction Mechanisms and Conformational Effects on Reactivity Dale L. Boger III. Reaction Mechanisms and Conformational Effects on Reactivity A. Ester Hydrolysis pKa = 15 CH3 O C OEt pKa = 5 OH– CH3 sp2 O C OEt OH CH3 O C OH CH3 + –OEt sp3 O C O + EtOH pKa = 17 Reaction driven to completion by final, irreversible step (compare pKa = 17 to pKa = 5). a OH– O CH3 C OEt a CH3 O CH3 O C OH c + HO OEt OEt b O b HO + OEt + EtOH CH3 O + H2C OEt H2O O O CH3 - So, possible competing reaction is α-H removal, but pKa difference means equilibrium strongly favors ester and OH–, i.e.; O HO– + CH3 C OCH2CH3 O H2O + H2C C OCH2CH3 - To deprotonate an ester, must use a strong base which is non-nucleophilic, such as tBuOK or LDA. CH3COOCH2CH3 O H2C C OCH2CH3 pKa = 25 1. tBuOK (pKa of tBuOH = 19) → generates low concentration of anion, and a significant amount of ester always present ⇒ self (Claisen) condensation 2. LDA (pKa of iPr2NH = 36) → generates a high concentration of enolate and thus is a good base to carry out stoichiometric alkylation of ester 23 Modern Organic Chemistry The Scripps Research Institute 1. Kinetics of Ester Hydrolysis (Stereochemistry and Rates of Reactions) ‡ NaOH tBu OEt tBu COOEt tBu COOH O OH Steric Effect COOEt no way to avoid a severe tBu-like 1,3-diaxial interaction H NaOH tBu H O OH OEt ‡ COOH tBu tBu A value = 1.2 kcal A value = 2.3 kcal ktrans The rate determining step for ester hydrolysis is the formation of tetrahedral intermediate and the ratio of ktrans/kcis >> 1. = 19.8 kcis Eliel J. Am. Chem. Soc. 1961, 83, 2351. - Difference in rates much greater than expected if simply considering the difference in either the product or reactant A values. - Reaction of axial ester decelerated due to more severe developing 1,3-diaxial interactions in transition state (i.e., an axial tBu-like group). 2. Same effect is observed, but to a lesser extent with acetate hydrolysis O O tBu O CH3 OH– tBu OH tBu O OH CH3 ktrans O O O CH3 tBu OH– O OH tBu OH CH3 tBu kcis A value = 0.7 kcal/mol ktrans = 6.65 kcis effect is smaller because of the more remote distance of the steric interactions Similarly, the rates of acetylation are ktrans / kcis = 3.7 Eliel J. Am. Chem. Soc. 1966, 88, 3334. 24 Reaction Mechanisms and Conformational Effects on Reactivity Dale L. Boger B. Alcohol Oxidations R H R' OH O fast R + HO Cr OH H R' O O slow O Cr O R O OH + R' OH Cr O OH ( CrO3 + H2O ) Westheimer J. Am. Chem. Soc. 1951, 73, 65. O fast OH tBu Cr O tBu O O slow tBu OH ktrans O O H OH fast tBu H tBu Cr OH O O slow H tBu kcis kcis The rate determining step for the alcohol oxidation is break down of the chromate ester with cleavage of C–H bond and O–Cr bond. = 4 ktrans Destabilizing 1,3-diaxial interactions in cis chromate ester accelerate its breakdown to the ketone (would be slower if the slow step for the reaction were formation of chromate ester). Eliel J. Am. Chem. Soc. 1966, 88, 3327. C. SN2 Reactions PhS H SPh H X tBu H less stable product formed and proceeds through a less stable T.S. cis' X PhS Na tBu cis tBu inversion ktrans trans H PhS Na PhS inversion kcis SPh tBu trans' 25 Modern Organic Chemistry The Scripps Research Institute - The free energy of activation (Ea, or ∆G‡) for reaction of the trans isomer is higher due to steric interactions felt in the transition state (interactions of incoming nucleophile with axial H's). ∆∆G‡ E cis → kcis > ktrans cis' trans ∆∆G‡ greater than ∆∆G of products. ∆∆G - The reaction of the trans isomer is kinetically slower and thermodynamically less favorable. trans' reaction coordinate D. Elimination Reactions H B H trans antiperiplanar X X E2 elimination H must have a good orbital overlap (i.e., via trans antiperiplanar orientation of C–H bond and C–X bond). X Stereoelectronic Effect - Alternatively, if dihedral angle = 0° (i.e., eclipsed X and H), elimination can take place (orbital overlap good). 1.0 ~ 1.3 kcal B H Cl H H Cl H H H HH H 1.0 kcal H eclipsed conformation is 3.0–3.3 kcal/mol higher in E, so elimination takes place mainly through trans antiperiplanar arrangement. 1.0 kcal - Alternate mechanisms also possible: E1 mechanism D A E H E1cB mechanism A D B E B via free carbocation 26 large groups (A,E) trans H H X H H Reaction Mechanisms and Conformational Effects on Reactivity Dale L. Boger Acyclic Substrate C2H5 – Examples: 51% CH3 EtONa CH3CH CH2 C2H5 Br CH3CH CH C2H5 69% CH3 Anti elimination trans C2H5 18% cis 0.5 kcal Br H H Me H H Me H H EtONa Et H Br Et H Et 18% Me 0.9 kcal cis trans is more stable than cis (1.0 kcal/mol) ∆E = 0.9 kcal 0.5 kcal Br H H Me H H Et H Br Et Et EtONa Me H H 51% H Me trans – For other possible mechanisms: Syn elimination 1.0 ~ 1.3 kcal H 1.0 H Br Br Me H H Et Et HH H H Me Et Me cis 4.0 kcal syn elimination also strongly favors formation of trans product 1.0 ~ 1.3 kcal H Br H 1.3 Br Et H H Me Et H Et H H H Me Me trans 1.3 kcal Both are very much destabilized relative to anti-elimination T.S. / conformations. Neither contribute to ground state conformation of bromide at room temperature. And, there is another product formed: Br H H H CH3 Et Br H H CH3Et H H H H H Et H Br Br H H H H H Et H H H or H H Et HH 27 Modern Organic Chemistry The Scripps Research Institute Cyclic Substrate Consider E2 elimination of Cl neomenthyl chloride Cl menthyl chloride Look at all conformations of each: 0.45 kcal 0.25 kcal H H Cl H H H H CH3 H 2.1 kcal 2.1 kcal 0.25 kcal CH3 Cl H H H 0.9 kcal Cl CH3 H 0.25 kcal 0.25 kcal ∆E= ~3.4 kcal/mol >99 :1 ratio for A : B B C D 4.5–5 kcal/mol more stable k1 k2 CH3 CH3 + 78 : 22 reactive conformer because it is the only one that can achieve a trans antiperiplanar relationship between the H atom and the Cl > 4 kcal/mol energy difference between ground state conformation and the reactive conformation The reaction of the neomenthyl chloride is much faster (k1/k2 = 193:1) From D (menthyl chloride) – only one product is possible Curtin–Hammett principle : Ground state conformation need not be decisive in determining product of a reaction. 28 CH3 ~1.5–2.0 kcal 1.8 kcal A Cl CH3 only product ! Reaction Mechanisms and Conformational Effects on Reactivity Dale L. Boger E. Epoxidation by Intramolecular Closure of Halohydrins – Must involve backside displacement → geomerical constraints ! CH3 HO CH3 K2CO3 Br O 72 h, 25 °C H backside attack not geometrically feasible OH– CH3 O CH3 5 ~ 10 kcal CH3 O O Br Br H reaction proceeds through very minor conformation available at room temperature Again, ground state conformation of reactant is not a determinant in reaction product (Curtin–Hammett principle). – Another example: Br CH3 OH Br CH3 K2CO3 H O CH3 H 1 min, 25 °C O H reaction much faster and proceeds from a ground state conformation F. Epoxide Openings (SN2) CH3 CH3 O CH3 SPh (b) O H atom under attack in epoxide moves towards Nu: twist boat conformation (b) (a) Nu sp2.27 O H H nucleophile can attack at either carbon atom (a) O H3C SPh H3C SPh 1,3-diaxial CH3 SPh O OH less stable product chair conformation HO more stable product This is the only product formed! Product ratio dependent on Ea (i.e., relative energy of two T.S.), route (a) proceeding through chair conformation and destabilizing 1,3-diaxial interaction is of lower energy than route (b) proceeding through twist boat T.S. - Conformational effects determine regioselectivity 29 Modern Organic Chemistry The Scripps Research Institute G. Electrophilic Additions to Olefins Follows same principles CH3 Br Br2 Br attacks from the less hindered face H CH3 CH3 Br Br HH transdiaxial opening H Br H PhSX, PhSeX, or HgX2 CH3 PhS SPh CH3 ∆ H H H kinetic product X reversible H CH3 X CH3 X b H H a b X a twist boat episulfonium ion H3C X CH3 X H H X kinetic H CH3 PhS PhS X H thermodynamic CH3 X H HX thermodynamic product H - Conformational effects control regioselectivity and stereochemistry But, it is not always possible to obtain the thermodynamic product ⇒ must have the 20–30 kcal/mol of energy required and a mechanism to reverse the reaction. 30 Reaction Mechanisms and Conformational Effects on Reactivity Dale L. Boger H. Rearrangement Reactions pinacol → pinacolone rearrangement HO OH HO CH3 CH3 CH3 O OH2 + H+ CH3 pinacolone – Prototype of rearrangement: heteroatom: O L.G. This process is conformationally dependent! leaving group –OH2+ M.G. –OSO2R –N2+ diazonium ion migrating group + NH2 H2 OH N N OH H O N OH OH2 NH N OH (HONO, H2ONO - protonated) NH N OH HCl + NaNO2 + N2 ↑ N N N N OH2 Tiffeneau−Demjanov Reaction Ring expansion of cyclic β-amino alcohols HO NH2 O HONO Tiffeneau Compt. rend. 1937, 205, 54. review: Org. React. 1960, 11,157. The course of rearrangement is conformationally dependent: A value of NH2/NH3+ (1.8–1.4 kcal) NH2 H H H H H NH2 H OH ∆E = 1.6 ~ 2.2 kcal OH A value of OH (0.7 kcal) Stereoelectronic Effect gauche (0.35–0.9 kcal) HONO backside attack N OH N2 OH H trans periplanar arrangement O only product observed 31 Modern Organic Chemistry The Scripps Research Institute Compare to: N2+ NH2 HONO H O OH H H O H H Stereoelectronic effects dominate the control of regioselectivity H H both good: trans periplanar relationships ~ 50:50 mixture both products observed H H NH2 N2 + H O OH H H O CH3 O Explain the following results: H3C NH2 HO H HONO CH3 H3C H CH3 + N O 2 H CH3 H3C H3 C NH2 H H3C HONO H3 C H OH H3C O + N H3 C 2 H O H H3C H HO NH2 CH3 H HONO CH3 H3C H CH3 O OH N2+ CH3 H3C H3 C H NH2 OH CH3 H HONO O H3C H3CH N2+ OH 32 CH3 Reaction Mechanisms and Conformational Effects on Reactivity Dale L. Boger - Additional examples HO H O OSO2Ar KOtBu migrating bond H H 89% H Me Me H OSO2Ar Me O Büchi J. Am. Chem. Soc. 1966, 88, 4113. O ArO2SO O O O O O O O AcO AcO AcO O CH3 Heathcock J. Am. Chem. Soc. 1982, 104, 1907. I. Pericyclic Reactions 1. Conservation of Orbital Symmetry, FMO Analysis - Concerted reactions where there is a single transition state and no intermediates proceed through cyclic transition states. - Cyclic transition state corresponds to an allowed arrangement of participating orbitals that can maintain a bonding interaction between the reaction components throughout the course of the reaction. This dictates features of relative reactivity, regioselectivity, and diastereoselectivity. - This also established and formalized the viability of utilizing Frontier Molecular Orbitals (FMO) composed of the Highest Occupied Molecular Orbital (HOMO) and Lowest Unoccupied Molecular Orbital (LUMO) to analyze pericyclic reactions. Woodward, Hoffmann The Conservation of Orbital Symmetry, Academic: New York, 1970. J. Am. Chem. Soc. 1965, 87, 395. Fukui Acc. Chem. Res. 1971, 4, 57; Angew. Chem., Int. Ed. Eng. 1982, 21, 801. Encouraged by E. J. Corey, Hoffmann began examining mechanistic problems in organic chemistry and, as a junior fellow at Harvard, entered into a collaboration with R. B. Woodward that combined his insights in MO theory with Woodward's knowledge of experimental pericyclic reactions. This led to five papers in 1965 before he was 30 years old, that were the foundation of what we now refer to as the Woodward–Hoffmann rules. R. Hoffmann received the 1981 Nobel Prize in Chemistry for the launch and development of the concept of orbital symmetry conservation. K. Fukui received the 1981 Nobel Prize in Chemistry for his Frontier Orbital theory of chemical reactivity. This followed and was not included in the 1965 Nobel Prize in Chemistry awarded to R. B. Woodward for his contributions to the "art of organic synthesis". 33 Modern Organic Chemistry The Scripps Research Institute 2. Electrocyclic Reactions - This is composed of a series of reactions in which a ring closure occurs with formation of a single bond at the ends of a linear, conjugated system of π electrons and the corresponding reverse reaction with ring opening. System π electrons Thermal Reaction Ground State (HOMO) hν Reaction Excited State (LUMO) 4 π e– conrotatory disrotatory 6 π e– disrotatory conrotatory 8 π e– conrotatory disrotatory 2 π e– disrotatory conrotatory 4 π e– conrotatory disrotatory 4 π e– conrotatory disrotatory 6 π e– disrotatory conrotatory 4 π e– thermal reaction (ground state, HOMO) R R R conrotatory movement R bonding interaction - Stereochemistry dictated by orbital symmetry allowed reaction course 6 π e– thermal reaction (ground state, HOMO) R R disroratory movement R R bonding interaction - Generalization: 34 No. of π electrons Thermal hν 4n π electrons (n = 0,1,...) conrotatory disrotatory 4n + 2 π electrons (n = 0,1,...) disrotatory conrotatory Reaction Mechanisms and Conformational Effects on Reactivity Dale L. Boger 3. Cycloadditions and Cycloreversions - These are discussed in terms of suprafacial or antarafacial addition to the ends of a π system. Suprafacial Antarafacial - Generalization: Total π electrons Allowed in Ground State 4n ms + na ms + ns ma + n s ma + n a ms + ns ms + na ma + n a ma + n s 4n + 2 - Notations π2s orbital type π, σ, ω Allowed in Excited State suprafacial (s) or antarafacial (a) number of e– - Diels-Alder Reaction (6π e–), Ground State Thermal Reaction Normal Diels–Alder Reaction HOMO diene bonding interaction LUMO dienophile Inverse Electron Demand Diels–Alder Reaction LUMO diene bonding interaction HOMO dienophile [π4s + π2s] cycloaddition - Suprafacial with respect to both reacting components and this defines the orientation with which the two reactants approach: boat transition state. - The FMO analysis may also be used to predict relative rates, regioselectivity, and diastereoselectivity (endo effect) and we will discuss this in detail along with the Diels–Alder reaction. - [2 + 2] Cycloaddition (4π e–) Ground State (thermal) bonding interactions Excited State (hν) LUMO (antarafacial) LUMO (suprafacial) HOMO (suprafacial) bonding interactions Excited state HOMO (SOMO) (suprafacial) [π2a + π2s] cycloaddition - Antarafacial with respect to one olefin and suprafacial with respect to the second, dicates perpendicular approach to permit bonding. [π2s + π2s] cycloaddition - Suprafacial with respect to both olefins. 35 Modern Organic Chemistry The Scripps Research Institute 4. Sigmatropic Rearrangements - Class of reactions characterized by migration of an allylic group from one end of a π system to the other. - Generalization: Total π electrons Ground State Excited State 4n antara - supra supra - antara antara - antara supra - supra 4n + 2 supra - supra antara - antara antara - supra supra - antara - These include a wide range of rearrangements including [1,3]-, [1,5]-, [1,7]-, [3,3]-, and [2,3]sigmatropic reactions which we will discuss in detail. J. Subtle Conformational and Stereoelectronic Effects on Reactivity and Reaction Regioselectivity 1. Kinetics, Stereochemistry, and Reaction Mechanisms - Two of the cornerstones of defining a mechanism rest with the establishment of the stereochemistry of the reaction in conjunction with kinetic studies of the reaction. - For example, for a reaction that might entail acid or base catalysis, it is common to examine the pH rate profile. OH OH + H2O O OH optically active OH 1 : 15 single enantiomer with clean inversion of absolute stereochemistry, therefore SN2, not SN1, ring opening. - Below pH 4, H+ catalyzed reaction dominates. acid-catalyzed reaction (k = 0.093 M–1s–1) kobs - Above pH 4 (pH 4–12), the uncatalyzed direct SN2 addition reaction dominates. uncatalyzed reaction (k = 4.2 x 10–5 s–1) 0 2 4 6 8 10 12 pH Boger J. Org. Chem. 1998, 63, 8004; J. Org. Chem. 1999, 64, 5666. 36 Reaction Mechanisms and Conformational Effects on Reactivity Dale L. Boger 2. Substituent Effects - These can be quantitated using a Hammett treatment and can provide insights into reaction mechanisms. ρ = −0.3 : small, almost negligible effect - C7 substituents (R) have little effect on reactivity ρ = −3.0 : huge effect R N R' C7 - N substituent (R') has a pronounced effect on reactivity and even subtle perturbations will change reactivity greatly (-SO2R → -CO2R, 10 ×) O ρ values are characterized in a log scale - The negative ρ value indicates δ+ charge buildup in the rate-determining step of the reaction. - 5.2 - 5.2 r = 1.0 ρ = –0.30 - 5.4 - 5.6 log k R' - 5.4 -CO2CH3 - 5.6 -OMe log k -H - 5.8 -CONCH3 R -COEt - 5.8 -CN - 6.0 - 6.0 - 6.2 - 6.4 - 0.4 ρ = slope r = 0.983 ρ = –3.0 - 6.2 -SO2Et - 6.4 - 0.2 0.0 0.2 0.4 0.6 0.8 - 0.2 0.0 0.2 0.4 0.6 0.8 σp σp Boger J. Am. Chem. Soc. 1994, 116, 5523. J. Org. Chem. 1996, 61, 1710 and 4894. 3. Structure versus Reactivity and Reaction Regioselectivity - Structure can have a pronounced effect on reactivity and reaction regioselectivity. One nice example of this can be illustrated with a series of analogues related to CC-1065 and the duocarmycins which are potent antitumor antibiotics that derive their biological properties from a sequence-selective DNA alkylation reaction. The reactivity changes that one sees as a consequence of the loss of the vinylogous amide stabilization are related to the source of DNA alkylation catalysis. Binding-induced conformational change: shape-selective catalysis Alexander R. Todd received the 1957 Nobel Prize in Chemistry for his work on the synthesis of nucleotides and nucleotide coenzymes. Francis Crick and James Watson shared the 1962 Nobel Prize in Physiology and Medicine for their elucidation of the structure of DNA. MeO2C MeO2C HN HN χ1 = 25–40° χ2 = 0° χ1 O N O OMe N H OMe OMe O N χ2 O OMe N H OMe OMe - DNA bound agent adopts helical conformation, twist adjusted at linking amide. - DNA bound agent maintains full amide. (χ2 = 0°) - Vinylogous amide stabilization diminished. (χ1 = 25–40°) - Cyclohexadienone structure destabilized. - Shape-dependent catalysis: Preferential activation in AT-rich minor groove. Binding induced twist greatest in the narrower, deeper AT-rich minor groove. - Shape-selective recognition: Preferential binding in AT-rich minor groove. Boger J. Am. Chem. Soc. 1997, 119, 4977 and 4987. Boger, Garbaccio Bioorg. Med. Chem. 1997, 5, 263. Acc. Chem. Res. 1999, 32, 1043. 37 Modern Organic Chemistry The Scripps Research Institute - N-Acylation and its effect on vinylogous amide and cyclopropane conjugation. vs N H O ° 1.337 A (–)-N-BOC-CBQ ca. 10–50 × increase in reactivity (–)-CBQ (+)-N-BOC-CBI (+)-CBI vs and N O O ° 1.336 A OtBu ° 1.390 A O t1/2 = 133 h (pH 3) t1/2 = 920 h (pH 3) O N H O OtBu t1/2 = 2.1 h (pH 3) t1/2 = 544 h (pH 7) t1/2 = 91 h (pH 3) t1/2 = stable (pH 7) X-ray N ° 1.415 A X-ray ° 1.508 A 12.7° 9a 9a ° 1.468 A 8b ° 1.468 A 9 ° 1.532 A 10a 16.5° 8b 45.0° 9 ° 1.528 A ° 1.525 A ° 1.521 A ° 1.445 A 9b 10 40.9° 28.7° ° 1.476 A 9b 10 36.4° 28.7° ° 1.543 A ° 1.539 A ° 1.544 A 10a 19.8° - N-acylation decreases the cross-conjugated vinylogous amide conjugation, increases the cyclopropane conjugation and bond lengths, and increases cyclopropane reactiviity. This can be observed in the corresponding X-ray crystal structures. - Amide twist effect on the vinylogous amide and cyclopropane conjugation. χ1 = 6.9° N O OtBu ° 1.390 A O H+ catalyzed reaction Uncatalyzed reaction and rates t1/2 = 133 h (pH 3) t1/2 = stable (pH 7) - Decreases vinylogous amide cross-conjugation χ1 = 34.2° O O N 1.415 A° O χ1 = 86.4° OtBu t1/2 = 2.1 h (pH 3) t1/2 = 544 h (pH 7) - Increases cyclopropane conjugation (bond lengths) N O OtBu ° 1.428 A t1/2 = 0.03 h (pH 3) t1/2 = 2.1 h (pH 7) - Increases cyclopropane reactivity 104 × increase in reactivity X-ray ° 1.521 A ° 1.565 A ° 1.528 A 9a 11a 10a 16.5° 9b 8b 9 1.544 A° 10b 10 40.9° > 20 : 1 11 28.7° ° 1.543 A regioselectivity: 38.5° 28.7° ° 1.525 A 3:2 < 1 : 20 - Note the change in solvolysis regioselectivity where the stereoelectronically aligned cyclopropane bond is the bond which is cleaved. The stereoelectronically aligned bond is that which is positioned to best overlap with the developing π-system of the product phenol. - In each case, the ring expansion occurred with generation of a single enantiomer by a SN2 mechanism. Boger J. Org. Chem. 1997, 62, 5849; J. Am. Chem. Soc. 1997, 119, 4977. 38 18.5° complete reversal of reaction regioselectivity Reaction Mechanisms and Conformational Effects on Reactivity Dale L. Boger K. Methods for the Synthesis of Optically Active Materials Morrison Asymmetric Synthesis, Academic: New York, 1983; Vol. 1–5. Note: A summary of approaches which will be highlighted throughout the following material. 1. Partial Synthesis - From readily available, naturally-derived optically active materials, examples include a. Progesterone from sapogenin diosgenin. b. Synthetic penicillins from the fermentation product 6-aminopenicillanic acid (6-APA). c. Vitamin D3 (1-hydroxycholecalciferol) from cholesterol. Louis Pasteur (1822–1895) conducted the first separation of a racemate into its enantiomers (by hand!) and by fractional crystallization. Thus, he conducted the first diastereomeric resolution (tartaric acid + quinine). His investigations into the process of fermentation led to the development of microbiology and the important method of preserving foods known as pasteurization. His research into immunity led to preventative vaccinations using weakened strains of bacteria. He developed the first vaccines for rabies. 2. Resolution a. Diastereomeric salts and selective crystallization. b. Diastereomeric derivatization and chromatography or selective crystallization. c. Direct chromatographic resolution of enantiomers on an optically active stationary support. d. Enzymatic resolution. e. Kinetic resolution with selective production of desired enantiomer or selective consumption of undesired enantiomer. Advantage: Both enantiomers are made available. Disadvantage: 1/2 of the material is wasted if only one enantiomer is desired. Ambiguous assignment of absolute configuration. See: Jacques, Collet, Wilen Enantiomers, Racemates, and Resolutions, Wiley: New York, 1981. A. J. P. Martin and B. L. M. Synge shared the 1952 Nobel Prize in Chemistry for developing the technique of liquid–liquid partition chromatography. Their collaboration also led to the invention of gas–liquid partition chromatography (GLC). The use of chromatography can be traced back to a Russian botanist, M. Tswett, who separated plant pigments by such methods in 1906. Martin and Synge pioneered the rapid progress in this area made in the 1940's and early 1950's. 3. Synthesis from Chiral Pool - Readily available, abundant or naturally occurring starting materials. a. Carbohydrates b. Amino acids c. α-Hydroxy carboxylic acids d. Terpenes e. Readily available, abundant natural products O. Wallach, a colleague and collaborator of A. Kekule, received the 1910 Nobel Prize in Chemistry for his work on essential oils that converted the field of natural products from a disorganized collection of confusing observations into a complete, organized and integrated field. He established the isoprene rule. 39 Modern Organic Chemistry The Scripps Research Institute 4. Asymmetric Synthesis a. Optically active reagent (Stoichiometric) b. Optically active auxiliary incorporated into substrate (Stoichiometric) c. Optically active catalyst (Catalytic) See: Koskinen Asymmetric Synthesis of Natural Products; Wiley: New York, 1993. Gawley, Aube Principles of Asymmetric Synthesis; Elsevier: Amsterdam, 1996. 5. Microbial, Enzymatic, or Catalytic Antibody Transformation See: Wong, Whitesides Enzymes in Synthetic Organic Chemistry; Pergamon: Oxford, 1994. 40 Oxidation Reactions Dale L. Boger IV. Oxidation Reactions A. Epoxidation Reactions: Oxidation of Carbon–Carbon Double Bonds Comprehensive Org. Syn.; Vol. 1, 819; Vol. 7, pp. 357 and 389 (asymmetric). First report: Prilezhaev Ber. 1909, 42, 4811. O R O H O O + O + C C R OH 1. Peracid Reactivity CO2H Rate increases: R = CH3 < C6H5 < m-ClC6H4 < H < p-NO2C6H4 < pKa of acid (RCO2H): 4.8 4.2 3.9 3.8 3.4 < CF3 2.9 0 The lower the pKa, the greater the reactivity (i.e., the better the leaving group). 2. Mechanism R R O O O R H + O H O O O H O O Butterfly mechanism (usual representation) Bartlett Rec. Chem. Prog. 1950, 11, 47. Refined representation: trans antiperiplanar arrangement of O–O bond and reacting alkene, n-π* stabilization by reacting lone pair in plane. The synchronicity of epoxide C–O bond formation and an overall transition state structure postulated using ab initio calculations and experimental kinetic isotope effects. Singleton, Houk J. Am. Chem. Soc. 1997, 119, 3385. 3. Stereochemistry a. Stereochemistry of olefin is maintained: diastereospecific. b. Reaction rate is insensitive to solvent polarity implying concerted mechanism without intermediacy of ionic intermediates. c. Less hindered face of olefin is epoxidized. R R R R R m-CPBA O R + CH2Cl2 O R=H R = CH3 20 min, 25 °C 24 h, 25 °C 99% < 10% 1% 90% Brown J. Am. Chem. Soc. 1970, 92, 6914. 41 Modern Organic Chemistry The Scripps Research Institute 4. Chemoselectivity _ Electrophilic reagent: most nucleophilic C=C reacts fastest. > > RO R > > EWG ≥ > > - Examples O m-CPBA cis : trans 1 : 1 –10 °C, 1 h C6H5CO3H O CHCl3, 10 min 0 °C HO2C H O HO2C C6H5CO3H H OH Concave face hindered toward peracid attack H H O CO2H O C6H6–dioxane 25 °C, 24 h Hückel Chem. Ber. 1955, 88, 346. Woodward Tetrahedron 1958, 2, 1. Tamm Helv. Chim. Acta 1975, 58, 1162. OH O H H OH H 80% Convex face open to peracid attack 5. Diastereoselectivity a. Endocyclic Olefins Rickborn J. Org. Chem. 1965, 30, 2212. Destabilizing steric interaction between reagent and axial Me H H Me H m-CPBA Me 25 °C, Et2O H Me + O H Me 87 : 13 Me Me O H H Me Me H Attack principally from this face 42 Oxidation Reactions Dale L. Boger R Me ∆∆G H O O O O H Me O H O R Me ∆∆G Me O vs. Me O H Me H Small difference for products: but larger difference for reagent approach in transition state. b. Exocyclic Olefins more hindered face Me Me Me Me O + Me Me less hindered face _ Me RCO3H Solvent dependent O Me Me less stable product 75% 80% 83% CCl4 C6H6 CH2Cl2 or CHCl3 25% 20% 17% Henbest J. Chem. Soc., Chem. Commun. 1967, 1085. _ The effective size of the reagent increases with increasing solvent polarity, i.e., the solvation shell of the reagent increases in size. _ Small reagent preference: axial attack and 1,3-diaxial interactions vary with size of the reagent. H H RCO3H H H H H O O + H H H H 41 _ H H H H H : 59 Large reagent preference: equatorial attack and 1,2-interactions (torsional strain) are relatively invariant with the size of the reagent. Carlson J. Org. Chem. 1967, 32, 1363. 43 Modern Organic Chemistry The Scripps Research Institute c. Allylic Alcohols (endocyclic) Henbest J. Chem. Soc. 1957, 1958; Proc. Chem. Soc. 1963, 159. O OR _ Diastereoselectivity OH 43% 9% Prefers equatorial position, locking conformation of substrate 38% yield 86% yield tBu tBu 4% 96% Original proposal for the origin of selectivity: H H-bonding to proximal peroxide oxygen directs epoxidation to the same face as OH group and accelerates/facilitates the reaction. O R O O H R = H, tBu O 120° R 120° _ 57% 91% and rate (ca. 10×) of reaction accelerated by unprotected allylic alcohol. O O OH OH m-CPBA + tBu _ OR + 20 °C C6H6 5 °C C6H6 R = COCH3 R=H O OR m-CPBA HO R H Equivalent to the ground state eclipsed conformation of acyclic allylic alcohols: H _ Metal-catalyzed epoxidations of allylic alcohols exhibit a more powerful directing effect and rate acceleration (ca. 1000×). Metal bound substrate (as an alkoxide) delivers olefin to metal bound peroxide (tighter association than H-bonding). OH O 83% OH + VO(acac)2 tBu O OH tBuOOH tBu tBu 0% 100% Sharpless Aldrichimica Acta 1979, 12, 63. _ 44 This may also be utilized to chemoselectively epoxidize an allylic alcohol vs. unactivated olefin. Oxidation Reactions Dale L. Boger d. Allylic Alcohols (exocyclic) Early transition state and the asynchronous bond formation places the reagent further from 1,3-interactions. small reagent H H tBu O m-CPBA R2 R2 R1 equatorial H(R2) R1 R2 H H H CH3 H H OH OCH3 OCH3 OAc OH OH OCH3 OCH3 O tBu + R2 R1 axial large reagent R1 tBu Equatorial substitution Axial substitution blocks equatorial reagent delivery H CH3 H CH3 69 60 60 88 75 : : : : : 31 40 40 12 25 11 13 83 83 : : : : 89 87 17 17 HO axial OH directs epoxidation to the syn-face of the exocyclic double bond Vedejs and Dent J. Am. Chem. Soc. 1989, 111, 6861. e. Acyclic Allylic Alcohols Generalizations: Eclipsed Conformations in m-CPBA Epoxidation HO H H R2 R4 R3 R1 OH O OH R4 R3 H R1 HO Erythro Product R1 OMet R4 R3 R1 H R4 R3 R2 Threo Product R2 R4 R3 HO R2 R1 R1 R2 R2 R4 R3 H OMet Bisected Conformations in Metal-Catalyzed Epoxidation 45 Modern Organic Chemistry The Scripps Research Institute _Examples R1 threo erythro m-CPBA VO(acac)2, tBuOOH 60 20 40 80 m-CPBA VO(acac)2, tBuOOH 61 20 39 80 OH R1 = Me = Et H vs. alkyl eclipsing HO interaction with H H double bond has little H H to no effect on R1 selectivity. H eclipsing interaction slightly threo more stable. R1 = iPr R2 m-CPBA VO(acac)2, tBuOOH R1 58 15 42 85 threo erythro H,H eclipsing in erythro T.S. favored over H,alkyl eclipsing in threo T.S. H R1 = Me R2 = nBu Me H H Me OH R1,R2 = Me H H OMet erythro H H m-CPBA VO(acac)2, tBuOOH 45 5 55 95 m-CPBA VO(acac)2, tBuOOH 41 2 59 98 threo erythro 64 29 36 71 threo erythro Erythro slightly favored due to Me,Me gauche interaction in threo T.S. HO erythro Me H,Bu eclipsing in erythro T.S. favored over Me,Bu eclipsing in threo T.S. Bu H H H OMet erythro R1 R4 OH R1,R4 = Me m-CPBA VO(acac)2, tBuOOH Similar to R4 = H. R4 does not sterically influence either T.S. The R1 steric effect predominates. R1 OH R3 R1,R3 = Me m-CPBA VO(acac)2, tBuOOH 95 71 5 29 Large 1,3-allylic strain avoided. HO H H H Me Me threo Me Me OH Me m-CPBA VO(acac)2, tBuOOH threo erythro 95 86 5 14 OMet Large 1,3-allylic strain avoided. H Me H threo 46 Me Me Oxidation Reactions Dale L. Boger f. Refined Models for Directed Epoxidation of Acyclic Allylic Alcohols R _ Peracid Mediated Epoxidation Sharpless Tetrahedron Lett. 1979, 4733. O O O 1. Trans antiperiplanar arrangement of O–O bond with alkene C=C. O H H H H 2. H-bonding to distal oxygen of peroxide through the lone pair out of O the plane of reaction. Top View 3. Lone pair in plane of reaction provides π∗−lone pair (n-π∗) stabilization. 120° 4. Secondary isotope effect suggests that the formation of the C–O bonds is asynchronous. _ Eclipsed Conformations in m-CPBA Epoxidation HO R2 H OH O O R4 R3 R4 R3 H OH R2 R1 H erythro product threo product _ R1 R4 R3 R2 HO R2 R1 Sharpless Aldrichimica Acta 1979, 12, 63. H R4 R3 R1 O Transition-metal Catalyzed Epoxidation 1. Trans antiperiplanar arrangement R O O O 2. 50° dihedral angle O Met O Met 3. In-plane lone pair Top View R 4. Lone pair bisects C=C bond _ Curtin-Hammett Principle: - The reactive conformation is not necessarily related to the ground state conformation. - The substrate is forced into a non-ground state conformation due to the geometrical constraints of the reaction. _ Bisected Conformations in Metal-Catalyzed Epoxidation R1 OMet R2 R4 R1 R3 R2 H R4 R3 R4 R3 R4 R3 OMet H OH O R2 O R1 H Threo Product R1 OH R2 H Erythro Product 47 Modern Organic Chemistry The Scripps Research Institute Take Home Problem Epoxidations of 3 of the 4 olefins below are diastereoselective; the fourth is not. Why? O Me BnO Me BnO Me OH OH O H BnO Me H BnO Me Me OH OH O BnO OH Me BnO Me BnO Me O OH Me OH Me BnO H Me OH 60% OH 40% H + O references: Kishi Tetrahedron Lett. 1980, 21, 4229. Tetrahedron Lett. 1979, 20, 4343 and 4347. BnO Me H g. Homoallylic Alcohols OH Me Ph Me VO(OnPr)3 t BuOOH CH2Cl2, 95% H L Ph Me OTBDPS O V OH L Ot O Me Bu O Ph Me Me OTBDPS H OTBDPS _ _ Alternative chair has two axial substituents. Intramolecular oxygen delivery occurs through most stable chair-like transition state. VS. OAc Me Ph Me major m-CPBA CH2Cl2, 25 °C 94% H OTBDPS OAc Me Ph OAc _ OTBDPS Me minor H-Eclipsed conformation Epoxidation from least hindered face _ Not a directed epoxidation! _ Diastereoselectivity still good and through H-eclipsed conformation. _ Schreiber Tetrahedron Lett. 1990, 31, 31. Hanessian J. Am. Chem. Soc. 1990, 112, 5276. Mihelich J. Am. Chem. Soc. 1981, 103, 7690. 48 O Ph Me OTBDPS 5:1 Oxidation Reactions Dale L. Boger h. Other Directed Epoxidations _ Studies suggest axial -NHCBZ delivers syn epoxide while equatorial does not. R R m-CPBA NHCBZ R = NHCBZ = CH2OH = CH2OAc = CO2Me = CH2NHCBZ = CH2OTBDMS CH2Cl2, 25 °C R + O O NHCBZ NHCBZ 100 100 100 100 100 0 86% 83% 72% 59% 81% 54% 0 0 0 0 0 100 Witiak J. Med. Chem. 1989, 32, 214. Rotella Tetrahedron Lett. 1989, 30, 1913. Presence of H-bonding, directing substituent enhances rate and yield of reaction. O O X iPr m-CPBA O X iPr O n = 1, X = NH X=O n = 2, X = NH X=O iPr + CH2Cl2, 25 °C n X 80% O n 20 3 20 3 n 1 1 1 1 Mohamadi Tetrahedron Lett. 1989, 30, 1309. OH O OH O O H2O2 / NaOH / MeOH / 0 °C Ti(iPrO)4 / tBuOOH / CH2Cl2 / –15 °C OH O + O 40 : 60 >99 : 1 Ollis Tetrahedron Lett. 1991, 32, 2687. 49 Modern Organic Chemistry The Scripps Research Institute 6. Scope and Limitations Peracid + O a. Olefin geometry is maintained. b. Reaction is diastereospecific: the stereochemistry of the reactant and product bear a definite relationship to one another. c. Reaction can be buffered to prevent epoxide opening. The pKa of parent acid is much lower than that of the peracid, and the peracid is not nearly as acidic. Reaction requires the protonated peracid so the buffer must not deprotonate the peracid but should deprotonate the product carboxylic acid. H H2O2 OH O O HCOOH O H Na2CO3 / NaHCO3 CH3COOH / NaOAc CF3CO3H / Na2HPO4 – NaH2PO4 e.g. _ HCOOH HCO3H OH NaOH H OH These reagents can be used as a buffer when the peracids are used as epoxidation reagents. pKa 3.6 pKa 7.1 CH3COOH pKa 4.8 CH3CO3H pKa 8.2 So, choose bases (Na2CO3, NaHCO3, Na2HPO4) to deprotonate only the RCOOH formed. d. Also, at higher temperatures, a free radical scavenger may be used to avoid peracid decomposition. e. Common side reactions 1. Baeyer–Villiger reactions of ketones and aldehydes O O m-CPBA e.g. O O not O _ When peracids are used to oxidize olefins to epoxides in the presence of carbonyl functionality (ketones or aldehydes), protection of the carbonyl group may be necessary. _ One may choose to select a reagent which attacks olefins preferentially. 2. Oxidation of amines _ m-CPBA N +N Nitrogen must be protected (e.g., as amide) or another reagent selected. O N m-CPBA N 3. Imine oxidation R 4. Sulfur oxidation R S R m-CPBA CO3H CO2H R m-CPBA R S O R + R R S O O Typical Peracids CO3H CO3H CO3H CF3CO3H Cl 50 O– O2N O2N NO2 Oxidation Reactions Dale L. Boger 7. Epoxidation of Electron-deficient Olefins a. α,β-unsaturated esters: can choose a strong peracid or vigorous reaction conditions CF3CO3H Me Me Na2HPO4 Emmons J. Am. Chem. 84% Soc. 1955, 77, 89. CH2Cl2, reflux CO2CH3 O CO2CH3 Ph CO2CH3 Ph m-CPBA CH2Cl2, reflux O 47% CO2CH3 MacPeek J. Am. Chem. Soc. 1959, 81, 680. b. α,β-unsaturated ketones: Baeyer–Villiger competes with epoxidation O R1 R Epoxidation Baeyer–Villiger Reaction Solution: different conditions (reagents) are needed B. Additional Methods for Epoxidation of Olefins 1. H2O2, NaOH O– O H H2O2, NaOH _ O O O 70% O The following reaction is diastereoselective (but not diastereospecific): a single stereoisomer of the product is formed which bears no relationship to the reactant. Me Me O Me Me H2O2, NaOH CO2CH3 H H2O2, NaOH Me CO2CH3 CO2CH3 Me The reaction occurs via a reversible process: Me Me Me Me HO H O CO2CH3 Me CO2CH3 OCH3 Me O– Similarly, tBuOOH/Triton B Ph3COOH/R4NOH tBuOOH/nBuLi + Triton B = Ph Payne J. Org. Chem. 1961, 26, 651. Corey J. Am. Chem. Soc. 1988, 110, 649. Jackson Tetrahedron 1988, 29, 4889. N –OH 2. Peroxyimidate RCN R _ O NH H2O2 O O O + R H NH2 This reagent permits the use of neutral reaction conditions. Unlike m-CPBA, the reagent behaves as a large reagent and thus approaches from the equatorial face of an exocyclic double bond. O O + small reagent large reagent m-CPBA PhCN / H2O2 59 14 41 86 51 Modern Organic Chemistry The Scripps Research Institute 1,3 m-CPBA small reagent, but the interaction will increase with the size of the reagent H H Carlson J. Org. Chem. 1967, 32, 1363. (m-CPBA & PhCN/H2O2) Vedejs J. Am. Chem. Soc. 1989, 111, 6861. (m-CPBA) H PhCN/H2O2 H larger reagent, but the interaction will not vary with size, predominately equatorial attack 1,2 Ph N C O + H2O2 _ Analogous reagent: Ph H N O O Christl Angew. Chem., Int. Ed. Eng. 1980, 19, 458. O H Mechanism Problem Provide mechanism for: m-CPBA, CHCl3 –5 °C then ∆, 160 °C AcO H AcO H O H AcO m-CPBA, CHCl3 AcO –5 °C then ∆, 160 °C H O H Johnson J. Org. Chem. 1961, 26, 4563. H + OO O O O H O– H Why does this reaction need to be heated to 160 °C? half-chair conformation Me Me OAc AcO H OAc Me H reagent attack from this face Me + O O Me O H O H H O O H H+ 52 O H Oxidation Reactions Dale L. Boger 3. Sulfur Ylides Me tBu Me O S CH2 tBu O O 77% Me Me _ S+ Me I– nBuLi, <0 °C tBu + : 87 Me Me 13 dimethylsulfonium methylide small reagent that prefers axial delivery S CH2 This is the result of kinetic control: reaction gives the thermodynamically less stable epoxide product. H H S+ tBu tBu O– O Equatorial Delivery 1,2-interaction disfavored tBu 13% O –O tBu S+ tBu O Me O S+ CH2– Me Axial Delivery 1,3-interaction favored over 1,2 tBu O 87% tBu + 89% O : 0 Me O S+ CH3 Me I– tBu O H H NaH, THF reflux Me O S+ CH2– Me Corey, Chaykovsky J. Am. Chem. Soc. 1965, 87, 1353. thermodynamic product 100 dimethyloxo sulfonium methylide small reagent that prefers axial attack OH S+ H tBu tBu equatorial attack O rapidly goes on to product O– 100% tBu O –O axial attack predominant O S+ –O tBu H H fails to go on to product tBu OH H S+ backside attack not possible due to destabilizing 1,3-interactions For this reaction: Initial reaction is reversible and is not capable of generating the axial delivery product because of the destabilizing 1,3-interactions in the transition state required for epoxide closure. 53 Modern Organic Chemistry The Scripps Research Institute Summary of Exocyclic Epoxide Formation Note: defined conformation of 6-membered ring required for comparisons O or X O X=O S X = CH2 m-CPBA O S+ CH2– X=O X X equatorial attack H O NH X = CH2 X axial attack X R O R = large group Learn reagents by: 1) Conditions required 2) Advantages and disadvantages 3) Competitive reactions 4) Stereochemistry limitations / highlights Sulfur ylides deliver "CH2" Peroxides deliver "O" 4. Dimethyl Dioxirane (DMDO) O O Murray J. Am. Chem. Soc. 1986, 108, 2470. Acc. Chem. Res. 1989, 22, 205. A mild neutral reagent Peracid reaction suffers from H+ catalyzed epoxide opening DMDO O O acetone, 96% O O O Adam Tetrahedron Lett. 1989, 30, 4223. O O Curci Tetrahedron Lett. 1989, 30, 257. CF3 Excellent for oxidation of O highly substituted enol ethers O CH3 O O Boyd Tetrahedron Lett. 1989, 30, 123. O Crandall J. Org. Chem. 1988, 53, 1338. Tetrahedron Lett. 1988, 29, 4791. • O O BnO BnO O O BnO OBn R3SiO BnO Danishefsky J. Am. Chem. Soc. 1989, 111, 6661. Useful for glycosidation reactions. OBn R3SiO O O OSiR3 stable and characterizable Danishefsky J. Org. Chem. 1989, 54, 4249. pH dependence: rate at pH 11 > 7, acetone−oxone Shi J. Org. Chem. 1998, 63, 6425. 54 Oxidation Reactions Dale L. Boger 5. Summary of Other Methods of Epoxide Formation a. Cyclization of Halohydrins HO H2O + X2 + O OH– X X X tBu tBu axial equatorial H2O NXS– H2O t Bu H2O OH CH2X t OH + Bu t Bu CH2X : Increased NCS–H2O 90 : reagent size NBS–H2O 82 yields increased : NIS–H2O 55 equatorial Analogous results observed with: approach Br , ClCH CH Cl 70 : 2 2 2 : Br2, MeOH 90 O O t Bu + major 90 10 18 45 31 30 10 t Bu minor 10 : vs 69 : For m-CPBA, complementary stereochemistries -The electrophilic reagents behave as small reagents and approach from the axial direction Chiappe J. Org. Chem. 1995, 60, 6214. E+ -For acyclic systems: LUMO electrophile HOMO alkene Houk Acc. Chem. Res. 1990, 23, 107. -Large or electropositive group L b. Cyclization of 1,2-diols R OH TsCl OH R OTs OH _ primary alcohol > secondary alcohol for tosylation reaction R O c. Epoxides from carbonyl compounds d. O + O R Cl R R1 Li Köbrich Angew. Chem., Int. Ed. Eng. 1972, 11, 473. R1 O e. f. R O + S CH2 O + O S CH2– O O O + Cl H X = OR, R, R O X N R O X O Darzen's Condensation: First Example: Erlenmeyer Ann. 1892, 271, 161. Generalized by Darzen through years 1904–1937 Compt. rend. 1904, 139, 1214. O Comprehensive Org. Syn., Vol. 2, p 409. Newman, Magerlein Org. React. 1968, 5, 413. Asymmetric variants: Lantos J. Am. Chem. Soc. 1986, 108, 4595. Shioiri Tetrahedron 1999, 55, 6375. 55 Modern Organic Chemistry The Scripps Research Institute C. Catalytic Asymmetric Epoxidation 1. Sharpless Catalytic Asymmetric Epoxidation (AE Reaction) Key references: Asymmetric Synthesis: Vol. 5, Morrison, J.D. Ed., Academic Press, Chapters 7 and 8. Reviews: Katsuki, Martin Org. React. 1996, 48, 1. Comprehensive Org. Syn.; Vol. 7, pp 389–436. Sharpless J. Am. Chem. Soc. 1980, 102, 5974; 1987, 109, 5765; 1981, 103, 6237; 1984, 106, 6430; 1991, 113, 106, 113; 1987, 109, 1279. 1. The enantiofacial selectivity of the reaction is general and dependable for assignments. D-(–)-DIPT R2 R1 tBuOOH, R3 Ti(OiPr)4 R2 O R1 R3 CH2Cl2, –20 °C, DET or DIPT OH ° 4 A molecular sieves anhydrous OH L-(+)-DIPT 2. Selectivity is catalyst dependent Ti(OiPr)4 Al(OtBu)3 MoO2(acac)2 VO(OiPr)3 Sn(OiPr)4 95% ee 5% ee 15% ee 17% ee NR Zr(OiPr)4 Hf(OiPr)4 Nb(OEt)3 Ta(OiPr)5 10% ee 3% ee 5% ee 39% ee yield 3. Chemical Conversion unsubstituted trans-disubstituted cis-disubstituted 1,1-disubstituted trans-1,1,2-trisub. cis-1,1,2-trisub. 1,2,2-trisubstituted R1 = R2 = R3 = H R1, R3 = H R2, R3 = H R1 = R2 = H R1 = H R2 = H R3 = H 95% ee >95% ee 85–95% ee 85–95% ee >95% ee >90% ee >95% ee 15% (isolation problematic) 70–90% 70–90% 70–90% 70–90% 70–90% 70–80% 4. Sharpless asymmetric epoxidation is one of the best known and practical asymmetric reactions utilized in organic synthesis. Discovered in 1980, this catalytic process utilizes an optically active ligand to direct a transition metal catalyzed reaction. Epoxidation from a single face of a prostereogenic allylic alcohol: H H E O R = Et DET RO HO OH E O Ti O RO R = iPr DIPT O R' O Ti O RO2C CO2R OE O tBu 2 C symmetry RO E = CO2R (Useful in ligand design- predictable and repetitive structural units which reduce number of diastereomeric transition states) a. Match of Ti / Tartrate such that a single complex dominates the chemistry. The concentration of each complex in the mixture of complexes is dictated by thermodynamic considerations. However, it could not be predicted that a single species would dominate the Ti–tartrate equilibrium mixture and that this species would be so kinetically active. The tartrate–Ti complex is perfectly matched and slight deviations in the ligand structure or change in the metal alkoxide reduces the effectiveness of the reaction. 56 Oxidation Reactions Dale L. Boger b. Ligand acceleration of reaction. This is not essential but extremely beneficial. It ensures that the enantioselective version of the reaction (the one in which the auxiliary ligand is present) will be the most viable kinetic pathway. c. Steric and stereoelectronic features of reaction control enantioselectivity. Stereoelectronic: 1. Alkyl peroxide is activated by bidentate coordination to the Ti(IV) center. 2. The olefin is constrained to attack the coordinated peroxide along the O–O bond axis. (stereoelectronic effect) 3. The epoxide C–O bonds are formed simultaneously. Steric factors: 1. Bulky hydroperoxide is forced to adopt a single orientation when bound in a bidentate fashion. 2. The allylic alkoxide is thereby restricted to reaction at a single coordination site on the metal center. Steric interactions of the bound substrate with the catalyst framework provide for the kinetic resolution patterns. 3. Efficient catalytic turnover provided by the labile coordinated ester, permitting rapid alkoxide–alcohol exchange. Scope R2 R1 Epoxidation with Titanium–Tartrate Catalysts unsubstituted (R1 = R2 = R3 = H) trans-disubstituted (R1 = R3 = H) OH R3 yield 95% ee 15% R2 = CH3 R2 = nC10H21 R2 = (CH2)3CH=CH2 R2 = Me3Si R2 = tBu R2 = Ar R2 = CH2OBn R2 = O O >95% ee >95% ee >95% ee >95% ee >95% ee ≥95% ee 98% ee >95% ee 45% 79% 80% 60% R2 = >95% ee 70% >99% ee 76% >99% ee 70% >93% ee 70–88% BnO O 0–90% 85% 78–85% O O R2 = BnO O R2 = BnO R2 = Ph cis-disubstituted (R2 = R3 = H) R1 O O BnO OSiEt3 R nC H 10 21 = R1 = CH2Ph R1 = CH2OBn O R1 = R = OBn, OH 90% ee 91% ee 92% ee 96% ee 82% 83% 84% 55% O 57 Modern Organic Chemistry The Scripps Research Institute 1,1-disubstituted (R1 = R2 = H) R3 = -cyclohexyl R3 = nC14H29 R3 = tBu >95% ee >95% ee 85% ee 81% 51% trans-1,1,2-trisubstitued (R1 = H) R3 = R2 = Ph R3 = Me, R2 = Et R3 = Me, R2 = >95% ee >95% ee >95% ee 87% 79% 70% >95% ee 92% 91% ee 90% >95% ee 94% ee 77% 79% 94% ee 90% 94% ee 90% AcO R3 = Me, R2 = O O R3 = CH3, R1= Bn cis-1,1,2-trisubstituted (R2 = H) 1,2,2-trisubstituted (R3 = H) R2 = (CH2)2CH=C(CH3)2, R1 = CH3 R2 = CH3, R1 = (CH2)2CH=C(CH3)2 tetrasubstituted R3 = CH3, R2 = Ph, R1 = Bn OH R4 Allylic Alcohols Undergoing Kinetic Resolution with Relative Rates >15 at –20 °C R3 R1 = nC6H13 R1 = (CH2)2Ph R1 = R5 OH R1 2 R R1 = nC4H9, R3 = CH3 R1 = cyclohexyl, R3 = CH3 R1 = nC4H9, R4 = Et or CH3 R1 = cyclohexyl, R4 = CH3 R1 = Et, R4 = Ph R1 = CH2CH(CH3)2, R4 = CH3 R1 = R5 = CH3 R1 = Et, R4 = nC6H13 O O R1 = cyclohexyl R1 = OH HO OH Poor Substrates for Asymmetric Epoxidation or Kinetic Resolution Catalyzed by Titanium−Tartrates t Ph OH BnO O Bu O OH OH OH tBu O O OH OH OBn CH3O O O O O H3CO2C OH OH OH OH OH Ph OH 58 OH OH OH OH tBu OH tBu OH Oxidation Reactions Dale L. Boger 5. Kinetic Resolution Sharpless J. Am. Chem. Soc. 1981, 103, 6237. Pure Appl. Chem. 1983, 55, 589. _ Sharpless epoxidation product is different from the directed oxidation of allylic alcohols by peracids (m-CPBA). HO R O Sharpless Epoxidation HO m-CPBA R H R H O H L-(+)-DIPT OH (1.2 equiv) 1.0 equiv Ti(OiPr)4, 0.6 equiv tBuOOH, CH2Cl2, –20 °C, 15 h HO O O OH H racemic OH OH + H 2 98 H (R)-enantiomer recovered relative rates = kS / kR = 104 (S)-enantiomer reacts 1.0 equiv Ti(OiPr)4 1.5 equiv D-(–)-DIPT 0.4 equiv tBuOOH CH2Cl2, –20 °C 0.8 equiv Ti(OiPr)4 0.8 equiv L-(+)-DET 0.8 equiv tBuOOH CH2Cl2, –20 °C O + OH OH O OH 27% yield >95% ee OH 75% yield 95% ee 33% yield 72% ee Roush J. Org. Chem. 1982, 47, 1371. HO O Me HO O OH OH Me OH OH Sato Tetrahedron Lett. 1987, 28, 6351. Sharpless epoxidation Kinetic resolution I OH 59 Modern Organic Chemistry The Scripps Research Institute 6. Total Synthesis of the L-Hexoses Sharpless, Masamune Science 1983, 220, 949. Tetrahedron 1990, 46, 245. "Reagent-control" Strategy: selection of reagent dictates ultimate absolute stereochemistry of reaction products irrespective of stereofacial bias of substrate. "Substrate-control" Strategy: stereochemistry of reaction products dictated by the inherent stereofacial bias of the substrate. Masamune Angew. Chem., Int. Ed. Eng. 1985, 97, 1. Sharpless Chemica Scripta 1985, 25, 71. O O O O OH O + OH O OH O O erythro threo Product Ratio (threo:erythro) Reagent 1 : 1.4 achiral reagents m-CPBA 1 : 1.8 "substrate control" VO(acac)2–TBHP i 1 : 2.3 Ti(O Pr)4–TBHP i "matched pair" 1 : 90 Ti(O Pr)4–(–)-tartrate–TBHP i "mismatched pair" 22 : 1 Ti(O Pr)4–(+)-tartrate–TBHP "reagent control" -Reiterative two-carbon extension cycle employed for the synthesis of all L-hexoses: OR'OR' R-CH-CH-CH=CH-CH2-OH Homologation R-CH=CH-CH2-OH OR'OR' Homologation R-CHO R-CH-CH-CHO AE And so on... O R-CH-CH-CH2-OH * * OR'OR' Pummerer Reaction OH RO R = CHPh2 OH PhSH, 0.5 N NaOH, tBuOH, reflux (4:1); ° mol. sieves 4A –20 °C, 92% (>20:1) O DIBAL-H 84% (>20:1) O O OR >95% ee CHO AcO SPh 60 K2CO3, MeOH, 93% (>20:1) (MeO)2CMe2, cat. POCl3, 71% AcO O O SPh m-CPBA; Ac2O, NaOAc 93% OR CHO O O OR SPh O O OR Diverging Intermediate erythro corresponds to C4 and C5 of allose, altrose, mannose, and glucose OR O O OR Payne Rearrangement R-CH-CH-CH2-SPh Ti(OiPr)4, (+)-DIPT, tBuOOH, CH Cl 2 2 AE threo corresponds to C4 and C5 of gulose, idose, talose, and galactose Oxidation Reactions Dale L. Boger CHO CHO O O O O OR OR erythro threo Ph3P=CHCHO benzene; NaBH4 MeOH Ph3P=CHCHO benzene; NaBH4 MeOH OH OH O O O O OR OR (+)-AE 76% (>20:1) (–)-AE 84% (>20:1) OH OH O O O t BuOH, PhSH NaOH reflux (16:1) 77% O O t SPh BuOH, PhSH NaOH reflux (7:3) 63% O O O O a CHO HO HO HO HO L-Allose t SPh O O BuOH, PhSH NaOH reflux (7:1) 79% OH L-Altrose OH L-Mannose O OR t SPh BuOH, PhSH NaOH reflux (15:1) 86% O OR e HO OH HO HO OH HO L-Gulose L-Idose CHO HO OH OH HO HO OH OH h CHO OH OH OH HO HO L-Glucose g CHO OH OH OH OR f CHO CHO OR SPh O O O O HO HO HO HO O O O O d CHO OH OH O O c CHO OH HO HO HO OH OR OR b OH O O O OR OH O O OR (–)-AE 73% (>20:1) (+)-AE 71% (>20:1) OH L-Talose OH L-Galactose For a, c, e, and g: 1. Pummerer reaction, 2. DIBAL-H, 3. Deprotection. For b, d, f, and h: 1. Pummerer reaction, 2. K2CO3/MeOH, 3. Deprotection. 61 Modern Organic Chemistry The Scripps Research Institute -Payne Rearrangement Payne J. Org. Chem. 1962, 27, 3819. Base-catalyzed (aq. NaOH) migration of α,β-epoxy alcohols: O CH3 CH3 OH CH3 0.5 N NaOH HO 1h 8% CH3 H O O H CH3 CH3 OH H CH3 CH3 O 7%, erythro 93% O OH H CH2OH CH3 58% 92% H CH2OH O O 42%, threo OH O H OH CH3 CH3 CH3 O 56%, erythro 44% OH CH3 CH3 CH3 CH3 CH3 O OH 95%, threo 5% 1. In general, the more substituted epoxide is favored as the reaction product. 2. However, steric factors and relative alcohol acidities (1° > 2° > 3°) are additional factors which determine the ultimate composition of the equilibrium mixture. 3. The more reactive epoxide can be trapped by strong nucleophiles (e.g., PhSH). H CH3 ROCH2 H O H CH2OH H OH OH PhSH ROCH2 O ROCH2 SPh OH Emil Fischer attended the lectures of A. Kekule, worked with A. Baeyer as a student and received the 1902 Nobel Prize in Chemistry for his work on carbohydrate and purine syntheses. Discoverer of the Fischer indole synthesis using arylhydrazones, he utilized phenylhydrazine to derivatize carbohydrates as crystalline solids for characterization that enabled him to elucidate their chemistry and structure. From the work of Le Bel and van't Hoff he knew glucose must have 16 stereoisomers and in the now classic studies synthesized most of them and established the correct configuration of glucose. He introduced the use of Fischer projection formulas. He proposed structures for uric acid, caffeine, theobromide, xanthine, and guanine and later synthesized theophylline and caffeine (1895), uric acid (1897), and coined the term purine. By 1900 he prepared more than 130 derivatives including hypoxanthine, xanthine, theobromide, adenine, and guanine. In 1914, he made glucose derivatives and from them the nucleosides. He is responsible for the "lock and key" analogy for describing enzyme–substrate interactions, prepared the D- and L-amino acids with fractional crystallization resolution and made a peptide of 18 amino acids. Having suffered from the effects phenylhydrazine, he is also among the first to implement safety precautions (ventilation) and designed the first exhaust system put into general use. "...the intimate contact between the molecules...is possible only with similar geometrical configurations. To use a picture, I would say that the enzyme and the substrate must fit together like a lock and key." Emil Fischer, 1895 W. Haworth received the 1937 Nobel Prize in Chemistry for his investigations on the structure determination of carbohydrates (cyclic monosaccharides, disaccharides, and polysaccharides) including their derivitization as methyl ethers and vitamin C. The latter was accepted with wide acclaim and Haworth was also one of the first to prepare vitamin C, the first vitamin to be prepared by synthesis. This made vitamin C available to the world population for the treatment of scurvy, eliminating the need for treatment with fresh limes or lemons. Albert Szent-Gyorgyi von Nagyrapolt received the 1937 Nobel Prize in Medicine. He was responsible for the isolation of vitamin C for the first time, but was recognized for his investigations into biological mechanisms of oxidation. 62 Oxidation Reactions Dale L. Boger Vitamins represent one of the great success stories of organic synthesis. They are necessary requirements of both animals and humans, but cannot be made by these species. The needs are met by dietary sources or through symbiotic relationships with microorganisms (intestinal bacteria). There are now 13 vitamins. All, except vitamin B12 which is produced by fermentation, are made commercially by chemical means. vitamin C (60,000 metric tons/yr)* - humans vitamin E (22,500 metric tons/yr)* - 75% for animal nutrition niacin (21,600 metric tons/yr)* - 75% for animal nutrition vitamin B12 (14 metric tons/yr)* - 55% animal/45% human * for 1994 OH OH OH Vitamin A N Vitamin B1 H2N N HO NH2 Vitamin B3 OH N O S NH N OH OH O Vitamin B2 N HSO4− N OH N O OH Vitamin B6 N H2NOC CONH2 HO HO O HO H O H2NOC H OH CN N Co N N CONH2 N H2NOC Vitamin D3 Vitamin C CONH2 O N NH HO N HO O −O P O O HO O O OH Vitamin E O Vitamin B12 O HN NH Vitamin K1 Biotin O OH S O CO2H OH O N HN H2N N N HN CO2H N H O Folic acid HO H N O OH O Pantothenic acid 63 Modern Organic Chemistry The Scripps Research Institute Paul Karrer received the 1937 Nobel Prize in Chemistry for his research on carotenoids, flavins, and vitamin A and B2. He published over 1000 papers in his career and his textbook on organic chemistry was a classic in the field (13 editions). He along with Hans von Euler-Chelpin (Nobel, 1929) discovered that carotene and vitamin A had the same activity and that the addition of two molecules of H2O to carotene produces two molecules of vitamin A, elucidating its structure before it had been isolated. It was in Karrer's lab that George Wald (Nobel Prize in Physiology or Medicine, 1967) showed that vitamin A plays an important role in the chemistry of vision. The total synthesis of the carotenoids was accomplished by Karrer in 1950. In 1931, he synthesized squalene, he confirmed the structure of vitamin C, and he completed the total synthesis of riboflavin and vitamin B2 (in 1934), and he completed the first total synthesis of vitamin E (tocopherols) in 1938. He also isolated vitamin K, at the same time as Henrik Dam (Nobel Prize in Physiology or Medicine, 1943) and Edward Doisy (Nobel Prize in Physiology or Medicine, 1943). He and Warburg (Nobel Prize in Physiology or Medicine, 1931) unraveled the role of NADPH and he prepared other coenzymes including thiamine pyrophosphate and pyridoxal-5-phosphate. Richard Kuhn received the 1938 Nobel Prize in Chemistry for his work on carotenoids and vitamins. He also put forth the concept of and coined the term atropisomerism. He isolated ca. 1 g of riboflavin, vitamin B2, from 5300 L of skim milk and carried out structural studies that led to its structure identification and a synthesis that confirmed it. Kuhn proved the structure of riboflavin-5-phosphate which clarified its double role as an enzyme cofactor (coenzyme) and a vitamin. Similar efforts led to the isolation, structure determination, and synthesis of vitamin B6, pyridoxol. G. Domagk received the 1939 Nobel Prize in Medicine for discovering in 1932 that prontosil protected mice from fatal infections of Streptococci. By the end of 1936, sulfa drugs were well on their way to becoming the first antibiotics in wide clinical usage. They are structural analogs of p-aminobenzoic acid and inhibit the bacterial formation of folic acid (antimetabolite), which we receive from our diet, selectively preventing bacteria from replicating without exhibiting mammalian toxicity. Sulfonamides SO2NH2 H2N Prontosil-1938 2. Jacobsen Epoxidation -Unactivated alkenes Jacobsen J. Am. Chem. Soc. 1991, 113, 7063. Me d H disfavored by bulky phenyl groups Ph Ph Me H H R1 N b Me disfavored by phenyl group Mn O Me t side-on perpendicular approach to metal oxo species Cl O t Bu O Bu t R,R-1 S,S-2 S,S-3 S,S-4 S,S-5 Cl 2 3 4 5 + NaOCl 88% 54% 87% 56% 81% 5 mol% cat. Ph CH2Cl2 H 84% ee 49% ee 80% ee 55% ee 92% ee Me O 1R,2S 1S,2R 1S,2R 1S,2R 1S,2R H R2 O t Bu Bu 1 Styrene still low: 70% ee 64 Mn R2 c disfavored by tBu groups Me R1 N N 1 Ph H Ph N a Ph R Me H Me H R2 Me Me t Bu t Bu Oxidation Reactions Dale L. Boger catalyst 5 Ph p-ClC6H4 Me 84% 92% ee cat. 0.04 equiv Me 67% 92% ee 0.04 equiv 72% 98% ee 0.02 equiv 96% 97% ee 0.03 equiv 63% 94% ee 0.15 equiv 65% 89% ee 0.10 equiv O O NC O O Ph CO2Me The above studies focused on steric effects of the catalyst. _ Electronic effects of the catalyst Jacobsen J. Am. Chem. Soc. 1991, 113, 6703. R R N Hammett Plot N 2 O Mn O X tBu 1 2 Cl X O tBu log enant. 1 ratio R = Ph = (CH2)4 1a X = OMe 96% ee = Me 1b =H 1c = Cl 1d = NO2 22% ee 1e -0.4 -0.2 0 1. ∆∆G 2.0 kcal/mol 2. 1e / 1a krel = 4 0.8 0.4 0.6 0.2 σ (para substituent) - conformational effects on catalyst? - provoke changes in Mn–oxo bond length? reactivity vs transition state structure: - the less reactive catalyst providing a tighter, more product-like T.S. -Example 0.05 equiv cat. 5 equiv NMO 2 equiv m-CPBA NBOC –78 °C, 30 min 86% OBn OBn tBu H N Mn O tBu Cl O NBOC NBOC Dibal-H 70%, 92% ee H N OH O tBu Bu3P ADDP NBOC 72% OR H2, Pd-C 97% O R = Bn R=H Boger, Boyce Synlett 1997, 515. tBu 65 Modern Organic Chemistry The Scripps Research Institute 3. Chiral Dioxiranes O H O oxone, CH3CN O O _ O O O H O O O catalytic amounts Examples of trans and trisubstituted olefins Ph H 1 Ph Ph (pH 10, K2CO3) H O Ph 73% yield >95% ee C3H7 H C3H7 OTBS 80% yield H O OTBS 93% ee Ph Ph O O O O 1 Shi J. Am. Chem. Soc. 1996, 118, 9806. J. Am. Chem. Soc. 1997, 119, 11224. J. Org. Chem. 1997, 62, 2328; 1998, 63, 8475. J. Org. Chem. 1998, 63, 2948. (conjugated dienes) 69% yield 91% ee - pH 10 (K2CO3) suppresses Baeyer–Villiger reaction of ketone precursor. Reagent generation with H2O2−CH3CN via in situ generation of CH3C(=NH)O2H Shi Tetrahedron Lett. 1999, 40, 8721. Terminal, disubstituted alkenes via vinylsilanes Me Me Bu4NF 1 TMS TMS Ph 82% 74% Ph O 94% ee Shi J. Org. Chem. 1999, 64, 7675. Kinetic resolution OTMS Ph OTMS Ph 1 Me Ph O 94% ee OTMS Ph O + 49% conv. 96% ee kf/ks > 100 Shi J. Am. Chem. Soc. 1999, 121, 7718. 95% ee > 20:1 trans:cis Enol ethers and esters O O K2CO3−MeOH Ph Ph OH 88% ee 92% OAc 90% ee Shi Tetrahedron Lett. 1998, 39, 7819. O PhOCO OCOPh YbCl3 O 66 O OCOPh 97% ee 97% ee Shi J. Am. Chem. Soc. 1999, 121, 4080. O R Note the stereoelectronic O alignment of lone pair with spiro T.S. R consistent with O 91% ee, 66% TsOH Spiro vs O R O R Planar Transition State O K2CO3−MeOH Ph CH3NO2 77% CH2Cl2 84% 96% ee OAc 195 °C 90% Ph OH 94% ee Oxidation Reactions Dale L. Boger Yang J. Am. Chem. Soc. 1996, 118, 11311; 1998, 120, 5943. O X O O 10 mol% 1, 5 equiv oxone, NaHCO3 CH3CN–H2O, 25 °C X Ph Ph Ph 90–95% yield 32–76% ee 56% ee 1 X=H 47% ee 5 X = Me 2 X = Cl 76% ee 6 X = CH2OCH3 66% ee 3 X = Br 75% ee 7 X= Ph O OXONE = 2KHSO5•KHSO4•K2SO4 O 71% ee O 4 X=I X = SiMe3 8 32% ee 44% ee Review: Roberts Bioorg. Med. Chem. 1999, 7, 2145. 4. Polymer Supported Poly Amino Acids (CHCH2)n Ph polyleucine: 92% yield, 99% ee H2O2, NaOH Ph toluene, catalyst O O H N N H Ar General for n Ph H H O Ph O Ar : 83–98%; 87–99% ee O Itsuno J. Org. Chem. 1990, 55, 6047. Vega Angew. Chem., Int. Ed. Eng. 1980, 19, 929. D. Stoichiometric Asymmetric Epoxidation _ To date, ee's are modest (<10%) CO2H _ Not catalytic, but stoichiometric reagent CO3H Ewins J. Chem. Soc., Chem. Commun. 1967, 1085. Montanari J. Chem. Soc., Chem. Commun. 1969, 135. Rebek J. Am. Chem. Soc. 1980, 102, 5602. Curci J. Chem. Soc., Chem. Commun. 1984, 155. 1. Chiral Peracids 2. Chiral N-sulfamyloxaziridines Bn N N S Ph O O C6F5 H O _ 2 _ Good ee's Stoichiometric reagent 65% ee Davis J. Am. Chem. Soc. 1983, 105, 3123. Tetrahedron Lett. 1986, 27, 5079. Tetrahedron 1989, 45, 5703. E. Baeyer–Villiger and Related Reactions Comprehensive Org. Syn. Vol. 7, pp 671–688. Org. React. 1957, 9, 73; 1993, 43, 251. 1. Baeyer–Villiger Reaction O O R R2 O H O R1 O R A. Baeyer received the 1905 Nobel Prize in Chemistry for his work on dyes (indigo). He also discovered barbituric acid and named it after his girlfriend Barbara. O NaOH O R1 R O H + 1 R OH Baeyer, Villiger Ber. 1899, 32, 3625. Ber. 1900, 33, 858. 67 Modern Organic Chemistry The Scripps Research Institute Note: Sometimes the Baeyer–Villiger reaction is used not only for preparing carboxylic acids or esters, but also for ROH. _ Mechanism: (Peracid nucleophilic addition reaction) R R R1 O Peracids R1 O– O O O O R2 R O + R1 R2 O– _ O Notes: 1. Alkyl group that migrates does so with retention of configuration. 2. The more electron-rich (most-substituted) alkyl group migrates in preference (in general). talkyl > salkyl > benzyl > phenyl > nalkyl > methyl Thus, methyl ketones invariably provide acetates. _ Examples: O Friess J. Am. Chem. Soc. 1949, 71, 2571. CHO Ogata J. Org. Chem. 1969, 34, 3985. O C6H5CO3H, CHCl3, 25 °C O 71% O C6H5CO3H O OH + MeOH–H2O, 5 °C X X=H X = OCH3 0% 73% 90% 19% CH3CO3H Meinwald J. Am. Chem. Soc. 1960, 82, 5235. 2 h, 25 °C, 88% O O _ Nucleophilic attack from least hindered exo face. _ Most substituted (electron-rich) carbon migrates. O O Migrating C–C bond and O–O bond must be trans antiperiplanar O O– O R trans antiperiplanar _ _ Antiperiplanar arrangement of C–Rm bond and the breaking O–O bond (stereoelectronic requirement). Hydroxyl lone pair or O–H bond antiperiplanar to the migrating C–Rm bond. Me Sauers J. Am. Chem. Soc. 1961, 83, 2759. O O H O O R Rm Me Me CH3CO3H NaOAc, HOAc 5 d, 25 °C, 94% O Me O Me Me O O O O _ In contrast to simple expectations, the less electron-rich bond migrates due to stereoelectronic considerations. _ Nucleophilic attack from endo face, exo face blocked by Me's. _ Reaction much slower than norbornone. H O R trans antiperiplanar bonds 68 O X X H Oxidation Reactions Dale L. Boger – Bis(trimethylsilyl) Peroxide H O Me3Si–OO–SiMe3 H Me3SiOOSiMe3 H Noyori J. Org. Chem. 1982, 47, 902. Nozaki Bull. Chem. Soc. Jpn. 1983, 56, 2029. O O cat., CH2Cl2 75–80% H cat. = Me3SiSO3CF3, SnCl4, BF3•Et2O The Baeyer–Villiger oxidation proceeds in a regio- and chemoselective manner and competing epoxidation does not occur. 2. Benzylic Hydroperoxide Rearrangement – Alternative to Baeyer–Villiger Reaction Would be oxidized by peracid BF3•OEt2, H2O2 N H R N+ BF 3 H R OH O R = H, CH3 O + RLi or NaBH4 OH H O+ BF3 CH3O2C N H Boger, Coleman J. Org. Chem. 1986, 51, 5436. J. Am. Chem. Soc. 1987, 109, 2717. Tetrahedron Lett. 1987, 28, 1027. CH3O2C HN CH3O HO NH BF3•OEt2, H2O2 CH3 81% HN N R CH3O CH3 OH R=H R = CONH2 (PDE-I) R = COCH3 (PDE-II) OBn OH OBn OH Boger, Yohannes J. Org. Chem. 1987, 52, 5283. TsOH, H2O2 60% CO2CH3 CO2CH3 NHCBZ NHCBZ 3. Carboxy Inversion Reaction Me H O Me H Cl Ph O m-CPBA Me H With O O Ph O Ar O Ph Retention O –O + Me Ar Ph H O O O O Ar + O 69 Modern Organic Chemistry The Scripps Research Institute Heaney Synlett 1990, 533. O 4. Urea–H2O2: a safe alternative to H2O2 O– N+ O O N+ O– O S N Ph O N O Ph S O O O O OH OH 6 H2N 6 HO-OH NH2 O O OH O O O O O OMe O O – – – – O OMe Alternative to 90% H2O2 as a source of anhydrous H2O2. White, crystalline powder. Commercially available. Dry over CaCl2 in a desiccator. Friedrich Wohlers' (1800–1882) synthesis of urea, an organic substance, from inorganic materials in 1828 dispelled the belief that biotic powers were needed to produce organic substances and is considered the birth of synthetic organic chemistry. This was first described in a letter to J. J. Berzelius. In a joint paper, the two wrote: "sugar, salicin (the natural product precursor to aspirin), and morphium will be produced artificially. Of course, we do not know the way yet by which the end result may be reached since the prerequisite links are unknown to us from which these materials will develop-however, we will get to know them." F. Beckmann Rearrangement and Related Reactions _ An analogous rearrangement reaction can be utilized to prepare lactams and amides. Heldt Org. React. 1960, 11, 1. 1. Beckmann Rearrangement Gawley Org. React. 1988, 35, 1. Comprehensive Org. Syn., Vol. 7, pp 689–702. O H H O Ph H O N S N O N 12 h, 0 °C O 95% H2O _ Prepared from the oxime. Beckmann Ber. 1886, 19, 988. _ A wide range of leaving groups and catalysts have been utilized. 1. Group anti to oxime leaving group migrates. 2. The alkyl group migrates with retention of configuration. O 70 H2NOSO3H HCO2H 97% N H 95% O + NH O 5% Oxidation Reactions Dale L. Boger Note: Isomerization of oxime or its activated derivative may occur under the reaction conditions and fragmentation to a nitrile may compete when the migrating center is 3°. N OH NH + O NH O retention POCl3, pyridine SOCl2, pyridine 20% aq. H2SO4 HCl / Et2O 98% 90% 43% 5% 2% 10% 57% 95% 2. Curtius Rearrangement Curtius Ber. 1890, 23, 3023. (initially not recognized) Smith Org. React. 1946, 3, 337. Comprehensive Org. Syn., Vol. 6, pp 806–816. O RCO2H H RNH2 or R N H2O or R N C O O R O _ (PhO) P(O)N (DPPA) is a useful reagent for the direct conversion of carboxylic acids to acyl azides 2 3 under in situ conditions for the rearrangement. Shiori, Yamada Tetrahedron 1974, 30, 2151. _ R group migrates with retention of configuration. R N3 ROH -Examples NO2 NO2 MeO MeO N N CO2Me N N CO2Me DPPA, Et3N HO2C BnO Me H2N BnO MeO MeO OMe MeO2C N Me OMe MeO2C CO2Me N CO2Me DPPA, Et3N HO2C Br Br Me N BnO Boger, Panek (streptonigrin) J. Am. Chem. Soc. 1985, 107, 5745. N OMe DPPA, Et3N HO2C MOMO H2N Br C6H6, reflux 72% Me C6H6, reflux 86% Br Me N BnO Boger (lavendamycin) J. Org. Chem. 1985, 50, 5782. N H2N MOMO OMe Me Boger (streptonigrone) J. Am. Chem. Soc. 1993, 115, 10733. MeO MeO OMe OMe 71 Modern Organic Chemistry The Scripps Research Institute n X CO2H X DPPA, Et3N NHBOC R N X O t BuOH OBn OBn O n = 1–3 X = H, Br, CN, OMe Boger J. Org. Chem. 1995, 60, 1271; 1996, 61, 1710 and 4894; 1997, 62, 5849. J. Am. Chem. Soc. 1994, 116, 11335. Synlett 1997, 515. 3. Hofmann Rearrangement Lane Org. React. 1946, 3, 267. Comprehensive Org. Syn., Vol. 6, pp 800–806. R O O O R NH2 N H Br R O C N R N Br Hofmann Ber. 1881, 14, 2725. N N NaOBr, CH3OH –40 °C; then 60 °C CONH2 N Boger, Coleman (PDE-I, PDE-II, CC-1065) J. Org. Chem. 1986, 51, 3250. J. Am. Chem. Soc. 1987, 109, 2717. NHCO2Me N OTBS OTBS >80% MeO MeO _ Reagents employed include basic hypohalides, Pb(OAc) , PhI(OCOCF ) , PhIO. 4 3 2 _ R group migrates with retention of configuration. 4. Schmidt Reaction Schmidt Angew. Chem. 1923, 36, 511. Wolff Org. React. 1946, 3, 307. Comprehensive Org. Syn., Vol. 6, pp 817–821. The Schmidt Reaction is a general name for what are three individual reactions: A. Conversion of Ketones to Amides H2O O OH HN3 and Protic or Lewis Acid R = alkyl, aryl catalyst R R R R N H N N –H2O –H+ R N N N R O tautomerization R N H R - Most studied of Schmidt variants, similar to Beckmann Rearrangement. - Asymmetric variant (Aube) utilizes chiral alkyl azide donors which provide products in high diastereoselectivity. - Bicyclic ketones slightly favor migration of less substituted group, opposite of Beckmann. - Reactivity: dialkyl ketone > alkyl,aryl ketone > diaryl ketone > carboxylic acid or alcohol. O Bn CO2Et 72 NaN3, 2.5 equiv MeSO3H, 9 equiv CHCl3, reflux, 83% >95% ee O NH Bn Georg Bioorg. Med. Chem. Lett. 1991, 1, 125. CO2Et retention of configuration Oxidation Reactions Dale L. Boger O OH + N3 1) BF3•OEt2; 2) NaHCO3, 90%; 3) PCC 4) NaH, THF, 57% t Bu O NH t N N O N Bu Aube J. Am. Chem. Soc. 1995, 117, 8047. one diastereomer t Bu B. Conversion of Carboxylic Acids to Amines O H+ cat. + HN3 R OH H2O R N C O R–NH2 - Acid catalyst usually H2SO4, PPA, TFA–TFAA, or sometimes Lewis acid. - Good results when R = alkyl, hindered alkyl or aryl. - Advantage in process length over Hofmann and Curtius Rearrangements, but more drastic conditions. - Mechanism controversy. Hayes J. Org. Chem. 1979, 44, 3682. Koldobskii Russ. Chem. Rev. 1978, 47, 1084. H O O O O H+ + HN3 R OH –H2O R R N N N R N N N R–NH2 H CO2H CO2H Me R N C O H NaN3, H2SO4 CHCl3, 76% NH2 NH2 Me C. Conversion of Aldehydes to Nitriles O H+ cat. + HN3 R H R Sato Tetrahedron: Asymmetry 1992, 3, 5. N - Acid catalyst usually H2SO4, can be Lewis acid. - Schmidt reaction is the usual byproduct under these conditions to provide formamide. - More common method is to convert aldehyde to oxime with hydroxylamine, followed by dehydration. - Aromatic aldehydes are good substrates. OHC Br MeO HO NC NaN3, SiCl4 MeCN, 50% Elmorsy Tetrahedron Lett. 1995, 36, 2639. Br N H CHO NaN3, H2SO4 70% MeO N H CN Houff J. Org. Chem. 1957, 22, 344. HO The airbag restraint system in cars is inflated in a fraction of a second by the release of N2 gas. The nitrogen comes from explosion of a mixture of NaNO3 and amorphous boron initiated by electronic priming with NaN3. 73 Modern Organic Chemistry The Scripps Research Institute 5. Lossen Rearrangement Lane Org. React. 1946, 3, 269 and 366. Comprehensive Org. Syn., Vol. 6, pp 821–823 (basic conditions) pp 824–825 (neutral/acidic) Lossen Liebigs Ann. Chem. 1872, 161, 347. O OH R1 N H Hydroxamic acid -prepared readily from carboxylic acids, esters or acyl halides O F O H3NOH NH OH F O R2X R1 N H O base OR2 R1 TsCl; NaOH, H2O 80% O F OH F Braish Syn. Commun. 1992, 22, 3067. NH2 H H O O R1 N C O N OR2 - R2X usually AcCl, ArSO2Cl, RPO2Cl - rate of reaction proportional to the acidity of leaving group conjugate acid - R1 migrates with retention of configuration O H –OR2 NH2 NaOH, H2O 80% O N O S O H Bauer J. Org. Chem. 1959, 24, 1293. OH O G. Olefin Osmylation (Dihydroxylation) epoxide opening RCO3H OH OH NaOH O O versus O OH H O O + Os O O Os(VIII) electrophilic, large reagent 1. Mechanism H O O Os O O H2O H O O Os O O OH HO O Os O HO Os(VI) Diastereospecific cis-1,2-diol First use: Criegee Justus Liebigs Ann. Chem. 1936, 522, 75. Milas J. Am. Chem. Soc. 1936, 58, 1302. OO Os O O [3 + 2] or :L O O O Os O product Sharpless J. Am. Chem. Soc. 1977, 99, 3120. Jorgensen Chem. Rev. 1990, 90, 1483. Sharpless Angew. Chem. Int. Ed. Eng. 1993, 32, 1339. L [3 + 2] Mechanism: Boeseken Recl. Trav. Chim. 1922, 41, 199. Criegee Angew. Chem. 1938, 51, 519. Criegee Justus Liebigs Ann. Chem. 1942, 550, 99. Comprehensive Org. Syn., Vol. 7, pp 437–448. Chem. Rev. 1980, 80, 187. [2 + 2] Mechanism: 2. Scope OH + H [2 + 2] + trans-1,2-diol R 1. OsO4 is an electrophilic reagent, and it behaves as a large reagent. 2. Strained, unhindered olefins react faster than unstrained, sterically hindered olefins. 3. Electron-rich olefins react faster than electron-deficient olefins. 4. Diastereospecific, with attack on the C=C from the least hindered face. 74 Oxidation Reactions Dale L. Boger - but OsO4 is expensive, volatile, and toxic - various improvements: 1) only catalytic amount of OsO4 used 2) use of an equivalent osmium salt (K2OsO2(OH)4) Examples: H2O2, cat. OsO4 tBuOOH, cat. OsO O J. Am. Chem. Soc. 1936, 58, 1302; 1937, 59, 2345; Synthesis 1989, 295. Sharpless J. Org. Chem. 1978, 43, 2063. 4 or N O (NMO) N O Tetrahedron Lett. 1976, 1973; Tetrahedron Lett. 1980, 21, 449. Note: Johnson–Lemieux Oxidation (NaIO4 and catalytic OsO4 cleaves C=C bonds, forms diol and then aldehyde: J. Org. Chem. 1956, 21, 478). R HO H R cat. OsO4 NaIO4 R OH H R O 2 R H -Alternative reagents to OsO4: KMnO4: Synthesis 1987, 85. Yields rarely as high as OsO4 but less hazardous and less expensive especially for large scale RuO4 or RuO2–2H2O/RuCl3–H2O + cooxidant More vigorous than OsO4 and olefin cleavage is observed 3. Diastereoselectivity a. Endocyclic Olefins OH OsO4 OH from least hindered side OsO4 -endocyclic allylic alcohols OsO4 OH from least hindered side OsO4 120o OH 100% OH OH OH Note: m-CPBA comes in cis to the allylic -OH, but OsO4 comes in trans to the allylic -OH. So, we obtain: OsO4 m-CPBA HO OH OsO4 m-CPBA OH HO OH OsO4 100% HO HO OH x HO OH x HO OH OsO4 OsO4 75 Modern Organic Chemistry The Scripps Research Institute Predominant conformation at 25 °C OH OH HO HO OsO4 OH OH HOHO OH > 50:1 OH OsO4 trans to allylic alcohol OH OH OsO4 OH 4:1 OH b. Acyclic Systems - OsO4 is delivered from face opposite the allylic hydroxyl group in the preferred (H-eclipsed) m-CPBA (cis to allylic alcohol 120°) ground state conformation. R2 HO R1 H HO R2 R4 R3 120o R4 R3 H R1 OsO4 (trans to allylic alcohol 120°) Tetrahedron Lett. 1983, 24, 3943, 3947. Tetrahedron 1984, 40, 2247. - Kishi model (empirical model). So, for the OsO4 oxidation: HO R2 OH OH 4 R or 1 3 H R 2 R3 R 1 R R 1 OH OH R OH R1 H 3 - Preferred ground state conformation (higher diastereoselection when R is not H). - Also observed with allylic ethers HO R2 OsO4 R4 R3 H R2 OsO4 OR R4 R4 R3 OH OH HO OR OH RO RO RO OH OH erythro threo : R = Bn 8.9 1 : R = CO2CH3 2 1 : R = COC6H4-NO2 1 1 electronic effect of alkoxy substituent directs osmylation to reverse face 1) electronic effects: 2) steric effects: OR OH + OBn OsO4 BnO OBn OH BnO 7:1, modest selectivity OH H - Higher diastereoselectivity of Z vs. E isomer implies eclipsed conformation important. OH OX R2 R1 R2 OX R1 OsO4 R2 R1 OH OsO4 < 8:1, modest selectivity (anti 1,2-diol relationship) OH OX R2 R1 OH 76 OX high selectivity Oxidation Reactions Dale L. Boger OX OH OX OsO4 moderate to high selectivity R1 R1 HO Me 1 - As R increases in size relative to OX, the selectivity increases. - X-effect (steric effect): smaller X provides better selectivity. - There are additional empirical models used to explain the acyclic allylic alcohol induced diastereoselectivity: H R2 1. Houk Model (inside alkoxy model): Science 1986, 231, 1108. OX R3 R4 non ground state conformation R1 H 2. Vedejs Model: J. Am. Chem. Soc. 1989, 111, 6861. R3 4 OX R 2 R 1 R R3 XO R4 3. Panek: J. Am. Chem. Soc. 1990, 112, 4873. H2 R SiR3 t ax. axial attack OsO4 Bu R1 eq. O NO OsO4 is a large reagent, prefers equatorial attack H H H CH3 H H OH OH OCH3 OCH3 OAc SCH3 OsO4 axial R2 RO OH R2 equatorial attack OH OH + tBu R1 (NMO) R1 Exception: tBu H2O–acetone R2 selectivity increases: a) OH > OR b) now E > Z c) with very large R1: inside alkoxy or anti Si c. Exocyclic Olefins: Vedejs J. Am. Chem. Soc. 1989, 111, 6861. H H OsO4 is large reagent; steric effects between reagent & allylic substituent are important factors OH R2 R1 R2 ax. eq. Consistent with Kishi empirical model H OH OCH3 OCH3 OAc SCH3 H CH3 H CH3 CH3 H 14 <5 <5 20 8 <5 33 14 88 90 67 92 86 95 95 80 92 95 67 86 12 10 33 8 Inconsistent with Houk model H-bonding? Equatorial attack predominates, except with axial OCH3, OAc, SMe: In these cases, equatorial attack further retarded and proceeds at even slower rate (kinetic studies) d. H-Bonding and Directed Dihydroxylation Cyclic allylic alcohols OH OH OsO4 OH OH OH + t Bu t Bu axial OH OH t Bu cat. OsO4, NMO, acetone–H2O 94:6 (90%) 1 equiv OsO4, CH2Cl2 (anhydrous) 75:25 (97%) OH tBu OH competing H-bonding delivery reduces diastereoselectivity 77 Modern Organic Chemistry The Scripps Research Institute TMEDA OR OR OR OH N N O Os O O O OH + tBu tBu tBu OH R = H: cat. OsO4, NMO, acetone–H2O 1 equiv OsO4, CH2Cl2 cat. OsO4, Me3NO, CH2Cl2 1 equiv OsO4, TMEDA, CH2Cl2, –78 °C R = CH3: 1 equiv OsO4, CH2Cl2 85:15 63:37 45:55 4:96 95:5 tBu OH OH cat. OsO4, NMO, acetone–H2O 1 equiv OsO4, TMEDA, CH2Cl2, –78 °C OH + OH 80:20 12:88 (76%) OH OH H-bond delivery OH OH HO OH HO OH + OH OH cat. OsO4, NMO, acetone–H2O 1 equiv OsO4, TMEDA, CH2Cl2, –78 °C 75:25 5:95 (54%) H-bond delivery OH HO HO OH HO O OH HO cat. OsO4, NMO, acetone–H2O 1 equiv OsO4, TMEDA, CH2Cl2, –78 °C O 94:6 14:86 HO + HO (63%) OH O H-bond delivery - OsO4–TMEDA can also be utilized to effect chemoselectivity by preferentially oxidizing allylic alcohols over unactivated (non allylic -OH) double bonds. Donohoe Tetrahedron Lett. 1996, 37, 3407; Tetrahedron Lett. 1997, 38, 5027. - Catalytic procedures require QNO (quinuclidine N-oxide) and a strong H-bond donor (−NHCOCCl3) NHCOCCl3 tBu NHCOCCl3 OH tBu cat. OsO4, NMO, acetone–H2O, 25 °C cat. OsO4, Me3NO, CH2Cl2, 25 °C cat. OsO4, QNO, CH2Cl2, 25 °C 78 NHCOCCl3 OH + OH 1.6:1 (96%) 1:6 (81%) 1:13 (77%) Donohoe Tetrahedron Lett. 2000, 41, 4701. O (91%) 120° OsO4 angle (45%) competing H-bond delivery equatorial OH (55%) H-bond delivery (91%) no H-bonding OH OH HO OH H tBu OH H-bond delivery Oxidation Reactions Dale L. Boger Acyclic allylic alcohols OH OH OH OH OH Pr + cat. OsO4, NMO, acetone–H2O 1 equiv OsO4, TMEDA, CH2Cl2, − 78 °C OH 80:20 (86%) 25:75 (84%) Pr Pr OH iPr OsO4 H-bond delivery (empirical model) OH OH OH N N Os O H O O O O R H H OH OH + Me Me cat. OsO4, NMO, acetone–H2O 1 equiv OsO4, TMEDA, CH2Cl2, − 78 °C Pr OH Me 90:10 (71%) 67:33 (75%) OH OH OH Pr R + R Pr cat. OsO4, NMO, acetone–H2O 1 equiv OsO4, TMEDA, CH2Cl2, − 78 °C 38:62 (76%) 4:>96 (74%) R = iPr: cat. OsO4, NMO, acetone–H2O 1 equiv OsO4, TMEDA, CH2Cl2, − 78 °C 20:80 (85%) 4:>96 (79%) HO Bu OH + Bu OH cat. OsO4, NMO, acetone–H2O 1 equiv OsO4, TMEDA, CH2Cl2, − 78 °C H H Pr R OH Bu R OH R = Pr: HO N N Os O O H O O O OH OH OH OH OH OH N N Os O O H O O O H 34:66 (96%) 4:>96 (78%) H R - Results with OsO4/TMEDA are analogous to the m-CPBA epoxidation of acyclic allylic alcohols and are derived from a H-bonded delivery from a H-eclipsed conformation. Donohoe Tetrahedron Lett. 1999, 40, 6881. 4. Comparison of Diol Stereochemistry Generated by Different Methods a. m-CPBA H m-CPBA O trans-diol OH H -Epoxidation from least CH3 H hindered face CH3 H2O H CH3 m-CPBA H OH H+, H2O O trans diaxial opening of epoxide CH3 H 79 Modern Organic Chemistry The Scripps Research Institute b. OsO4 CH3 H OH H OsO4 H OsO4 H - cis dihydroxylation from least hindered face (OsO4 is a large reagent) c. Via Bromohydrin CH3 OH H Br2 or NBS OH H+, H2O O H2O; NaOH H cis-diol trans-diol OH - Epoxidation on most hindered face of olefin (to give different epoxide from m-CPBA oxidation), trans diaxial ring opening (to give same hydrolysis product as from m-CPBA oxidation) CH3 OH trans diaxial trans diaxial H CH3 CH3 OH opening of epoxide attack O H CH H 3 Br CH H 3 CH3 CH3 Br H2O OH H bromonium ion H H formation on least CH3 Br hindered face H -Corey Tetrahedron Lett. 1982, 23, 4217: cis dihydroxylation from most hindered olefin face. Br Br OH O O NaH CN O CN 1) H O+ 3 O 2) NaOH H d. Prevost Compt. rend. 1933, 196, 1128. OH I2 PhCO2Ag Me O2CPh trans H Me I H H Ph Me Me O O anti opening H e. Woodward J. Am. Chem. Soc. 1958, 80, 209. Ph Me O O Me NaOH O H2O OCOPh trans-dibenzoate Me 1) I2 PhCO2Ag OH OH2 O H2O Me trap Ph Me C O O OH Me -Same intermediate as Prevost, but different conditions (+ H2O) 80 trans-diol - Complements OsO4 reaction (i.e. cis dihydroxylation from most hindered face) OH H Me O - Neighboring Group Participation OH 2) H2O, ∆ Ph OH Ph Me O PhCO2 I OH NaOH H2O cis-diol Oxidation Reactions Dale L. Boger H. Asymmetric Dihydroxylation Reaction Catalyzed by OsO4 and Related Reagents 1. Catalytic Methods Sharpless Catalytic Asymmetric Dihydroxylation (AD) Reaction, Review: Chem. Rev. 1994, 94, 2483. J. Am. Chem. Soc. 1980, 102, 4263. J. Am. Chem. Soc. 1988, 110, 1968. J. Am. Chem. Soc. 1989, 111, 1123. Tetrahedron Lett. 1989, 30, 2041. Tetrahedron Lett. 1990, 31, 2999, 3003, 3817. J. Org. Chem. 1991, 56, 4585. R1 R2 DHQD: dihydroquinidine (R = H) R1 R2 H R3 H R3 J. Org. Chem. 1992, 57, 2768. J. Am. Chem. Soc. 1992, 114, 7568, 7570. Tetrahedron Lett. 1993, 34, 7375. J. Org. Chem. 1993, 58, 3785. J. Am. Chem. Soc. 1994, 116, 1278. Angew. Chem., Int. Ed. Eng. 1996, 35, 448. Et Et DHQD R2 R1 HO K2OsO2(OH)4 or OsO4 K3Fe(CN)6, K2CO3 tBuOH-H O 2 H 3 H R R3 OH HO AlkO OAlk N MeO O R H R2 N N OH First Generation Ligands (Alk = DHQ or DHQD) AQN O OAlk PHN MEQ OAlk N N N OMe R1 PYR Ph AlkO N R O H DHQ Second Generation Ligands (Alk = DHQ or DHQD) PHAL DHQ: dihydroquinine (R = H) CLB Cl Me N N O Ph OAlk OAlk OAlk O OAlk Catalyst: OsO4 (1.25 mol%) or K2OsO2(OH)4 (0.05 mol%, nonvolatile) Solvent: tBuOH or cyclohexane, H2O, K2CO3 Ligands: DHQD or DHQ (0.2 to 0.004 mol%) Oxidant to recycle OsO4: K3Fe(CN)6 Note: Ligand accelerated catalysis, Sharpless Angew. Chem., Int. Ed. Eng. 1995, 34, 1059. -Addition of pyr led to marked increase in rate of formation of cyclic osmate ester from alkene and OsO4. First noted by Criegee Justus Liebigs Ann. Chem. 1936, 522, 75; 1940, 550, 99. -The "Criegee effect" (or the facilitation of osmylation step by nitrogen donor) has been examined with quinuclidine and cinchona alkaloid ligands: Sharpless J. Am. Chem. Soc. 1994, 116, 1278, 8470. -Results: Good to excellent selectivity (ee%) for: R1 R R1 R2 R2 R3 R2 84–93% ee 74–93% ee 82–88% ee 94–99% ee R2 Poor selectivity for: R1 R1 R3 R1 R4 R2 81 Modern Organic Chemistry The Scripps Research Institute 2. Stoichiometric methods Ph Ph -Tomioka J. Am. Chem. Soc. 1987, 109, 6213. N Using 1 as a chiral ligand, good selectivity for: R1 R3 R R2 N 1 Ph Ph Poor selectivity for: O R2 R1 R1 R2 - Product does not seem to reflect most favorable steric approach for [3 + 2] cycloaddition but is more easily rationalized by [2 + 2]. H H OsO4 (+)-1 Ph H O O O H R2 Ph Os Ph R1 R3 N O N Ph Ph X-ray structure OsO4 (–)-1 stoichiometric reagent (LiAlH4 to reduce off osmate ester) O Ph CO2Me Ph Et Ph ee: 90% Ph Ph 97% 95% MeO2C Et 90% 93% 83% 41% 26% -Corey J. Am. Chem. Soc. 1989, 111, 9243. Ph R2 Ph H Ligand accelerated reaction OsO4, –90 °C, 2 h R2 NH HN N O N Os R1 O O O H C2-symmetry in ligand Os (6 coordinate) nucleophilic equatorial oxygen electrophilic axial oxygen Ph R1 92% ee 82–98% ee 60% ee -Other stoichiometric reagents: Chem. Lett. 1986, 131. Chem. Commun. 1989, 665. Tetrahedron Lett. 1986, 27, 3951. J. Org. Chem. 1989, 54, 5834. Tetrahedron Lett. 1990, 31, 1741. Tetrahedron 1993, 49, 10793. 3. Examples -Total synthesis of Bouvardin and RA-VII: Boger J. Am. Chem. Soc. 1994, 116, 8544. O Ti(OiPr)4 OH I (+)-DIPT, tBuOOH I 90%, >98% ee PDC (AE) OH R CO2H I CO2CH3 I 82 90%, >95% ee (AD) OH CO2CH3 AD mix-α I NHMe R = CH2OH R = CO2H OH OR R=H R = SO2Ar CO2CH3 NaN3 I N3 Ph Oxidation Reactions Dale L. Boger -Vancomycin central amino acid: Boger J. Org. Chem. 1996, 61, 3561; J. Org. Chem. 1997, 62, 4721. OCH3 OBn BnO AD-mix-α BnO OCH3 OBn 1) DPPA BnO Ph3P–DEAD 97%, 87% ee (AD) TBDMSCl 85% BnO OTBDMS H2N CBZN(Cl)Na 4 mol% K2OsO2(OH)4 OCH3 OBn BnO H NHCBZ OCH3 OBn BnO + NHCBZ HO OH CBZNH : 1 7 69%, 96% ee 64%, >99% ee recrystallization 1× O tBuO C 2 R=H R = TBDMS 5 mol% (DHQD)2PHAL 50% nPrOH/H2O (AA) O OCH3 OBn BnO 2) Ph3P, 65% OR HO OCH3 OBn OCH3 OBn -Luzopeptin Htp amino acid: Boger J. Org. Chem. 1998, 63, 6421; J. Am. Chem. Soc. 1999, 121, 1098. OH AD-mix-α 1) NaN3 CO2Bn 80%, >99% ee 2) Ph3P O OH O OH CO2Bn 87 × 93% CO2Bn N CO2Bn (AD) R O O N OR NH2 O R = H NosCl R = Nos 68% -Prediction of absolute stereochemistry is so firmly documented that it may be used to assign absolute stereochemistry. However, there are a few rare exceptions to be aware of, for example: Boger J. Am. Chem. Soc. 1997, 119, 311. Boger J. Am. Chem. Soc. 1996, 118, 2301. NCOPh reversed enantioselectivity OR NHCOPh SnBu3 NC OBn NCOPh BF3 Et2O 89% HO NHCOPh TBDMSOTf (DHQD)2PHAL NC OBn 70%, 78% ee NHCOPh (AD) R=H TsCl, Bu2SnO R = Ts 94% 75% TBDMSO NHCOPh NaH 97% NC OBn NHCOPh TBDMSO OTs TBDMSO NC cat OsO4 NMO, 95% or OBn NHCOPh NC PhCON H NCOPh NH2NH2 EtOH 65% OBn Chiralcel OD resolution, α = 2.30 NC RN H NR (+) and ent-(–)duocarmycin A OBn BOC2O; TFA, 88% R=H R = BOC -Appears to be general for the class of olefins ArCH2CH=CH2 83 Modern Organic Chemistry The Scripps Research Institute I. Sharpless Catalytic Asymmetric Aminohydroxylation (AA) - Reviews: Transition Metals for Fine Chemicals and Organic Synthesis; Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim, 1998. Angew. Chem. Int., Ed. Eng. 1996, 35, 451, 2810 and 2813. Angew. Chem. Int., Ed. Eng. 1997, 36, 1483 and 2637. J. Am. Chem. Soc. 1998, 120, 1207. Tetrahedron Lett. 1998, 39, 2507 and 3667. - Development of AA reaction (reactions generally run with 4 mol% catalyst (K2OsO2(OH)4) and 5 mol% ligand ((DHQ)2PHAL or (DHQD)2PHAL): in situ generation and reactions of RN=OsO3. a. Sulfonamide variant -α,β-unsaturated esters: CO2CH3 Ph R= p-Tol 1:1 CH3CN–H2O Me 1:1 nPrOH–H2O Me3Si O O S HN R CO2CH3 Ph OH O Cl R S N O Na cat. K2OsO2(OH)4 (DHQ)2PHAL Reductive cleavage of sulfonamides requires harsh conditions (Birch 95% ee (65%) reduction, Red-Al, or 33% HBr/AcOH). 70% ee (48%) Sulfonamide cleaved with Bu4NF in CH3CN 83:17 regioselectivity 81% ee (64%) 1:1 nPrOH–H2O -α,β-unsaturated amides: no enantioselection, AA gives racemic products. -reaction works well without a ligand. TsN(Cl)Na cat. K2OsO2(OH)4 TsHN O Ph NMe2 tBuOH–H O 2 O Ph Ts N 1) MsCl, Et3N NMe2 Ph NMe2 2) Et N or DBU 3 O OH 5:1 regioselectivity, racemic (94%) Cl N b. Carbamate variant RO -α,β-unsaturated esters: Ph R= Bn Et tBu 84 Na HN Ph cat. K2OsO2(OH)4 (DHQ)2PHAL 1:1 nPrOH-H2O 1:1 nPrOH-H2O 2:1 nPrOH-H2O CO2iPr OR CO2CH3 O CO2CH3 OH 94% ee (65%) 99% ee (78%) 78% ee (71%) Me3Si Ph O Cl N O Amine can be deprotected by hydrogenolysis. Amine can be deprotected by acid. O Na HN O cat. K2OsO2(OH)4 (DHQ)2PHAL Ph O CO2iPr OH SiMe3 99% ee (70%) Carbamate cleaved with Bu4NF in CH3CN. Oxidation Reactions Dale L. Boger -Reversal of regioselectivity using (DHQ)2AQN ligand CO2CH3 Ph NHCBZ OH 3 equiv BnOC(O)N(Cl)Na cat. K2OsO2(OH)4 BnO 1:5 nPrOH–H2O CO2CH3 Ph cat. K2OsO2(OH)4 (DHQ)2AQN -Styrenes: BnO OH CBZN(Cl)Na NHCBZ 95% ee (58%) 79:21 regioselectivity OH NHCBZ + A B BnO -Influence of ligand and solvent on regioselectivity: solvent ligand (DHQ)2PHAL nPrOH–H2O (DHQ)2AQN CH3CN–H2O 97% ee (76%) 88:12 A:B A:B 88:12 25:75 - However, enantioselectivities for B regioisomers are poor (0–80% ee). t - Bu carbamate based AA affords slightly poorer regioselectivities and yields compared to benzyl carbamate series, but enantioselectivities approach 100% in both cases: OH NHBOC tBuO CN(Cl)Na NHBOC OH 2 + 99% ee (68%) cat. K2OsO2(OH)4 C D 83:17 C:D BnO BnO BnO 2:1 nPrOH–H2O O (DHQ)2PHAL HN OR OH RO2CN(Cl)Na R= cat. K2OsO2(OH)4 (DHQ)2PHAL 99% ee (70%) >10:1 regioselectivity 98% ee (70%) 88:12 regioselectivity 97% ee (48%) 86:14 regioselectivity Bn tBu Me3Si -Oxidation of α-arylglycinols to corresponding α-arylglycines, see: Boger J. Org. Chem. 1996, 61, 3561. NHCBZ OH NHCBZ TEMPO, NaOCl 80% COOH BnO BnO 80:20 mixture of regioisomers -Teicoplanin α-arylglycines Boger J. Am. Chem. Soc. 2000, 122, 7416. BOCNClNa K2OsO2(OH)4 (DHQD)2PHAL 75%, 97% ee F HO NHBOC F CBZNClNa K2OsO2(OH)4 MeO HO (DHQ)2PHAL OBn 78%, > 99% ee MeO NHCBZ OBn NO2 NO2 c. Amide variant Ph CO2iPr AcNHBr/LiOH Ph NHAc CO2iPr cat. K2OsO2(OH)4 OH 1:1 tBuOH–H2O 99% ee, 81% (DHQ)2PHAL (>10:1 regioselectivity) 10% HCl Ph NH3Cl CO2H OH 77% overall 85 Modern Organic Chemistry The Scripps Research Institute J. Ozonolysis Comprehensive Org. Syn., Vol. 7, pp 541–591. Introduced by Harries Justus Liebigs Ann. Chem. 1905, 343, 311. P. Crutzen, M. Molina, and F. S. Rowland shared the 1995 Nobel Prize in Chemistry for their work in atmospheric chemistry, particularly concerning the formation and decomposition of the protective ozone layer. -Electrophilic reagent, rate: electron-rich > neutral > electron-deficient olefin -Chemoselectivity: OMe O O3, MeOH; Me2S CO2Me CO2Me H 85–90% CO2Me CHO -O3 exhibits very light blue color, ozonolysis complete when color persists -Controlled ozonolysis (very reactive agent): KI–starch: characteristic blue color O3 sensitive dyes with varying reactivities and detect color disappearance: Mitscher Synthesis 1980, 807. -Oxidative workup: H2O2, KMnO4, Cr(VI), RuO4 -> ketones, carboxylic acids NaBH4, LiBH4 -> alcohols Me2S, Ph3P, Zn/HOAc, H2N , H2, Pd/CaCO3 -> aldehydes, ketones S H2N -Reductive workup: -Mechanism, Review: Criegee Angew. Chem., Int. Ed. Eng. 1975, 14, 745. O R R O O 1,3-dipolar carbonyl oxide O O O O O + (Criegee zwitterion) R cycloreversion 1,3-dipolar R O R R R cycloaddition R RR in situ R R 1,3-dipolar reduction O O cycloaddition O O -Zn/HOAc Note: Alternative recombination -Me2S RR Note: Ozonide explosive mechanisms observed with -Ph3P when isolated or concentrated. ozonide ketone vs. aldehyde ozonides. R R 86 R R Oxidations of Alcohols Dale L. Boger V. Oxidation of Alcohols Comprehensive Org. Syn., Vol. 7, pp 251–327. Stoichiometries: 3 R2CHOH + 2 CrO3 + 6 H+ 5 R2CHOH + 2 MnO4 + 6 H+ 3 R2CHOH + 2 MnO4 3 R2C=O + 2 Cr3+ + 6 H2O 5 R2C=O + 2 Mn2+ + 8 H2O 3 R2C=O + 2 Mn2+ + 2 H2O A. Chromium-based Oxidation Reagents 1. Collins Reagent: Collins Tetrahedron Lett. 1968, 3363; Org. Syn. 1972, 52, 5. -CrO3–pyr2, alkaline oxidant -Hygroscopic, red crystalline complex -Can also be isolated and stored, but usually generated in situ by CrO3 + pyr (Sarett Reagent) J. Am. Chem. Soc. 1953, 75, 422. Note: Add CrO3 to pyr, not pyr to CrO3 (inflames) -Good for acid sensitive substrates -Ratcliffe modification: in situ preparation and use in CH2Cl2, J. Org. Chem. 1970, 35, 4000. H OH RCH2OH CrO3−pyr2 RCOOH RCHO no over oxidation RCH2OH O O Provide a mechanism for this transformation. CH2Cl2, DMF R HOAc, tBuOH O General except for ArCHO Corey, Samuelsson J. Org. Chem. 1984, 49, 4735. Review of Cr(VI)-amine oxidizing agents: Luzzio Org. React. 1998, 53, 1. 2. Jones Reagent: Jones J. Chem. Soc. 1953, 2548; J. Chem. Soc. 1946, 39. CrO3 in aq. H2SO4/acetone H2O H2Cr2O7 2 H2CrO4 -Acetone solvent serves to protect substrate from over oxidation -Not good for oxidations of acid sensitive substrates H OH RCH2OH O H2O RCHO R OH H OH RCOOH -Acidic oxidation conditions, H+ catalyzed reactions possible -Another common side reaction for primary alcohol oxidation: RCH2OH RCHO RCH2OH Solution: run under dilute reaction conditions to circumvent esterification OCH2R H OH hemiacetal R RCOOCH2R ester -Brown oxidation: run under two phase reaction conditions, Et2O–H2O, J. Org. Chem. 1971, 36, 387. -[R4N]2Cr2O7 Synth. Commun. 1980, 75. Oxidation of allylic/benzylic alcohols under neutral conditions. 87 Modern Organic Chemistry The Scripps Research Institute 3. Pyridinium Chlorochromate (PCC): Corey and Suggs Tetrahedron Lett. 1975, 2647. O Cr Cl O O H N - Chloride facilitates formation of chromate ester (slow step in oxidation reaction) - Stable, commercially available reagent HCl + CrO3 + pyr -Reaction usually carried out in CH2Cl2 -Rates: R O OH RCH2OH and R2CHOH > no over oxidation RCHO R2C=O R H -Usually only need 1–2 equiv of Cr(VI) reagent (Jones & Collins usually require 6 equiv) -PCC slightly acidic which can cause side reactions, for example: –H+ H+ PCC OH O OH OH O -To avoid H+ catalyzed side reaction, use sodium acetate buffer: PCC OH CHO NaOAc -Can take advantage of acidity in PCC reaction (Boger and Corey Tetrahedron Lett. 1978, 2461): O CHO O CHO 78% OH 41% O OH 55% OH O 62% O R = CH3, 68% R = Ph, 69% R -Oxidation of 3°, allylic alcohols MeLi R O PCC O Cr O O H O Cr O O O O Me Me Me [3,3]-sigmatropic rearrangement, Dauben J. Org. Chem. 1977, 42, 682. -Aromatic amine effect: dampens reactivity so only selective oxidation of allylic alcohols may be observed PCC, pyr (2%) in CH2Cl2 Chem. Phys. Lipids 1980, 27, 281. PCC, 3,5-dimethylpyrazole (2%) in CH2Cl2 J. Org. Chem. 1983, 48, 4766. PCC, benzotriazole (2%) in CH2Cl2 Synth. Commun. 1985, 15, 393. ° MS accelerate rate of oxidation (PCC and PDC) -3 A J. Chem. Soc., Perkin Trans. 1 1982, 1967. -Pyridinium fluorochromate, related stable reagent that is slightly less acidic (Corey and Suggs) - Other related reagents include bipyridinium chlorochromate (BPCC), DMAP chlorochromate, quinolinium chlorochromate, and pyrazinium chlorochromate. O 88 OH Me Oxidations of Alcohols Dale L. Boger 4. Pyridinium Dichromate (PDC): Corey Tetrahedron Lett. 1979, 399. N H Cr2O7-2 CrO3 + pyr + H2O CH2Cl2 RCH2OH PDC RCHO DMF RCO2H MeOH 2 RCO2Me PDC, DMF -Stable, commercially available reagent -Not as acidic as PCC OH -Oxidations slower than PCC or other oxidation reagents CO2H 25 °C, 7 h 83% -Can selectively oxidize 1° alcohols to aldehyde or carboxylic acid depending on solvent -2° alcohols oxidize only slowly and sometimes require an acid catalyst (pyridinium trifluoroacetate or 3° A MS) - Note: Original reagent made in search of more acidic reagent, attempted preparation of pyridinium trifluoroacetyl chromate (Boger, Ph.D. dissertation, Harvard Univ., 1980). -Other related reagents include nicotinium dichromate, quinolinium dichromate, and imidazolium dichromate - Note: Cr based reagents will oxidize amines and sulfides. Substrates with these functional groups must be oxidized with other reagents (PDC will sometimes leave sulfides unaffected). 5. CrO3–H5IO6: Zhao and Reider Tetrahedron Lett. 1998, 39, 5323. -Catalytic in CrO3 (1–2%, Industrial scale chromium-based oxidations) -1° alcohols carboxylic acids with no racemization -2° alcohols ketones Ph 2.5 equiv H5IO6 OH 1.1 mol% CrO3 Ph wet CH3CN NHCBZ 0 oC, 83% CO2H Ph Ph NHCBZ 98% OH O B. Manganese-based Oxidation Reagents 1. Manganese Dioxide (MnO2) -Very mild oxidizing reagent, special "activated" MnO2 preparation required -Selectively oxidizes allylic and benzylic alcohols to aldehyde or ketone -Requires nonpolar solvent (CH2Cl2, CHCl3, pentane, benzene, etc.) -Oxidizing reagent : substrate = 10:1 (10 wt. equiv) OH CHO OH MnO2 OH MnO2 HO O -No isomerization of conjugated double bond. Cr-based reagent will cause problem due to H+ catalysis -Chemical MnO2 (CMD), commerically available, also works well R Shioiri Synlett 1998, 35; Tetrahedron Lett. 1992, 33, 4187. -NiO2: alternative reagent that behaves similar to MnO2 -Oxidize alcohol to ester, no isomerism of C=C bond (Corey and Ganem J. Am. Chem. Soc. 1968, 90, 5616) O OH MnO2 MeOH CHO CO2Me CH2OH R cat HOAc R H R CN R CN NaCN, MeOH 2. KMnO4 a. KMnO4/H2SO4 -Good for RCH2OH RCOOH -Reaction runs in aqueous solution because of the insolubility of KMnO4 in organic solvents b. KMnO4 in tBuOH–5% NaH2PO4 aqueous buffer (Masamune Tetrahedron Lett. 1986, 27, 4537). -For highly oxygenated systems where multiple side reaction pathways are present with other oxidants 89 Modern Organic Chemistry The Scripps Research Institute 5 min, 25 °C CHO 98% TBDMSO OMOM TBDMSO c. Lemieux–von Rudloff oxidation: aqueous KIO4/cat. KMnO4 -For cleavage of carbon–carbon double bonds 3. R4NMnO4 -Same capabilities as KMnO4 but soluble in organic solvents 4. Cu(MnO4)-6H2O and BaMnO4 OH OH OH CO2H CO2H OMOM BaMnO4 O OH C6H6 Lee J. Am. Chem. Soc. 1983, 105, 3188; J. Org. Chem. 1982, 47, 2790. Hauser J. Am. Chem. Soc. 1984, 106, 1862. Jefford J. Chem. Soc., Chem. Commun. 1988, 634. Kim Tetrahedron Lett. 1989, 30, 2559. C. Other Oxidation Reagents 1. RCH2OH or R2CHOH oxidation a. Sodium Hypochlorite (NaOCl): Used primarily to oxidize alcohols or aldehydes to carboxylic acids. RCH2OH RCHO RCOOH Stevens, Chapman J. Org. Chem. 1980, 45, 2030; Tetrahedron Lett. 1982, 23, 4647. b. Sodium Chlorite (NaClO2) Pinnick Tetrahedron 1981, 37, 2091. Also Calcium Hypochlorite (Ca(OCl)2): McDonald Tetrahedron Lett. 1993, 34, 2741. H2O RCO2H NaClO2 RCH2OH MeOH RCO2Me -Good for oxidation of sensitive aldehydes to carboxylic acids - Becoming the method of choice for the oxidation of RCHO to RCO2H. - Two-step procedures for RCH2OH to RCO2H (i.e., MnO2, Swern, Dess−Martin for RCH2OH to RCHO and NaClO2 for RCHO to RCO2H most often better than single step reagent conversions. - Scavengers are often added to trap or eliminate positive Cl species leading to byproducts. Typical scavengers are resorcinol, 2-methyl-2-butene, DMSO, H2NSO3H. OMe Cl O O TBSO H N O H R Cl O H N H H O NH MeO O N H H OTBS H N Dess−Martin NH CN O NHBOC O NaClO2 77% overall Boger J. Am. Chem. Soc. 1999, 121, 3226 and 10004. OMe OMe c. Ag2O and Ag2CO3 RCH2OH Ag2O RCHO Ag2CO3 Celite or AgO d. AgO RCH2OH R CH2OH RCHO or RCO2H R CO2H Corey, Ganem J. Am. Chem. Soc. 1968, 90, 5616. 90 R = CH2OH R = CHO R = CO2H RCOOH Oxidations of Alcohols Dale L. Boger 2. m-CPBA and NaIO4 (Amine and sulfide oxidation) O NaIO4 m-CPBA O O S S S R R R R R R m-CPBA 3. TPAP, [Pr4NRuO4] HO CO2Et 5% TPAP NMO TPAP HO ° 93% R CH2Cl2, 4A MS OHC R O CO2Et Ley J. Chem. Soc., Chem. Commun. 1987, 1625. Aldrichim. Acta 1990, 23, 13. Synthesis 1994, 639. 4. Dess–Martin Oxidation: Dess and Martin J. Am. Chem. Soc. 1978, 100, 300; J. Am. Chem. Soc. 1979, 101, 5294; J. Org. Chem. 1983, 48, 4155; J. Am. Chem. Soc. 1991, 113, 7277. OAc RCH2OH -periodinane RCHO AcO o I OAc R2CHOH -CH2Cl2, 25 C R2C=O O O O O O O 70% MeO CHO OH Danishefsky, Coleman J. Am. Chem. Soc. 1991, 113, 3850. - Precursor to Dess–Martin reagent - Insoluble in almost all organic solvents but is soluble in DMSO and oxidations in this solvent work effectively (25 °C): Frigerio Tetrahedron Lett. 1994, 35, 8019. O OH O OH MeO HO O I O IBX O R R R R OH R R OH R O R R H O Ph Ph O OH R H Ph Ph OH OH 5. Oxoammonium Salt: Torii J. Org. Chem. 1990, 55, 462; Skarzewski Tetrahedron Lett. 1990, 31, 2177. Bobbitt J. Org.Chem. 1998, 63, 9367. OCOR 1 N O 1 OH CH Cl 2 2 OH OH CHO OH OH 1 Ph Ph 6. Trityl Cation: Jung J. Am. Chem. Soc. 1976, 98, 7882. Ph3C+BF4– TMSO OTMS CH2Cl2 H 25 °C 25 °C 72 h, 95% O O OTMS + Ph3CH O 3° carbon H abstracted faster 7. Pt–O2: Fuchs and Hutchinson J. Am. Chem. Soc. 1987, 109, 4755. -Good for oxidation of 1° alcohols directly to carboxylic acids HO HO2C 1° alcohols > 2° alcohols 2° axial alcohols > 2° equatorial alcohols Pt–O2 acetone–H2O C5H11 HO OH 57% C5H11 HO OH 91 Modern Organic Chemistry The Scripps Research Institute 8. Via Hypohalite Just Tetrahedron Lett. 1980, 21, 3219. Hanessian Synthesis 1981, 394. Doyle Tetrahedron Lett. 1980, 21, 2795. Kanemitsu Chem. Pharm. Bull. 1989, 37, 2394. Oshima, Nozaki Tetrahedron Lett. 1982, 23, 539. Stevens Tetrahedron Lett. 1982, 23, 4647. NaOCl, HOAc -For example: (Bu3Sn)2O, Br2 NiBr2, (PhCO2)2 NIS, Bu4NI NaBrO3, CAN Mechanism: OH OH Br2 O (Bu3Sn)2O O X O HO HO O OMe OMe H HO CHCl3, reflux OH B: OH O OH O (Bu3Sn)2O (Bu3Sn)2O Br2 Br2 O OH CH2Cl2 CH 2Cl2 OH OH Tetrahedron Lett. 1976, 4597. 2° alcohol > 1° alcohol 9. Oppenauer Oxidation: see Meerwein–Pondorff–Verley reduction, Review: Org. React. 1951, 6, 207. Oppenauer Rec. Trav. Chim. 1937, 56, 137. - Suitable for oxidation of 2° alcohol in the Cl3CCHO SePh SePh presence of 1° alcohol which do not react Al2O3 Good for oxidation of substrates containing OH O 55 °C, 24 h easily oxidized functional groups Posner Angew. Chem., Int. Ed. Eng. 1978, 17, 487; Tetrahedron Lett. 1977, 3227; 1976, 3499. OH O Al(OiPr) OH OH 3 CH3O CH3 Boger J. Org. Chem. 1984, 49, 4045. toluene 110 °C, 1.5 h 72% CH3O CH3 RCH2OH RCO2H 10. Ruthenium Tetroxide (RuO4) R2CHOH -in situ generation from RuO2–NaIO4 or RuO2–NaOCl: Tetrahedron Lett. 1970, 4003. J. Org. Chem. 1987, 52, 1149. from RuCl3–H5IO6: Sharpless J. Org. Chem. 1988, 53, 5185. J. Org. Chem. 1981, 46, 3936. -Note: RuO4 attacks C=C bonds and will cleave 1,2-diols. Often used to cleave aromatic rings: BOCHN MeO cat. RuCl3−NaIO4 BOCHN O 60% BnO NH2 NH2 BnBr, 80% OTBS O OTBS O Boger J. Org. Chem. 2000, 65, 6770. (total synthesis of ramoplanin) MeCN 11. TEMPO -with cat. NaOCl or NaBrO2: -with cat. Ca(OCl)2: OMe BnO OBn NaOCl TEMPO RCO2H RCH2OH J. Org. Chem. 1985, 50, 1332. TEMPO CH2Cl2 J. Org. Chem. 1987, 52, 2559. RCHO J. Org. Chem. 1990, 55, 462. Dess and Martin J. Org. Chem. 1983, 48, 4155. Corey J. Am. Chem. Soc. 1996, 118, 1229. Smith J. Am. Chem. Soc. 1989, 111, 5761. OMe BnO OBn NaBrO2 Vancomycin central amino acid J. Org. Chem. 1996, 61, 3561. KBr, 78% CBZHN 92 R2C=O OH CBZHN CO2H Oxidations of Alcohols Dale L. Boger -With NaClO2, NaOCl Zhao, Reider J. Org. Chem. 1999, 64, 2564. RCH2OH NaOCl N O N O O − N O O H NaOCl H R R NaClO2 RCO2H N OH 12. Pd−O2: J. Org. Chem. 1976, 41, 957 and 3329. O2 cat. Pd(OAc)2 Ph OH pyr, toluene ° MS, 80 °C 3A O Pd(OAc) PhCHO Ph H 100% H + O2 HOOPd(OAc) OH H HPd(OAc) O RCH2OH 100% RCHO OH ° MS absorbs or decomposes H O 3A 2 2 (O2 + H2O) O Uemura J. Org. Chem. 1999, 64, 6750. R R R R D. Swern Oxidation and Related Oxidation Procedures 1. Swern Oxidation: J. Org. Chem. 1976, 41, 957 and 3329. O CH3 Cl S Cl DMSO + Cl CH3 O CH3 Reviews: Chem. Rev. 1967, 67, 247. Tetrahedron 1978, 34, 1651. Synthesis 1981, 165. [DMSO–(COCl)2] Org. React. 1990, 39, 297. S O [DMSO–TFAA] CH3 O CF3 -Also DMSO–Ac2O, DMSO–SO3/pyr, DMSO–SOCl2, DMSO–Cl2 DMSO–Ac2O is often referred to as the Albright–Goldman reagent Albright, Goldman J. Am. Chem. Soc. 1965, 87, 4214, 1967, 89, 2416. 2. Corey–Kim Oxidation: Tetrahedron Lett. 1974, 287; J. Am. Chem. Soc. 1972, 94, 7586. O CH3 CH3 S + N Cl S Cl [DMS–NCS] CH3 CH3 O 3. Moffatt–Pfitzner Oxidation (DCC–DMSO): J. Am. Chem. Soc. 1963, 85, 3027; J. Am. Chem. Soc. 1965, 87, 5670. DMSO + TFAA S DMSO + -Mechanism: 1. RCH2OH + O N C N N C N S O N C N CH3 + RCH2O S [DMSO–DCC] O H H N C N CH3 93 Modern Organic Chemistry The Scripps Research Institute CH3 H + B: R C O S B: CH3 H CH3 CH3 S X RCH2O S 2. RCH2OH + CH2 CH3 B: H N X = Cl or O C HN RCHO + Me2S CH3 H R C O S CH2 H RCHO + Me2S -All Swern type complexes react with alcohols, in presence of base, to give "activated alcohol complexes". -Examples: OH OH -Other oxidants cleave diol C–C bond -Swern oxidation run under very mild conditions O OH (usually –78 °C to –50 °C) O MnO2 OH OH H OH or PCC CHO Swern OH OH O HO H CHO O O Boger J. Org. Chem. 1990, 55, 1919. Boger J. Org. Chem. 1991, 56, 2115. Boger Tetrahedron Lett. 1989, 30, 2037. -Fredericamycin A: Boger J. Am. Chem. Soc. 1995, 117, 11839. MOMO MeO MOMO OMe OH TFAA–DMSO DBU –78 °C, 1 h –78 °C to 25 °C, 20 h OBn OH BnO EtO MOMO MeO MeO O MOMO BnO O BnO MOMO MeO MeO MOMO BnO OH TFAA–DMSO Et3N O BnO EtO N BBr3; air O OH O O OH O HO N MeO TsOH–NaBr EtO N H Note: Kornblum oxidation, J. Am. Chem. Soc. 1957, 79, 6562 via DMSO oxygen based displacement of halide (usually activated: benzylic or α-keto halide) to provide aldehyde or ketone. Common byproducts of Swern oxidations are (methylthio)methyl ethers and the amount varies with DMSO coactivator and reaction temperature. It is derived from alcohol trap of a Pummerer rearrangement intermediate: CH2=+SCH3. Note: Pummerer rearrangement is also a formal oxidation reaction Pummerer Chem Ber. 1909, 42, 2282; Chem Ber. 1910, 43, 1401. Ph O S CO2Et N Fredericamycin A Ac2O Ph OAc S CO2Et Ph S O CO2Et S CO2Et OAc H H AcO AcO Reviews: Org. React. 1991, 40, 157. Comprehensive Org. Syn., Vol. 7, pp 194–206. 94 Ph Reduction Reactions Dale L. Boger VI. Reduction Reactions A. Conformational Effects on Carbonyl Reactivity O Dihedral angle 4° H H Hax H sp2 sp3 120° 109.5° introduces torsional strain Eclipsed conformation of carbonyl O This torsional strain accounts for the increased reactivity of six-membered ring cyclic ketones over acyclic ketones. H O H Nu– H OH H Nu Overall, the addition to cyclohexanones is favorable: 1. gain 1,3-diaxial interactions (A value = 0.7 kcal/mol for OH) 2. lose the torsional strain (~3–5 kcal/mol) - So, additions to cyclic ketones are thermodynamically and kinetically favorable. 1. Reversible Reactions O HCN HO CN reversible reaction Keq for cyclohexanone acyclic ketone ~ ~ 70 - Thermodynamically more favorable for cyclohexanone due to the loss of torsional strain. - Thermodynamic effect of sp2 hybridization: the strain free acyclic system does not suffer the strain destabilization of the ground state, so little gain going from sp2-> sp3. 2. Irreversible Reactions (kinetic effect is pertinent) O HO LiAlH4 Rate (k) for cyclohexanone acyclic ketone ~ ~ H 335 *Implication: One can selectively reduce a cyclic carbonyl in the presence of an acyclic carbonyl: under kinetic or thermodynamic conditions. - Synthetic consideration: may not have to protect acyclic ketone. 95 Modern Organic Chemistry The Scripps Research Institute 3. Additional Conformational Effects O H O H H Boat destabilization reduced Only ~2.7 kcal/mol higher in energy H -Cyclohexanones potentially have more accessible conformations available. 0.6 kcal/mol Me H O Theoretical prediction (0.9 kcal/mol), actually this 1,3-diaxial Me–H interaction is only about 0.6 kcal/mol. This difference (0.3 kcal/mol) in energies observed between theoretical and experimental results is due to the fact that the sp2 carbonyl carbon moves these groups (Me and H) further away from each other: bond angle of 120° vs. 109.5°. A = 1.8 kcal/mol 1/2 = 0.9 kcal/mol Predicted! - Substituents on the ring benefit from a reduced A value since one axial substituent is removed and the opened bond angle of the carbonyl further reduces the remaining 1,3-diaxial interaction (greater distance). B. Reactions of Carbonyl Groups - Three primary reactions which we will discuss relative to nucleophilic addition: O Nucleophilic addition: X HO Nu Nu– H H X Me (or R) O O α-Deprotonation: (enolate formation) Me (or R) Base H X X Me (or R) Me (or R) Addition of e–, formation of radical anion: O H X O e– H X Me (or R) Me (or R) - Each reagent will display competitive reactions among the three primary pathways. Nature of each reagent and the nature of X will determine the course. C. Reversible Reduction Reactions: Stereochemistry - Meerwein–Ponndorf–Verley Reduction (the reverse reaction is the Oppenauer Oxidation). O + Al O tBu 96 3 Reversible Reduction Review: Djerassi Org. React. 1951, 6, 207. Meerwein Justus Liebigs Ann. Chem. 1925, 444, 221. Ponndorf Angew. Chem. 1926, 39, 138. Verley Bull. Soc. Chim., Fr. 1925, 37, 537. OH iPrOH OH + tBu 95 t : Bu 5 Reduction Reactions Dale L. Boger - Mechanism: Reversible Intramolecular Hydride Transfer. O O Al H axial H– delivery O H H H H tBu H O tBu H t Bu Al O O equatorial H– delivery Al O Al O H tBu H H H H Steric interaction - Since it is freely reversible, one obtains the most stable alcohol from the reduction. The reaction is driven to completion by use of excess reagent and by distilling off the acetone formed in the reaction. - But, the A value of OH = 0.7 kcal/mol and K = e–∆G/RT would predict a 72:28 ratio. Why does the experimental result give better selectivity than the prediction (95:5 > 72:28)? - We must not only consider the A value, but the larger 1,2-destabilizing steric interactions of the isopropoxy group in the transition state for the equatorial delivery of the hydride: that is, the larger ∆E in the transition state. OH O OH O Ph Al(OR)3 OH OAlCl2 Ph 22% ee 70% ee Doering J. Am. Chem. Soc. 1950, 72, 631. Nasipuri J. Indian Chem. Soc. 1967, 44, 165. D. Irreversible Reduction Reactions: Stereochemistry of Hydride Reduction Reactions and Other Nucleophilic Additions to Carbonyl Compounds 1. Cyclic Ketones a. Examples H O H H H H OH LiAlH4 t Bu H H H H Al Li H 1,3-interactions H O H H Li H H Al H H H H tBu OH H H H + t H H Bu H H : 10 90 Nearly the same ratio obtained under these kinetic and the above thermodynamic conditions. Why? - Difference in the relative rates: 1,2-interactions slow the equatorial addition by a factor of ~ 10 - LiAlH4 = small reagent favor axial hydride delivery 1,2-interactions - 1,3-interactions are more remote (i.e., smaller), when compared to the 1,2-interactions (larger). - The destabilizing 1,3-interactions increase as the size of the reagent increases or with the size of the 1,3-diaxial substituents while the 1,2-interactions are not nearly so sensitive to the size of reagents or the size of the substituents. 97 Modern Organic Chemistry The Scripps Research Institute - For the reduction of cyclohexanone and derivatives, we see the following generalizations: Small H– Reagent H O H Large H– Reagent R H H Examples: O Me H OH Me H LiAlH4 Me Me Me Me H Me H OH + H Me H H Me H : 45 55 Increased steric hinderance of the 1,3-diaxial interactions (Me/reagent) make axial hydride delivery more difficult. O Me Me OH Me Me LiAlH4 H + H H H H H H Me Me OH H H H H : 100 0 Serious 1,3-interactions preclude axial delivery of the hydride, but the axial Me's have no effect on the 1,2-interactions. Me Reagent Me Me H OH O Me H Me H H Me + H Me H H Me H : : : 52–63 55–64 92–98 LiAlH4 NaBH4 LiAl(OMe)3H OH Me 37–48 36–45 2–8 Larger reagent: greater selectivity for equatorial H– delivery. Effect of the size of the reagent H O B H–K+ OH H H H H H OH H H + tBu H H tBu H 3.5 tBu H : H H 96.5 Much larger reagent! Now, even the 1,3-H/reagent interactions are large while the 1,2-torsional interactions are not affected. Brown J. Am. Chem Soc. 1972, 94, 7159. 98 Reduction Reactions Dale L. Boger - Comparison of Diastereoselectivity of Hydride Reducing Reagents. O O tBu Me Reagent % axial OH NaBH4 20 LiAlH4 8 LiAl(OMe)3H 9 LiAl(OtBu)3H 9 (sBu)3BHLi 93 (Me2CHCHMe)3BHLi >99 LiMeBH3 2 Me Me Me O Me Me % axial OH 25 24 69 36 98 >99 13 O % axial OH 58 63 92–98 95 99.8 66 Me % endo OH 86 89 98 94 99.6 >99 - O % endo OH 14 8 1 6 0.4 no reaction - Brown J. Am. Chem. Soc. 1970, 92, 709; 1972, 94, 7159; 1976, 98, 3383. - Stereochemistry of Other Representative Nucleophilic Additions to Cyclohexanones. Me O O O tBu Me Me Me Reagent MeLi/Et2O MeMgI/Et2O EtMgBr/Et2O PhMgBr/Et2O PhLi % axial OH 65 53 71 49 58 % axial OH 85 84 95 91 88 % axial OH 100 100 100 100 - Note: Typically alkyllithium reagents behave as large nucleophiles and approach from the equatorial direction Ashby Chem. Rev. 1975, 75, 521. V. Grignard received the 1912 Nobel prize in Chemistry for his discovery of the role of organomagnesium halides in organic synthesis which he made as a graduate student working with P. A. Barbier. I Mg CN O Barbier Compt. rend. 1899, 128, 110. Grignard Comp. rend. 1900, 130, 1322. b. Origin of Diastereoselectivity Axial attack Note: The direction of attack is not from the axial or equatorial vector, but with a 109.5° approach of the nucleophile. no – RH versus O yes Hax Steric Interactions H– Felkin - equatorial attack (largely torsional strain - when R = H, worse than axial attack mode) H O Torsional Strain H H H yes no Eclipsed Conformation - Stereoelectronic effects (105°± 5°) 109.5° 90° R R O R versus O R Dunitz angle: Tetrahedron 1974, 30, 1563. Good overlap and ~ approaches bond angle required of sp3 hybridization. Better σ – π∗ overlap (FMO) for nucleophilic addition. 99 Modern Organic Chemistry The Scripps Research Institute - Cyclic Ketones: Steric vs. Torsional Interactions. Nu– Ha He He Ha Ha Ha OH - As the nucleophile gets larger, this steric interaction with the C3-axial H gets worse and equatorial approach becomes the preferred line of attack. e Ha - For C3 and C5-H substituents, this torsional interaction is worse than the steric interaction of Nu– / C3 and C5-H's (for small, unhindered Nu–). Nu– - All H– reductions have transition states that resemble reactant geometry. - Diastereoselectivity is influenced by: 1) Steric interactions (1,3-diaxial interactions) 2) Torsional strain (1,2-interactions) 3) Remote electronic effects (electrostatic interactions) - In contrast to early theories of "product development control" / late transition state vs "steric approach control" / early transition state. c. Baldwin's Rules and Burgi−Dunitz Angle of Attack Recent review: Acc. Chem. Res. 1993, 26, 476. Dunitz angle of attack: Burgi, Dunitz Tetrahedron 1974, 30, 1563; J. Am. Chem. Soc. 1973, 95, 5065. - Nucleophile addition to carbonyl compound takes place not at 90° (perpendicular) to the C=O, but at an angle of ~105° ± 5° sp3 = 180° sp2 = 105° ± 5° Nu– Nu– Nu– 120° SN2 R sp = 120° R O O R Nu– R 120° X Ring closure reactions - Importance of approach trajectory first detailed by Eschenmoser Helv. Chem. Acta 1970, 53, 2059. - Expanded and elaborated to: Baldwin's Rules for Ring Closure J. Chem. Soc., Chem. Commun. 1976, 734, 736. - Vector analysis and approach trajectory on sp2, sp, and sp3 systems. - For intramolecular reactions the favored pathways are those where the length and nature of the linking chain enables the terminal atoms to achieve proper geometry for reaction. Exo X– Y Endo X– Y X X Y sp3 = tet sp2 = trig sp = dig Y Baldwin's Rules Rule 1: tetrahedral (sp3) systems (a) 3 to 7-exo-tet are favored (b) 5 to 6-endo-tet are disfavored 100 Rule 2: trigonal (sp2) systems (a) 3 to 7-exo-trig are favored (b) 3 to 5-endo-trig are disfavored (c) 6 to 7-endo-trig are favored Rule 3: digonal (sp) systems (a) 3 to 4-exo-dig are disfavored (b) 5 to 7-exo-dig are favored (c) 3 to 7-endo-dig are favored Reduction Reactions Dale L. Boger -Baldwin: Approach Vector Analysis (Vector Sum establishes the approach of reagent). Nu– O 1. Amides O 1 N R 1 Nu– R R 1 N R R1 R O O R Nu– 2. Carboxylate Nu– nonequivalent contributions of each resonance form 1 N R R1 not 1 R N R Nu– R1 O line of attack is weighted average of the two contributing resonance forms O R O R O Nu– equivalent and Nu– approaches over (eclipsing) the R group O R Nu– O Nu– O 3. Cyclohexenones O substituents in the C5 and C6 position will have a more significant effect on the rate and the stereochemical outcome Nu– O Nu– Examples: Nu– CH3 β-face O α-face H H major LiAlH4 - locked trans diaxial ring fusion preferential axial delivery of reagent equatorial OH is major product addition of Nu– from β-face (equatorial delivery) suffers from repulsive interaction with axial Me Houk and Trost J. Org. Chem. 1991, 56, 3656. CH3 HO 70–90% H H 101 Modern Organic Chemistry The Scripps Research Institute - vs. HCH3 H CH3 HO O H H single 1,3-diaxial interaction major - but major product H– CH3 H OH CH3 Large H–/CH3 interaction O H H– H– major CH3 H H Smaller H–/CH3 interaction O CH3 HO - With enones, the substituents in the 5,6-positions play a more dominant role in determining stereochemical outcome of nucleophilic addition to the carbonyl. 2. Acyclic Carbonyl Groups Review: Comprehensive Org. Syn., Vol. 1, pp 49-75. - Cram's Rule J. Am. Chem Soc. 1952, 74, 5828. Empirical and no mechanistic interpretation is imposed on model J. Am. Chem Soc. 1959, 81, 2748. (chelation-controlled addition) - Prelog Helv. Chim. Acta 1953, 36, 308. (1,3-induction) - Felkin model: (or Felkin–Anh) Tetrahedron Lett. 1968, 2199, 2205. Tetrahedron Lett. 1976, 155, 159. Nouv. J. Chim. 1977, 1, 61. V. Prelog received the 1975 Nobel prize in Chemistry for his research into stereochemistry of organic molecules and reactions. O D. J. Cram was awarded the 1987 Nobel prize in Chemistry for his "host – guest" complex studies. a. Cram's Rule - Empirical Model Nu– O M S M S Nu R L L R - Large group L eclipsed with R and not the carbonyl, Nu– approach from side of small (S) group. - Stereoselectivity observed usually modest. - But, most populated (most stable) conformation of acyclic ketone would be the eclipsed carbonyl conformation. Nu– R' R O RL R R' RL O R Nu O RL R Nu RL O R' RMR' RM This is not the observed stereochemistry! Note: Reaction is not from the ground state carbonyl eclipsed RL conformation, i.e., the ground state conformation is not the reactive conformation (Curtin–Hammett Principle). RM 102 RM Reduction Reactions Dale L. Boger b. Felkin (–Anh) Model - Large group (L) trans antiperiplanar to forming bond the sterically next most demanding substituent is gauche to carbonyl versus O O S minimizes torsional M O OL M strain (Pitzer strain) Nu– L Nu L L R in transition state M M S S R (Felkin Model) S R Nu R Same as Cram Product: sterically most demanding group is perpendicular to the plane of the carbonyl, anti to incoming nucleophile - Here, L is either the largest group (sterically) or the group whose bond to the α-carbon provides the greatest σ–π* overlap (e.g. halide, alkoxy groups). - Computational studies of Anh confirmed this is the most stable transition state and extended it to α-chloroketones. In the latter case, this minimizes destabilizing electrostatic interactions between the halogen (electronegative group) and the incoming nucleophile. Anh further refined the Felkin Model, i.e., Felkin–Anh Model, as shown below M O Nucleophile prefers approach that minimizes torsional strain and incorporates Burgi–Dunitz trajectory. Primary interaction is now between the Nu– and the small or medium substituent. O S L L versus M S R Nu– Nu– R O R R Nu– Preferred Note: Karabatose proposed a similar model as an alternative to the original Cram empirical rationalization based on computational studies that suggested the most favored conformation would have the medium-sized group eclipsing the carbonyl and addition of H– occurs from the side of the small substituent. M O Nu Nu– L S M OH Karabatose J. Am. Chem. Soc. 1967, 89, 1367. L S ) R R The model incorporating the Burgi–Dunitz angle has been even further refined to reflect the impact of substantially different sized R groups on the carbonyl. As the size difference between the two substituents increases, the incoming nucleophile would try to avoid the larger one and the approach vector would be tilted away from the normal plane by an angle referred to as the Flippin–Lodge angle (αFL). RL Nu– RS αFL Heathcock Aldrichchim. Acta 1990, 23, 99. Nu– Examples: O O MeMgCl –75 °C, THF O Cl O HO Me Johnson J. Am. Chem. Soc. 1968, 90, 6225. Cl O R Cl Et H Me – HO R Et R Me H HO Et H Me Cl Me H Cl 92% H H HO Me O R Cl Et H Me R Et 103 Modern Organic Chemistry The Scripps Research Institute -First observed in cyclic systems: Cornforth J. Chem. Soc. 1959, 112 and 2539. J. Chem. Soc. 1957, 158. -For cyclic ketones Nu– J. W. Cornforth received the 1975 Nobel prize in Chemistry jointly with V. Prelog for outstanding intellectual achievement on the stereochemistry of reactions catalyzed by enzymes. O Cl axial -For acyclic ketones Axial R' R' S H O H O M L H Equatorial O D A Allylic bonds prefer to be staggered (axial attack) with respect to the incoming nucleophile rather than eclipsing (equatorial attack). c. Cieplak Model Nu– J. Am. Chem. Soc. 1981, 103, 4540. vacant σ* σ* O σ* O O O H adjacent σ bonds considered axial attack stabilization equatorial attack stabilization 1. C–H bond is more electron-rich, better σ e-donation in stabilization of the developing σ* of bond formation than C–C bond, therefore axial approach preferred. 2. σ C–O > σ C–H > σ C–C > σ C–S. 3. Nucleophile can affect intensity of effect, σ* (LUMO of developing bond). LUMO, effect, overlap/stabilization (a) Electron donation of solvent (polarity) will increase σ*, equatorial attack, i.e. preferentially LUMO, overlap, axial attack (b) Counterion effect: its ability to complex/stabilize σ*, lower σ* effect, axial attack. (c) Electron-rich σ* nucleophile, overlap/effect, axial attack equatorial attack. 4. Heteroatom at 4-position exhibits preference for axial attack: n–σ* stabilization. Review: Cieplak Chem. Rev. 1999, 99, 1265. Nu–: d. Additional Models - Product development/steric approach control Dauben: J. Am. Chem. Soc. 1956, 78, 2579. - Torsional strain (preference for staggered conformation in the transition state) higher level calculations Felkin: Tetrahedron Lett. 1968, 2199, 2205. than Anh or Cieplak: C–C > Houk: J. Am. Chem. Soc. 1987, 109, 906. C–H electron donation. J. Am. Chem. Soc. 1988, 110, 3228. Science 1986, 231, 1108. J. Am. Chem. Soc. 1991, 113, 5018. remote-through space J. Am. Chem. Soc. 1993, 115, 10992. electrostatics and Angew. Chem., Int. Ed. Eng. 1992, 31, 1019. torsional effects account cf. Chemtracts: Org. Chem. 1988, 1, 65. for Cieplak observations. Houk–Trost: J. Am. Chem. Soc. 1987, 109, 5560. - Principles of least motion J. Am. Chem. Soc. 1974, 96, 3141. Yates: - Stereoelectronic control and smallest change in conformation Toromanoff: Tetrahedron 1980, 36, 2809. - Electrostatic model Kahn, Hehre, Chamberlin: J. Am. Chem. Soc. 1987, 109, 650, 663, 666. J. Am. Chem. Soc. 1986, 108, 7396, 7399. 104 Reduction Reactions Dale L. Boger - Electronic nonequivalence of carbonyl faces Klein: Tetrahedron Lett. 1973, 4307; 1974, 30, 3349. - Dissymmetric π-electron clouds Fukui: J. Am. Chem. Soc. 1976, 98, 4054. Burgess, Liotta: J. Am. Chem. Soc. 1984, 106, 4849. - Antiperiplanar approach of Nu– to other bonds - Preferential attack antiperiplanar to the best electronic acceptor Anh: Tetrahedron Lett. 1976, 155, 159. Nouv. J. Chim. 1977, 1, 61. Top. Curr. Chem. 1980, 88, 145. Dunitz, Eschenmoser: Helv. Chim. Acta 1980, 63, 1158. - Preferential attack antiperiplanar to the best electronic donor Cieplak Model: J. Am. Chem. Soc. 1981, 103, 4540. J. Chem. Soc., Perkin Trans. 1 1997, 530. Chem. Rev. 1999, 99, 1265. - Others Ashby: J. Org. Chem. 1976, 41, 2890. Wigfield: J. Org. Chem. 1976, 41, 2396; 1977, 42, 1108. - Bent bond or Tau-bond model Vogel, Eschenmoser: Chem. Lett. 1987, 219. Winter: J. Chem. Educ. 1987, 64, 587. - Hyperconjugation Coxon, Luibrand: Tetrahedron Lett. 1993, 34, 7097. - Recent reviews of the various models: Chem Rev. 1999, 99, 1225−1467. e. Comparative Examples of Diastereoselection - Diastereoselection depends on the size of the ketone substituent. Kobayashi, Ohno J. Am. Chem. Soc. 1988, 110, 4826. Me SiMe3 R O Me Nu– Nu R Me3Si OH 1 Felkin Product Me Me H R O Nu– R 2 Me Me Nu + Nu R HO SiMe3 Bu4NF Me + R Nu OH OH From 1 From 2 R = Ph nBuLi > 100:1 5:1 R = Ph MeLi > 40:1 4:1 R = Ph SiMe3 > 100:1 2:1 R = Ph MgBr 11:1 1.7:1 nBuLi > 30:1 1.6:1 MeLi > 100:1 1.9:1 SiMe3 > 30:1 1:1 MgBr 11:1 2.5:1 15:1 3.5:1 R= R= nBuLi MeLi 21:1 2:1 SiMe3 > 100:1 1.5:1 MgBr 3.5:1 2:1 Ph Me Bu 1) TMSLi Ph Bu 2) Bu4NF OH > 50:1 Complementary stereochemistry to that illustrated with acylsilanes. O Note: Desilylation proceeds with complete retention (>99:1): Hudrlik J. Am. Chem. Soc. 1982, 104, 6809. Note: Typical Felkin diastereoselection is modest. Note: Diastereoselection is increased dramatically with very large ketone substituent. O M L O M L R S Nu– – S Nu SiMe3 Increase size, increase diastereoselectivity 105 Modern Organic Chemistry The Scripps Research Institute Me R ratio Me 74 : 26 R R Ph Et 76 : 24 iPr O OH 83 : 17 tBu 98 : 2 - Diastereoselectivity depends on size of nucleophile. Me Felkin Tetrahedron Lett. 1968, 2199 and 2205. Diastereoselectivity for reduction with LiAlH4 LiAlH4 Ph Me Me Nu– Me Ph Me Me Ph + LiAlH4 (sBu)3BHLi OH H Ph Me– Me Nu Ph O MeLi MeMgBr MeTi(OiPr)3 MeTi(OPh)3 MeMgOTs MeMgOPiv Yamamoto J. Am. Chem. Soc. 1988, 110, 4475. 26 <1 Me Me Me Ph OH 74 >99 O R = tBu > iPr > Et > Me OH 65 66 88 93 92 94 Felkin Product + Ph Nu OH 35 34 12 7 8 6 Reetz Top. Curr. Chem. 1982, 106, 1. Reetz Angew. Chem., Int. Ed. Eng. 1992, 31, 342. f. Chelation-controlled Addition - Review: Acc. Chem. Res. 1993, 26, 462. - 1,2-chelation-controlled additions (α-chelation-controlled additions) also formulated by Cram: J. Am. Chem. Soc. 1959, 81, 2748. So please do not refer to as anti-Cram addition as many have! Met OMet XO Can usually provide excellent X diastereoselectivity S Nu– L S Nu R LR 1,2-chelation X = OH, OR Nu– Nu R S OR O S Met OH R R O L L Nu– H RS RL Axial delivery on most stable R R chair-like transition state O Met R RL Nu O Asymm. Syn. Vol. 2, 125. syn-1,3-diol OH OH R RS 1,3-chelation - Examples of 1,2-chelation-control - Nicolaou J. Am. Chem. Soc. 1980, 102, 6611. H O R O MeMgBr O O 106 O >95:5 Zoapatanol synthesis H O R O HO Me Reduction Reactions Dale L. Boger -But to invert the stereochemistry O O H O O Me HO BrMg O R Me O Zoapatanol Monensin synthesis Me OH - Still J. Am. Chem. Soc. 1980, 102, 2117, 2118 and 2120. CH3 OTBS O H MgBr O O Ph TBS = H O R OTBS O H O Ph 50:1 Stereoselectivity Si - Note that non chelation-controlled additions exhibit relatively modest stereoselectivities, but chelation-controlled additions can exhibit very good stereocontrol. - Kishi Tetrahedron Lett. 1978, 2745. J. Am. Chem. Soc. 1979, 101, 260. H Et O Me Me EtMgBr H BnO O MeEt OH OBn O Et Me OBn - Evans J. Am. Chem. Soc. 1990, 112, 5290. BnO H Me MeMgBr O O Met OAc CH2Cl2−Et2O H BnO Me O Me OH OH H H R Nu– Nuc O HO R O O Met Nu– = PhMgI MeMgBr or MeLi LiAlH4 (sBu)3BHLi (sBu)3BHLi R = CH3 Ph Ph Ph CH3 Met - Chelation Model O OO Nu– Nu - Felkin Model OH H H R chelation-controlled product R O O R H Note: here Felkin model will predict wrong product 100:0 100:0 84:16 100:0 78:22 R O OH H Nu Nu– Felkin model predicted product 107 Modern Organic Chemistry The Scripps Research Institute - Effect of metal and solvent chelation product H C7H15 O O I II pentane CH2Cl2 Et2O THF 90 93.5 90 100 10 6.5 10 0 Me C7H15 O II I II M = Li pentane 67 33 " CH2Cl2 75 25 " Et2O 50 50 " THF 41 59 Note: Li is less able to coordinate to two O atoms and THF has good solvation capabilities (ie., removes Li+; no α-chelation control) Still Tetrahedron Lett. 1980, 21, 1031. H Bu OH I solvent solvent Nu– MEMO HO Bu MEM protecting group M = MgBr " " " + MEMO –78 °C O H C7H15 H C7H15 nBuM O Felkin product H Nu O R M chelation model Me OR C7H15 OH chelation-controlled product Two models provide different products Me H Me H RO OC7H15 Felkin model H Nu C7H15 Nu RO Me OH HO C7H15 OR Felkin model predicted product Nu– _ _ _ - Effect of protecting group H C7H15 nBuMgBr THF, –78 °C RO O H C7H15 RO HO Bu R = MEM > 99:1 = MOM > 99:1 = MTM > 99:1 = CH2Ph 99.5:0.5 = CH2OCH2Ph 99:1 = THP 75:25 Still Tetrahedron Lett. 1980, 21, 1035. RO Note: THP poor for chelation-control. RO RO LiAlH4 O Note: OTBS does not chelate OH R = Bn R = TBS Et2O, –10 °C THF, –20 °C 98 5 + : : Overman Tetrahedron Lett. 1982, 23, 2355. 108 OH 2 95 chelation-controlled Felkin addition Reduction Reactions Dale L. Boger H Me Nu– Et R'O H Me –78 °C Et R'O HO R O R' = CH2Ph chelation-controlled > 99:1 MeMgCl Et2O 60:40 MeLi THF 60:40 MeMgCl Et2O R' = TBS MgCl 10:90 THF Reetz J. Chem. Soc., Chem. Commun. 1986, 1600. OH OH R1 2 R O Zn(BH4)2 R 1 Et2O, 0 °C 2 R OH Note: Silyl ether poor for chelation-control. Felkin addition anti-1,2-diol chelation-controlled addition 77–99 : 23–1 versus OTBS Note: TBS very good at suppressing chelation. R 1 R2 1) Red-Al toluene, –78 °C R1 2) Bu4NF OH R2 O OH Nakata Tetrahedron Lett. 1983, 24, 2653 and 2661. syn-1,2-diol Felkin addition 76–98 : 24–2 - Effect of metal OBn Lewis Acid O OH BF3•OEt2 2:3 ZnBr2 3:1 MgBr2 > 250:1 TiCl4 > 250:1 Keck Tetrahedron Lett. 1984, 25, 265. O Zn(BH4)2 K-selectride OH R OBn SnBu3 H THF, –95 °C OBn 90:10 Felkin addition R Et2O, –30 °C OBn OH R OBn 95:5 chelation-controlled Note: Red-Al was anti selective due to coordination of OBn Tsuji Tetrahedron Lett. 1985, 26, 5139. Ph O O Met O Back side attack blocked by phenyl group O MeMgBr O OH H Me H 98% de Metal chelate and preference for H-eclipsed carbonyl conformation provides a dominant conformation. Whitesell Acc. Chem. Res. 1985, 18, 280. J. Org. Chem. 1986, 51, 5443. -1,3-Chelation-Controlled Additions (β-chelation-controlled additions): - First highly selective method was developed with R3B/NaBH4 and later with Et2BOCH3–NaBH4 in THF–MeOH: Pai Tetrahedron 1984, 40, 2233. Shapiro Tetrahedron Lett. 1987, 28, 155. (syn:anti 98:2) - Dibal-H (> 92:8 syn:anti) Kiyooka Tetrahedron Lett. 1986, 27, 3009. 109 Modern Organic Chemistry The Scripps Research Institute L external H– delivery M O Chelation control with L O R' H _ _ _ H– HO H R' O R'' Axial H– or Nu– delivery Note: Typically easy to achieve chelationcontrolled syn-1,3-diol. R'' H– OH R' H L O M L O R' OH R'' syn-1,3-diol R'' H Controlled with internal H– R' delivery OH O L – B O L R'' H R' OH R'' anti-1,3-diol - Examples of anti-1,3-diol preparation: Evans, Carreira, Chapman J. Am. Chem. Soc. 1988, 110, 3560. OH H O tBu OH + tBu NaBH4 90 : Me4NBH(OAc)3 OH H tBu 10 no reaction O OH tBu tBu OH H OH OH H tBu NaBH4 1 : 1 Me4NBH(OAc)3 300 : 1 HOAc, low temperature protonates carbonyl, activation for reduction, no reduction without HOAc - Note that Me4NBH(OAc)3 is unreactive toward carbonyl unless carbonyl oxygen is protonated. - The key to success is the lack of reactivity of the reagent in the intermolecular reaction, which permits formation of complex: First example of NaBH(OAc)3/HOAc intramolecular reduction of a ketone, see: Saksena, Mangiaracina Tetrahedron Lett. 1983, 24, 273. For the reduction of aldehydes in the presence of ketones which are not reduced, see: Gribble J. Chem. Soc., Chem. Commun. 1975, 535. AcO O 110 – B OAc HO internal axial hydride delivery H Reduction Reactions Dale L. Boger OH OH O OH Me4NBH(OAc)3 HOAc 92% Me H Me 98:2 OAc H O B O Me has two equatorial substituents, on the chair-like transition state excellent diastereoselectivity OAc R H H OH O OH OH Me4NBH(OAc)3 HOAc 84% Me H H O OAc B O axial alkyl group, but no destabilizing 1,3-diaxial interactions R1 still observe excellent diastereoselectivity Me O Si H O H R + Lewis acid (to activate carbonyl) R2 iPr 2SiHO iPr 2SiHCl R2 OAc R H -Also, works with OH O Me 98:2 Lewis acid activation O R1 Et3N, DMAP 1) SnCl4, –80 °C R2 Davis Tetrahedron 1988, 44, 3761. OH OH R1 R2 internal H– delivery anti-1,3-diol 2) HF - Nucleophiles other than H− BnO −78 °C H Me O Me BnO CH2Cl2 MeMgCl, THF MeTiCl3 OH SnBu3 Me H Me Lewis Acid BnO OH CH2Cl2, −78 °C TiCl4 95:5 SnCl4 95:5 BF3•OEt2 85:15 Reetz Tetrahedron Lett. 1984, 25, 729. BnO 40:60 90:10 Reetz J. Am. Chem. Soc. 1983, 105, 4833. O g. Felkin Addition to Other π-Systems - Reetz Angew. Chem., Int. Ed. Eng. 1989, 28, 1706. R NBn2 Bu2CuLi R H H Bu CO2Et NBn2 >95:5 (R = CH2Ph) _ _ _ H CO2Et NBn2 - Felkin Model H H NBn2 H H R CO2Et H H CO2Et R Bu _ _ _ H CO2Et NBn2 R Bu Nu– (Bu– ) 111 Modern Organic Chemistry The Scripps Research Institute But, CO2Et R CO2Et H R H Bu CO2Et NBn2 CO2Et NBn2 >95:5 (R = CH2Ph) _ _ _ H Bu2CuLi Bu– smaller interaction R H H Bu R CO2Et CO2Et H H CH(CO2Et)2 NBn2 NBn2 compared with NBn2 H H Bu H CO2Et H R CO2Et R CO2Et NBn2 CO2Et serious destabilizing interaction Nu– (Bu– ) - Rationalize the following results: R H tBuOOH CO2Et KOtBu THF/NH3 NBn2 O R H R = CH3 46% R = PhCH2 60% R= 68% R = TBDMSOCH2 80% CO2Et + NBn2 > 96 R H : O CO2Et NBn2 4 E. Aluminum Hydride Reducing Agents - LiAlH4 coordinates with carbonyl oxygen and activates it towards reduction. H O H Al Li H H H k1 FAST O Al H H H H O Al H O H k2 H O O k3 k4 - Rate of addition decreases as additional alkoxy groups are placed on Al: k1 > k2 > k3 > k4, especially for hindered ketones. - The aluminum alkoxide hydrides are stable in that they do not disproportionate. - Reagents have been designed which are less reactive, thus more selective: - Reactivity: LiAlH4 > LiAl(OR)H3 > LiAl(OR)2H2 > LiAl(OR)3H LiAlH4 3 ROH LiAlH(OR)3 - Most common are LiAlH(OCH3)3 and LiAlH(OtBu)3 112 Reduction Reactions Dale L. Boger - Examples: more reactive towards nucleophiles OH H LiAlH4 H HO O H H H O H O OH H H H LiAlH(OR)3 0 °C, Et2O O H O H H Chemoselectivity: differentiation between competitive functional groups vs. Regioselectivity: differentiate between orientations. - Lithium trialkoxyaluminumhydrides can be chemoselective. OH O OH H O + NaBH4 36–45 : 55–64 LiAlH4 37–48 : 52–63 LiAlH(OCH3)3 2–8 : 92–98 LiAlH(OtBu)3 4–12 : 88–96 - this is actually dimeric in solution, so effective bulk greater than LiAlH(OtBu)3 - degree of stereocontrol is concentration dependent with LiAlH(OCH3)3 (dimer and higher aggregates) but not LiAlH(OtBu)3 (monomeric) F. Borohydride Reducing Agents - Borohydrides (Na+, Li+, K+, Zn2+) are nucleophilic H– sources. - Alkoxyborohydrides (RO)3B–H tend to disproportionate. Na (RO)3BH NaBH4 - Therefore, k1 ~ k2 ~ k3 ~ k4 for the stepwise reactions and you can't typically moderate the reactivity (electronically) by introducing alkoxy substituents. - However, substitution with bulky alkyl groups on boron will moderate reactivity and diastereoselectivity. 113 Modern Organic Chemistry The Scripps Research Institute OH O OH CH3 CH3 + CH3 LiAlH4 75 : 25 BH3•THF 74 : 26 21 : 79 <1 : >99 <1 : >99 2 BH Li-Selectride 3 BHLi K-Selectride 3 BHK - NOTE: on diborane B2H6 = H H H B B H H H 2 BH3 O 2 H3B - THF optimally provides uncomplexed, monomeric BH3 available for reduction (or other reactions). - In ether (B2H6), or in the presence of amines (BH3•NR3), less reactive borane-complexes are formed. B2H6 BH3•THF BH3•OEt2 BH3•SMe2 BH3•NR3 H3B stable B2H6 NR3 2 BH3 O H3B not stable reactions of B2H6 in Et2O or in the presence of 3° amines will be slower than reactions run in THF - NaBH4 requires activation of the carbonyl by hydrogen-bonding with alcoholic solvent for reductions. Therefore the reactions are run in alcoholic solvents. The reagent slowly reacts with solvent: MeOH (30 min) > EtOH (slow) > iPrOH (stable) > tBuOH (stable). H O R O R' R H B H H H - But trialkylborohydrides (R3B–HM+) are reactive enough to use in ethereal solvents (e.g., THF) and don't require this activation of C=O by solvent. - LiBH4 is also more reactive than NaBH4 (Li+ coordinates better to carbonyl oxygen, activating the carbonyl toward attack by H– ). - Differences in reactivity can give rise to Chemoselectivity: 114 Reduction Reactions Dale L. Boger OH O NaBH4 O O O O LiBH4 OH Carbonyl Reduction Reagents: Larock pp 528–552. Chem. Soc. Rev. 1976, 5, 23. Tetrahedron 1979, 35, 449. J. Am. Chem. Soc. 1981, 103, 4540. J. Org. Chem. 1991, 56, 4718. Top. Stereochem. 1979, 11, 53. HO G. Hydride Reductions of Functional Groups LiAlH4 RCH2NR'2 H H R NR'2 decreasing reactivity Substrate Product RCOCl RCH2OH RCHO RCH2OH RCOR' RCH(OH)R' OH O RCH2OH + R'–OH RCOOR' RCOO RCHO H2O RCH2OH (slow) OAlR2 R H NR'2 requires vigorous H reductant to further reduce this R N Al LiAlH4 RCONR'2 RCH2NH2 or RCHO RC N RCH2NH2 or RCHO - DIBAL-H + RC N (at 0 °C) gives good yields of RCHO N OH NHOH NH2 or R X = Br, Cl, I, OSO2R R' R R' RNO2 RNH2 RCH2X RCH3 RCHX R' RCH2R' R R' 115 Modern Organic Chemistry The Scripps Research Institute O O - Reductions of R R O O R NR'2 R H OH H OAl NR'2 R R NR'2 OH H+ LiAlH4 R' N R' R best procedure is use of DIBAL as reducing agent at –78 °C - quench with MeOH at –78 °C to avoid over reduction. R NR'2 quench NR'2 H - or other specially selected amides will cleanly give aldehyde: enlisting these electrons disrupt the aromaticity of pyrazole R Al O O 1. R H LiAlH4 N N R Et2O, 0 °C (–20 °C) R N N very slow breakdown to iminium ion intermediate very slow Ried Angew. Chem. 1958, 70, 165. O 2. R N R N N no longer aromatic H O Al LiAlH4 N very slow R N too strained Brown J. Am. Chem. Soc. 1961, 83, 2016 and 4549. 3. Weinreb amide - A more recent and now widely employed method for controlled reduction and nucleophilic addition (i.e. RLi) to carboxamides was introduced by Weinreb (Tetrahedron Lett. 1981, 22, 3815). O Ph OMe N Me LiAlH4 H Ph O Al O OMe N Me H3O Chelation stabilizes intermediate which does not breakdown during the reaction, but only upon workup. O O OMe DIBAL-H N Me 0 °C H 74% 116 NR'2 Ph H Reduction Reactions Dale L. Boger O O OMe DIBAL-H N 0 °C Me H OH + 76% O BOCHN 3% O OMe LiAlH4 N Me O RLi H + H BOCHN 88% O THF OMe N −78 to 25 °C R H Me Lipshutz Tetrahedron Lett. 1999, 40, 7889. Castro Synthesis 1983, 676. 4. The Rosenmund reduction is a much older method that may be utilized to convert carboxylic acids to aldehydes via the acid chloride. RCO2H RCOCl H2 Pd/BaSO4 RCHO Rosenmund Ber. 1921, 54, 425; Ber. 1918, 51, 585. Review: Org. React. 1948, 4, 362. Burgstahler Synthesis 1976, 767. 5. Bu3SnH will selectively reduce selenoesters to aldehydes without further reduction by a free radical mechanism. O R Bu3SnH SePh 80 °C O Bu3SnSePh R O Bu3Sn R acyl radical - Also possible to promote decarbonylation prior to H reduction to achieve conversion to the Bu3SnH corresponding hydrocarbon. Bu3SnSePh Pfenninger Helv. Chim. Acta 1980, 63, 2328. - Review of RCOX RCHO: Comprehensive Org. Syn., Vol. 8, pp 259 and 283. 6. Bu3SnH−InCl3 RCOCl Bu3SnH 0.1 equiv InCl3 RCHO 0.2 equiv Ph3P > 80% Baba Tetrahedron Lett. 2000, 41, 113. 7. McFadyen–Stevens reduction: J. Chem. Soc. 1936, 584. O O B: N NHTs R N R N H X X CO2Me CHO NH NH NH NH X = OCH3 X=H O R H 34% 39% Boger J. Org. Chem. 1988, 53, 1405. (Prodigiosin) 117 Modern Organic Chemistry The Scripps Research Institute - Reactions of Borane (BH3) Carboxylic acids may be selectively reduced in the presence of a wide range of functional groups. an electrophilic reagent Substrate Product O RCOOH decreasing reactivity Amides may be reduced selectively in the presence of esters. R O B 3 X RCH2OH RHC CHR' RCH2CH(B)R' RCONR'2 RCH2NR'2 RCHO, RCOR' RCH2OH, RCH(OH)R' RC N (slow) RCH2NH2 (very slow, Lewis acid activation required) O OH RCH2OH RCOOR' NH2 NOR RCOCl RCH2OH RCOO , RNO2 no reaction or But: see Tetrahedron Lett. 1982, 23, 2475. H. Characteristics of Hydride Reducing Agents Borohydrides 1. NaBH4 - Review: Aldrichim. Acta 1979, 12, 3. - Mild reducing agent used primarily for the reduction of aldehydes and ketones. - Also available as NaBD4, NaBT4 (although somewhat less reactive) for labelling. - H+ workup of NaBH4 reductions may form BH3 (if excess NaBH4 used) might react with other functional groups (this is the origin of the discovery of BH3 and its hydroboration of alkenes). - NaBH4 reacts with H2O, CH3OH at 25 °C ca. 30 min reacts only slowly with EtOH (good solvent), is stable in iPrOH or tBuOH and can also be used in diglyme but the latter reduction is very slow. Although amides are not reduced by NaBH4, the corresponding imino ester salts can be Et3O+BF4− O Ph NEt2 OEt NaBH4 NEt2 EtOH, 25 °C 75% Borch Tetrahedron Lett. 1968, 61. CH2Cl2 Ph Ph NEt2 2. NaCNBH3 - Less reactive than NaBH4. - Stable in aqueous solutions even at pH > 3 (permits activation of C=O by protonation). - Can be used in CH3OH. - Can be used in THF but reduction very slow. 118 NHOH Reduction Reactions Dale L. Boger - Reductive amination (Borch reduction): O + H2NR N NaCNBH3 pH 3–6 relatively unreactive toward NaCNBH3 R H+ HN R H N R very good way to make 2° amines CHO + MeNH2 Under acidic conditions the protonated imine is more reactive than starting ketone or aldehyde. NaBH3CN N Me CHO Borch J. Am. Chem. Soc. 1969, 91, 3996; 1971, 93, 2897. J. Chem. Soc., Perkin 1 1984, 717. - Review: Comprehensive Org. Syn., Vol. 8, pp 25–78. This review also discusses the diastereoselectivity of cyclic/acyclic imine/iminium reductions with comparisons to the corresponding ketone. Many similarities but also many important distinctions. 3. LiBH4 - More reactive than NaBH4 (Li activates C=O by coordination). - Can be used in THF, diglyme and non protic solvents. Reactivity: Et2O > THF = diglyme > iPrOH - Excellent reagent for mild reductions. O OH OEt 98% - clean 1,2-reduction! - NaBH4 does not typically reduce esters 4. Me4NBH4, Et4NBH4 - Soluble in nonpolar aprotic solvents (e.g., THF, benzene). 5. Zn(BH4)2 - Good in instances of potential competing 1,4-reduction. - Zn+2 coordinates to and activates carbonyl. - Good for chelation-controlled reductions. O OH OH + 96% 59% Zn(BH4)2 NaBH4 - Review: Narasimhan Aldrichim. Acta 1998, 31, 19. 4% 41% 6. NaBH4/CeCl3 (catalytic amount (0.1 equiv)) - Luche J. Am. Chem. Soc. 1981, 103, 5454; 1978, 100, 2226. - Readily enolizable carbonyl can be reduced. - also true of other nucleophiles O RMgBr RLi OH CeCl3 R - clean addition, no enolization O O RMgX R RMgX CeCl3 OH Imamoto J. Am. Chem. Soc. 1989, 111, 4392. Review: Liu Tetrahedron 1999, 55, 3803. 119 Modern Organic Chemistry The Scripps Research Institute - No conjugate reduction: clean 1,2-reduction. -Reagent comparisions for 1,2- vs. 1,4-reduction O 1,2 : 85 : 0 : 97 : 64 : 98 : 99 : >99 : 90 : 0 : Reagent LiAlH4 NaBH4 NaBH4/CeCl3 LiAlH4/CeCl3 DIBAL-H DIBAL-H/nBuLi 9-BBN LiAlH(OMe)3 LiAlH(OtBu)3 1,4 15 100 3 36 2 1 1 10 100 (100%) (100%) (100%) (99%) (81%) (83%) (85%) O 1,2 : 94 : 59 : >99 : 98 : 98 : 94 : >99 : 95 : 22 : 1,4 6 41 1 2 2 6 1 5 78 (97%) (90%) (100%) (100%) (100%) (96%) (85%) !!! Masamune J. Chem. Soc., Chem Commun. 1970, 213. Brown J. Org Chem. 1977, 42, 1197. 7. NaBH4–CoCl2 - Selective reduction of nitriles. H2N NC CO2Et CO2Et Ganem J. Am. Chem. Soc. 1982, 104, 6801 - But will also reduce olefins, allylic alcohols, and ketones. OMOM OMOM MOMO MOMO OH OH Iwata Chem. Pharm. Bull. 1990, 33, 361. 8. Me4NBH(OAc)3 and NaBH(OAc)3 - Unreactive, no intermolecular ketone reductions. - OAc can exchange with substrate alcohol and provides opportunity for intramolecular reductions (CH3CN–HOAc). Used to form anti-1,3-diols from acyclic β-hydroxyketones. 9. KBH(OiPr)3 - Stable (does not undergo disproportionation reaction as with other alkoxy BH), mild reagent. - Used in THF and only reduces aldehydes and ketones; bulky reagent so it gives equatorial attack on cyclohexanones. H B 10. 9-BBN - Stable solid; more stable and less reactive/more selective. - Gives good 1,2- vs. 1,4-reduction selectivity. - Very selective reagent. K-Selectride 11. Li-Selectride BHK 3 3 - Large reagents, near exclusive cyclohexanone equatorial H– delivery. - Very bulky. BHLi 120 Reduction Reactions Dale L. Boger - Very reactive and give preferential 1,4-reduction. O - Reductive alkylation with regiospecific enolate generation. OBR3 can alkylate these enolates Ganem J. Org. Chem. 1976, 41, 2194. 12. LiBHEt3 (Super Hydride) - Very powerful (stronger than LiAlH4), so good for reductions which are otherwise slow. O OH H R X R H Relative reactivity: Et3BH– (10,000), AlH4– (240), BH4– (1). Brown J. Org. Chem. 1983, 48, 3085. 13. NaBH4–HSCH2CH2SH H S B H S - Used in THF. - Guida J. Org. Chem. 1984, 49, 3024. RCO2Et PhCO2iPr THF 83% RCH2OH PhCH2OH Note the selectivity available PhCO2tBu PhCN PhCONH2 PhCH2NH2 Yet powerful enough to reduce amides Aluminum Hydrides 1. LiAlH4 - LiAlD4 and LiAlT4 are also available for labelling. - Reductions can be conducted in ether, THF, DME, diglyme. - Workup best conducted by 1,2,3 method: for 1.0 g LiAlH4 used, add 1 mL H2O (slowly) then 2 mL of 10% aqueous NaOH, then 3 mL H2O Al salts are now easily filtered 2. NaAlH4 - Not quite as reactive as LiAlH4, but still quite strong reducing agent. - THF, DME, diglyme solvents. 3. LiAlH(OtBu)3 LiAlH(OEt)3 LiAlH(OMe)3 this is the largest reagent (due to aggregation) of the three - Use in THF, diglyme. - Review on alkoxyaluminum hydrides: Org. React. 1985, 34, 1; 1988, 36, 249. 121 Modern Organic Chemistry The Scripps Research Institute 4. NaAlH2(OCH2CH2OMe)2 = REDAL-H OH benzene 80 °C COOCH3 OH powerful reducing agent CH3 OH Cerny, Malek Tetrahedron Lett. 1969, 1739. xylene 140 °C OH - Xylene, benzene, toluene good solvents. - Good for epoxide openings (especially if able to be directed by proximal OH), halide and sulfonate reduction. 5. = DIBAL-H 2 AlH R NAl H - Because there is no metal cation (Li+, K+, etc.) in the reagent, very good for directed reductions (i.e., chelation-controlled reductions). - Good for 1,2- vs. 1,4-reduction. H H CO2Et OH NBOC NBOC 80% - Good for RC N RCHO via - Also good for RCOOR' CO2Me O NBOC RCHO CHO DIBAL-H O –78 °C via Garner Org. Syn. 1992, 70, 18. NBOC O Al R OR' H stable at –78 °C but breaks down at higher temperatures to give alcohol (upon further reduction) to get RCHO, quench must be conducted at –78 °C (use MeOH or HOAc as proton source, H2O freezes into a solid) then warmed to 25 °C - Also, use of noncoordinating hydrocarbon solvent (toluene) provides better control than THF for reductions to RCHO. 6. AlH3 AlH3–NR3 - Park J. Org. Chem. 1990, 55, 2968. RCO2H Cl RCH2OH CO2Et Cl COCl O2N OH OH O2N 122 Reduction Reactions Dale L. Boger O NMe2 NMe2 CN NH2 7. Cl2AlH Strong electrophilic reducing agent O O Cl2AlH AlCl3 Et2O, reflux O O OH Cl2Al O O ClAlH OH H 94% Eliel Org. Syn. 1967, 47, 37. A related and often overlooked alternative enlists NaBH4 + Lewis acid CO2tBu Me NaBH4 H H Me BF3 diglyme, THF H OtBu Me Me H H H H H 76% Pettit J. Org. Chem. 1962, 27, 2127. Eliel J. Org. Chem. 1964, 29, 1630. (thiol ester dialkylsulfide) Other Representative Reagents R F 1. Bu3SnH–Bu4NX, X = Cl, F R Sn R H - Shibata Chem. Lett. 1991, 307. Br Br O OH O OH - Can alkylate intermediate directly: O OSnR3 Bu3SnH OR' R'X Bu4NCl OCH3 Ph O OCH3 Bu3SnH Bu4NF 81% 100% Felkin addition Ph OH 2. PhMe2SiH OH Ph OBz Felkin addition 96 : 4 O 1) PhMe2SiH Ph Bu4NF, HMPA, 0 °C 2) KOH 82% OH OBz 1) PhMe2SiH TFA, 0 °C 2) KOH 72% Ph OBz chelation-type control 93 : 7 Hiyama J. Org. Chem. 1988, 53, 5405 and 5415. J. Am. Chem. Soc. 1984, 106, 4629. 123 Modern Organic Chemistry The Scripps Research Institute 3. Et3SiH Et3SiH cat. O OSiEt3 - Regioselective enolate trap, conjugate reduction. 4. (EtO)3SiH/catalytic Ti(OiPr)4 - No solvent, stable to air. - Reduces esters to alcohols in the presence of a wide variety of functional groups. RCO2Et RCH2OH - Buchwald J. Org. Chem. 1992, 57, 3751. 5. [(Ph3P)CuH]6 O O [(Ph3P)CuH]6 85% O O H 94:6 cis:trans Stryker Tetrahedron Lett. 1988, 29, 3749; 1989, 30, 5677; 1990, 31, 3237. J. Am. Chem. Soc. 1988, 110, 291. Tetrahedron 2000, 56, 2153. I. Asymmetric Carbonyl Reductions - Review: Comprehensive Org. Syn., Vol. 8, pp 159. - Itsuno Org. React. 1998, 52, 395. 1. Catalytic Asymmetric Reduction - Corey J. Am. Chem. Soc. 1987, 109, 5551. Ph Ph H HN BH3 Ph B H H O H Ph H N O H3B B H H Ph N O B H Better catalyst 80–97% ee H3B B H O N H3B - Corey J. Am. Chem. Soc. 1987, 109, 7925. (catalytic) N B R O β-naph R >90% ee R = H, Bn, CH3, Bu 124 R R O B N O H2B H intramolecular H– delivery through boat-like T. S. O O RS β-naph B H RL H Ph Ph Ph Ph N H Ph RS RL coordinates anti to large substituent (in plane) RS vs. RL in plane carbonyl lone pair complexes boron Reduction Reactions Dale L. Boger - Corey Tetrahedron Lett. 1989, 30, 6275. H Ph Ph N O R O B Bu H OH O CCl3 R BH N3 H COCl H O Cl R Cl 92–98% ee O R CCl3 OH N3 H2N H H2 CO2H Pd–C 88–98% N3 H 80–98% R R CO2H - General, catalytic, enantioselective synthesis of α-amino acids. - Corey J. Am. Chem. Soc. 1992, 114, 1906; Tetrahedron Lett. 1992, 33, 3431, 3435. - Review: Corey Angew. Chem., Int. Ed. Eng. 1998, 37, 1986. 2. Stoichiometric Reagents for Asymmetric Carbonyl Reductions - Bothner-By J. Am. Chem. Soc. 1951, 73, 846 (camphor ligand and first report of an asymmetric reduction with optically active reagent). Most subsequent efforts have used chirally modified LiAlH4. O OH - LiAlH4/N-methylephedrine Ph HO H R NMe2 R= R= R= R= R Me Et iPr tBu 75 % 62 % 30 % 36 % ee ee ee ee Mosher J. Am. Chem. Soc. 1972, 94, 9254; J. Org. Chem. 1973, 38, 1870. Me Ph N Li R Al OH R R= O O HO H > 90% 89% ee R-alcohol - Vigneron Tetrahedron Lett. 1974, 2065; 1979, 2683; Tetrahedron 1976, 32, 939; used in cationic cyclization approach to steroids. - Early work with acetylenic ketones, W. S. Johnson HO O O O O asymmetric total synthesis of steroids via cation–olefin cyclizations 84% ee Brinkmeyer J. Am. Chem. Soc. 1977, 99, 8339. Johnson J. Am. Chem. Soc. 1977, 99, 8341. 125 Modern Organic Chemistry The Scripps Research Institute Me2N - N Li AlH2 O O HO H Me2N 92% 47% ee Seebach Chem. Ber. 1974, 107, 1748. - LiAlH4/N-methylephedrine/N-ethylaniline or N-ethyl 2-pyridylamine (high ee's for enones: >90% ee) - Koga, Terashima Tetrahedron Lett. 1980, 21, 2753. O - BINAL-H Li H O Al O OEt OH R R R = Me 95% ee R = nBu 100% ee R = Et 98% ee R = iPr 71% ee R = nPr 100% ee R = tBu 44% ee Noyori J. Am. Chem. Soc. 1984, 106, 6709. (R)-BINAL-H O (S)-BINAL-H 73% 99.9% ee N N O N N (–)-mappicine O OH Boger J. Am. Chem. Soc. 1998, 120, 1218. Cl B - Ipc2BCl O Cl Ipc B H O Ph 72% CH3 98% ee Me Midland J. Org. Chem. 1989, 54, 159. Brown J. Org. Chem. 1989, 54, 4504. OH H 3. Enzyme-catalyzed Ketone Reductions have been extensively used in organic synthesis - Review: Comprehensive Org. Syn., Vol. 8, pp 183. 4. Baker's Yeast O CO2Et 126 Baker's Yeast 60–70% OH CO2Et 84–87% ee Seebach Org. Syn. 1985, 63, 1 Reduction Reactions Dale L. Boger J. Catalytic Hydrogenation - Amine and sulfur-containing groups will tend to poison catalysts (especially Pd/C). H - Comprehensive Org. Syn. Vol. 8, 479. - Comprehensive Org. Syn. Vol. 8, 524. Li/NH3 H O H Solvent H O EtOH–HCl 93 : 7 53 : 47 EtOH H2–Pd/C P. Sabatier received the 1912 Nobel Prize in Chemistry for his contributions to catalysis, especially the hydrogenation of unsaturated organic compounds. cis : trans O H 93% : 7% - Comprehensive Org. Syn., Vol. 8, pp 417 and 533. - Comprehensive Org. Syn., Vol. 8, pp 471. DMF 79 : 21 EtOAc Et2O 57 : 43 hexane 48 : 52 MeOH nPrOH t BuOH 41 : 59 58 : 42 68 : 32 91 : 9 1. H2 delivery from least hindered face of double bond. 2. Cis H2 delivery - activity of catalysts toward C=C: Pd > Rh > Pt > Ni > Ru 3. Increasing substitution on olefin decreases reactivity. - note potential isomerization of olefin and H-migration/allylic exchange in D2/T2 hydrogenations - propensity for olefin isomerization: Pd >> Rh/Ru/Pt > Ir 4. Alkynes are more reactive than alkenes. Reagents have been developed to selectively prepare olefins from alkynes without over reduction: - Lindlar catalyst: Pd(CaCO3)/Pb, poisoned or deactivated catalyst - will only reduce an alkyne to an alkene (cis) R R R' H H Lindlar Helv. Chim. Acta 1952, 35, 446. R R' R' slow 5. Many kinds of catalyst, but most common are 5–10% Pd/C or PtO2 - Pd(BaSO4): Rosenmund catalyst (RCOCl → RCHO) Rosenmund Chem. Ber. 1918, 51, 585. - Pd(OH)2: Pearlman catalyst, often used for difficult debenzylations where other, more typical, Pd catalysts fail. Pearlman Tetrahedron Lett. 1967, 17, 1663. - PtO2 H2 Pto (Adam's catalyst) Roger Adams (Ph.D. 1912, Harvard Univ.; postdoctoral with Diels and Willstatter) was the central figure in US organic chemistry in the 1930−40's. He established the structures of tetrahydrocannabinol, gossypol, chaulmoogric acid, and the Senecio alkaloids, and contributed to the development of many fundamental organic reactions. 127 Modern Organic Chemistry The Scripps Research Institute NR' - PtO2 is particularly good for imine reduction to amines. - Amines will poison Pd/C catalyst, but not Pt(0). R HNR' R" R H R" - Raney-Ni (Ra–Ni) also useful (especially for removing sulfide groups). Generally stored in alcoholic solvent, ignites upon contact with air. It loses its activity over ca. 6 months. Various reactivities depending upon the preparation (i.e. W-1 through W-7 Ra–Ni). N N Husson Heterocycles 1991, 32, 663. W-2 Ra–Ni N H S EtOH, reflux 85% S N H Chem. Rev. 1962, 62, 347. Comprehensive Org. Syn. Vol. 8, p 835. - Rh/Al2O3, the high activity of rhodium often permits the use of room temperature and atmospheric pressure even for difficult reductions. Rh/Al2O3 Biali J. Am. Chem. Soc. 1990, 112, 9300. 60% 1 note: what would you expect the ground state conformation of 1 to be? Good for the reduction of nitriles and aromatic rings: H2 CN 5% Rh/Al2O3 HN NHTs 25 °C, 1 atm MeO2C NHTs 76% O H H2 O O 5% Rh/Al2O3 25 °C, 3 atm OMe H Mendoza J. Org. Chem. 1991, 56, 452. Tarbell J. Am. Chem. Soc. 1964, 86, 2902. OMe - (Ph3P)3RhCl Wilkinson's catalyst (homogeneous). - a homogeneous catalyst (e.g., dissolve in organic solvent for reaction). - Review: Org. React. 1976, 24, 1. - One of the earliest, successful examples of catalytic asymmetric synthesis entailed the homogeneous hydrogenation of enamides to provide amino acid derivatives G. Wilkinson received the Nobel Prize in Chemistry in 1973 for deducing the structure of metallocenes. CO2H NHAc DIOP 73% ee DIPAMP 34% ee CO2H H2, 1 atm Rh-diphosphine* H NORPHOS BPPM 90% ee 99% ee BINAP 98% ee NHAc BPPFA 93% ee Kagan J. Chem. Soc., Chem. Commun. 1971, 481. Knowles (Monsanto) J. Chem. Soc., Chem. Commun. 1972, 10; J. Am. Chem. Soc. 1977, 99, 5946. K. Dissolving Metal Reductions 1. Birch Reduction R - Reviews: Comprehensive Org. Syn., Vol. 8, 489. Org. React. 1992, 42, 1 (aromatic ring reduction). Org. React. 1976, 23, 1 (carbonyl and enone reductions). - First reported by Wooster J. Am. Chem. Soc. 1937, 59, 596. - Extensively developed by Birch Quart. Rev., Chem. Soc. 1950, 4, 69. 128 H R' R' R H trans alkene - most stable product Reduction Reactions Dale L. Boger a. Reduction potential and solubility Metal Li Na K Solubility (g/100 g NH3) 10.9 24.5 47.8 Reduction Potential –2.99 –2.59 –2.73 Arthur Birch, along with Robert Robinson, was one of the earliest chemists to perform biosynthetic studies using radiolabels although he is best known for the Birch reduction of aromatic rings. b. Solvent system - Typical solvent system NH3 : : 2 THF 1 : : tBuOH 1 Charles A. Kraus (1875–1967) demonstrated that the blue color arising from dissolving sodium in liquid ammonia is a consequence of solvated electrons in the course of research on ammonia. - Liquid NH3 (bp –33 oC) is used to dissolve metal, ether cosolvent (Et2O or THF) is used to dissolve substrate, and a proton source tBuOH; EtOH; MeOH; NH2 is used to quench the reaction. - If proton source is absent: NH3 NH2 NH2 isomerization of diene and overreduction NH3 further reduction - Be sure to use an argon atmosphere, not N2 which forms lithium nitrides. William Ramsay received the 1904 Nobel Prize in Chemistry for his experimental work that included the discovery and isolation of the noble gas family. Hamilton P. Cady (1843−1943) and D. McFarland (1978−1955) discovered He in natural gas in 1905 in Bailey Hall, University of Kansas, an element that had been previously detected only on the sun. "It assures the fact that He is no longer a rare element but a very common element existing in goodly quantities for the uses that are yet to be found for it." A drilling company in Dexter, Kansas thought they hit paydirt with a well that released 9 million cubic feet of gas each day. At a celebration to culminate the discovery, and stock issuance, a burning bale of hay expected to produce a great pillar of flame was extinghuished when pushed into contact. E. Haworth (Univ. of Kansas) collected a sample of the gas which McFarland analyzed as 15% CH4, 72% N2, O2 (0.2 %), H2 (0.8%), and 12 % unknown. H. Cady helped indentify the remainder. Using a method described by Sir James Dewar, all atmospheric gases except H2, Ne (and He) were completely removed (adsorbed) by coconut charcoal at the temperature of boiling liquid air (−310 °F). What remained exhibited spectroscopic properties identical with He detected only on the sun. One of the first secret uses was to inflate blimps and the Allies dirigibles filled with "Gas X" did not explode like the Axis powers zeppelines which were filled with flammable H2. Today, 60% of the He isolated is used for cryogenic applications including NMR and MRI. Commercial NH3 production is second in size only behind H2SO4 and is used extensively in the production of fertilizers (>102 × 106 tons/yr, 1998). Benzene production through the refinement of crude oil reached 37 × 106 metric tons in 1997 and serves as the starting material for a host of derivatives including styrene/EtC6H5. 129 Modern Organic Chemistry The Scripps Research Institute W W W = COOH COO CONR2, SiMe3, Ar (electron-withdrawing groups) Li/NH3 - but CO2R, COR, CHO CH2O , so they are part of donor (D) grouping. e. Common application: hydrogenolysis Ph O Li/NH3 R or H2, Pd/C PhCH3 + RO– 5–10% Pd on C as catalyst H2 can be replaced by HCOONH4 or as the source of H2 and this type of reduction is a transfer hydrogenation: Comprehensive Org. Syn., Vol. 8, 955. f. Examples Me Me - Krapcho J. Am. Chem. Soc. 1959, 81, 3658. CONMe2 CONMe2 - Schultz J. Org. Chem. 1986, 51, 4983. OMe O O OMe N N OMe 130 OMe - Dryden J. Org. Chem. 1961, 26, 3237. OMe - Magnus Tetrahedron Lett. 1997, 38, 1341. OMe Reduction Reactions Dale L. Boger - can also be used for enone reduction and/or reductive alkylation with alkylative trap of the final enolate H /H2O MeO MeO Robinson annulation type product used extensively in steroid synthesis. H O O H O H H H Li/NH3 CH3O H NH4Cl dioxane ether H O H CH3O 78% Johns J. Org. Chem. 1963, 28, 1856. more stable product trans ring fusion Dryden J. Org. Chem. 1961, 26, 3237. - As opposed to cis stereochemistry H O H H H H2 (1 atm) H 5% Pd/C EtOH CH3O H H CH3O - or more vigorous Birch conditions: H O H H H tBuOH CH3O THF H OH H+ H CH3O OH via enone reduction with protonation (ROH present), carbonyl reduction (to give most stable equatorial alcohol) and aromatic ring reduction. H H H Li/NH3 H O H O 2. Dissolving Metal Carbonyl Reduction a. Ketone Reduction - Review: Comprehensive Org. Syn., Vol. 8, 107. - Rule: O t Bu H Li/NH3 Et2O, tBuOH tBu OH 98:2 Birch reduction forms the most stable product. 131 Modern Organic Chemistry The Scripps Research Institute - Exception: Li/NH3 + OH H EtOH O H OH sterically hindered or strained ketones 87 : 13 endo : exo - Mechanism: e O t O OH t Bu Bu Li(0) ROH Li e Bu H OH tBu Li(0) t ROH Li tBu OH Special variants of this reaction include the: b. Acyloin Condensation First report: Freund Justus Liebigs Ann. Chem. 1861, 118, 33. CO2Me OSiMe3 Na toluene TMSCl (H2C)4 CO2Me OSiMe3 Comprehensive Org. Syn., Vol. 3, 613. Org. React. 1976, 23, 259. Org. React. 1948, 4, 256. - Ruhlmann modification: Synthesis 1971, 236. - Mechanism: diketyl generation and diradical coupling or: O O OMe (H2C)4 e OMe OMe OMe e O (H2C)4 OMe O OMe O O O O OMe O O e O O O - Sheehan J. Am. Chem. Chem. 1950, 72, 3376. - Bloomfield J. Org. Chem. 1975, 40, 393. - Bloomfield Tetrahedron Lett. 1968, 591. - Macrocyclization: Finley Chem. Rev. 1964, 64, 573. c. Pinacol Coupling - Review: Comprehensive Org. Syn., Vol. 3, 563. O 2 132 O O e O O O Reduction Reactions Dale L. Boger d. McMurry Coupling - Review: McMurry Chem. Rev. 1989, 89, 1513. McMurry J. Org. Chem. 1977, 42, 2655. Zn–Cu/TiCl3 olefin product LiAlH4/TiCl3 McMurry J. Am. Chem. Soc. 1983, 105, 1660. Mg–Hg/TiCl4 - diol product Corey J. Org. Chem. 1976, 41, 260. e. Radical-Alkyne/Alkene Addition - The ketyl (radical anion) can be trapped in intramolecular reactions: - Stork J. Am. Chem. Soc. 1979, 101, 7107. O O Li/NH3 O OH O or Na/NH3 O H O O O O O O H f. Reductive Alkylation e O O Li CH3 Li(0) Li H Et2O NH3 pKa 35–36 tBuOH pK 16–18 a OH CH3 CH3 ROH H H O enol radical Li(0) e - Regiospecific enolate generation O CH3 CH3 H H ROH second equivalent Li O OH CH3 MeI (E ) H transfer CH3 H H H 133 Modern Organic Chemistry The Scripps Research Institute L. Amalgam-derived Reducing Agents 1. Na−Hg Sodium amalgam is used for the reduction of a variety of functional groups including those leading to the preparation of alkenes and alkynes and for the reductive cleavage of C−S and N−O bonds. SO2Ph Ph 6% Na−Hg OP(O)(OEt)2 Lythgoe J. Chem. Soc., Perkin 1 1979, 2429. DMSO−THF 2 h, 72% Julia Olefin Synthesis: Bu SO2Ph Na−Hg OAc EtOH 79% Bu Bu Bu 6% Na−Hg SO2Ph Ph Julia Tetrahedron Lett. 1973, 4833. EtOH, reflux 92% Posner Tetrahedron Lett. 1973, 935. Ph O O 6% Na−Hg SPh Trost Tetrahedron Lett. 1976, 3477. MeOH, Na2HPO4 90% TBSO TBSO H N O O 6% Na−Hg H N H OH EtOH, Na2HPO4 82% O Keck Tetrahedron Lett. 1978, 4763, 4767. 2. Al−Hg Aluminum amalgam is another metal-based reducing agent. It is quite mild and used effectively in a number of reductions. O OH 10 equiv Al−Hg Cyclic ketones and aldehydes are reduced. Acyclic ketones are inert. THF−H2O (9:1) −10 °C to 25 °C 70% Hulce Tetrahedron Lett. 1988, 29, 525. S nBuLi S RI N Me N R 10 equiv Al−Hg S Et2O−H2O 90% N H Meyers J. Org. Chem. 1975, 40, 2021, 2025. 134 R HgCl2 CH3CN−H2O 71% R CHO Reduction Reactions Dale L. Boger O2N OH H2N OH Al−Hg O O O Et2O−MeOH 100% Ph It is an excellent reagent for reducing nitro groups and azides to amines. O Ph Corey J. Am. Chem. Soc. 1968, 90, 3247. Trost J. Am. Chem. Soc. 1989, 111, 5902. Shin Chem. Lett. 1976, 1095. O O O H OMe H OMe Al−Hg EtOH−H2O THF 99% H HO H Green, Crabbe J. Org. Chem. 1982, 47, 2553. O 1) Al−Hg THF−H2O O MeS Ph N O Ph HN OAc SMe 2) Ac2O 41% OH OAc Keck Synth. Commun. 1979, 9, 281. O O O O Al−Hg SMe N O O N R R Me Ph Me O N O CO2Me Ph O S Ph O N O CO2Me Al−Hg Me N Br Me PhSOCH2Li CH3COHN Br Me THF−H2O −15 °C Me CH3COHN Br N CO2Me Me Boger, Panek J. Org. Chem. 1985, 50, 5790. (total synthesis of lavendamycin) 3. Zn(Hg) Clemmensen reduction Clemmensen Chem. Ber. 1913, 46, 1838. Me Me Zn(Hg) O H HCl 90% H Dauben J. Am. Chem. Soc. 1954, 76, 3864. Reviews: Martin Org. React. 1942, 1, 155. Vedejs Org. React. 1975, 22, 401. 135 Modern Organic Chemistry The Scripps Research Institute M. Other Reduction Methods 1. Diimide Reduction - Review: Org. React. 1991, 40, 91. N N H CO2H H Me CO2H CO2H H CO2H Me + H H H CO2H CO2H CO2H CO2H - Mechanism: H H N N + H H - Cis delivery of H2 N N (N2) complements H2/cat. same results but: many functional groups are stable to conditions/reagent - From least hindered face of olefin - trans > cis olefin (rate) - Rate decreases with substitution of olefin - C=O, NO2, CN, S O , stable S S KO2CN=NCO2K O O –78 °C O O Adam J. Org. Chem. 1977, 42, 3987. no reduction of endoperoxide Relative reactivities toward diimide reduction krel krel krel 1.0 2.04 450.0 20.2 0.28 2.59 0.50 - Decreases with alkyl substitution - Increases with strain 29.0 47.0 2.65 Garbisch J. Am. Chem. Soc. 1965, 87, 2932. OH 136 HN NH OH Mori Tetrahedron 1972, 28, 3739. Reduction Reactions Dale L. Boger - Formation (generation) of reagents (diimide) H i. H2O2 /H2NNH2 H N N old method ii. recent method O H H S N NH O Me N N H H Base + - related to McFadyen–Stevens Reduction. iii. KO2C N N CO2K N N CO2K cat H 25 °C, –CO2 (anhydrous) H H N N KO2C iv. retro Diels–Alder reaction NH NH NH NH + - Example of use: Br H H N N Br Ph Ph - Other reduction methods would give substantial debromination. 137 Modern Organic Chemistry The Scripps Research Institute 138 Hydroboration-Oxidation Dale L. Boger VII. Hydroboration–Oxidation (Reduction–Oxidation) - Review: Comprehensive Org. Syn., Vol. 8, pp 703–732. Brown Organic Synthesis via Boranes, Wiley: New York, 1975. Brown Boranes in Organic Chemistry, Cornell Univ. Press: New York, 1972. A. Mechanism Brown J. Am. Chem. Soc. 1956, 78, 2583; Org. React. 1963, 13, 1. H R R'2BH + R H H2O2 NaOH BR2' R OH + B(OH)3 OH H R H R' B R' O O H R' B R' O H OR' B OR' O R R - anti-Markovnikov addition of H2O to C=C H H H B B H H H + - reversible. - syn (cis) addition. - attack from least hindered face. - boron attaches to least substituted carbon of C=C BH3 H B H B BH3 - rate - Increased by electron-donating substituents on olefins. - Increased by strain of olefins. - Increased by decreased steric hinderance of olefins. The discovery of the unusual bridged structure of diborane vs a once more conventional ethane-like structure H3B−BH3 (G. N. Lewis, S. H. Bauer) occupied the efforts of many of the very best chemists, enlisting newly emerging experimental and theoretical tools, including H. I. Schlesinger, C. Longuet-Higgins, F. Stitt and W. C. Price (IR), J. N. Shoolery (NMR), R. S. Mulliken, K. S. Pitzer, A. D. Walsh (MO and valence bond descriptions), K. Hedberg and V. Schomaker (electron diffraction). Essay: Laszlo Angew. Chem. Int. Ed. 2000, 39, 2071. The reaction is characterized by a slight tendency for H (H–) to add to carbon most capable of stabilizing a δ+ charge or, in other words, for the nucleophilic carbon to attack the electrophilic B. However, it is also characterized by a nonpolar transition state where the rate of reaction and regioselectivity are determined principally by steric factors with unsymmetrical olefins. BH3 B2H6 )2BH disiamylborane (Sia2BH) BH2 thexylborane (ThxBH2) H B 9-BBN H. C. Brown (Purdue University) received the Nobel Prize in Chemistry (1979) for the discovery and development of the hydroboration reaction. He is also responsible for the discovery and development of NaBH4 and most of the many, subsequent boron and aluminum hydrides used widely in organic synthesis today. 139 Modern Organic Chemistry The Scripps Research Institute B. Regioselectivity 1. Steric Effects C4H9CH CH2 6 6 1 0.1 BH3•THF ThxBH2 Sia2BH 9-BBN : : : : 94 94 99 99.9 - diisoamylborane CH3 C6H5CH CH2 19 : 6 : 2 : 1.5 : 43 : 34 : 3 : 0.2 : 81 94 98 98.5 CH2 57 66 97 99.8 2 : 98 <1 : >99 larger than BH3•THF and more selective. 2. Electronic Effects Brown J. Am. Chem. Soc. 1966, 88, 5851. X X X BH3•THF + BR2' H H X=H OCH3 Cl CF3 BR2' 81 93 73 66 R1 R2 OEt R1 95 : 5 R = iPr R2 = = Me R1 = R2 = Et R = SiMe3 Me3Si CH3 43 : 57 3 : 97 95 : 5 BH3 Sia2BH BH3 Bu vs (BH3) (Sia2BH) (9-BBN) 60 : 40 5 : 95 0 : 100 19 7 27 34 R CH3 CH3 Me3Si 100 : 0 : : : : 6 : 94 1 : 99 0.1 : 99.9 C. Diastereoselectivity 1. Endocyclic Olefins Me CH3 Me t Bu 3% 13% H tBu CH3 H 36% 48% 140 - predominant attack from least hindered face. Hydroboration-Oxidation Dale L. Boger - cis addition H B - from least hindered side Pasto, Klein J. Org. Chem. 1968, 33, 1468. H3C H tBu - least substituted position CH3 H B H 38% H tBu with BH3•THF 43% H H tBu tBu tBu with BH3•THF H Me H Me Me Me H 62% 57% with BH3•THF Better with bulkier boranes 2. Exocyclic Olefins 33% R 67% 3. Acyclic Olefins OH OR BH3•THF R1 Me R1 larger than CH3 Me OR R1 Me Me OH CH2OBn Me O Me H 1) BH3•THF 2) H2O2, NaOH CH2OBn O Me Me 89% de Kishi J. Am. Chem. Soc. 1979, 101, 259. (Monensin) B H Me H R1 OR H Me Considering the top case: attack on least hindered face of H-eclipsed conformation R1/BH2 interactions are worse than Me/BH2 interactions Kishi Aldrichim. Acta 1980, 13, 23. 141 Modern Organic Chemistry The Scripps Research Institute 4. Allylic Alcohols and Ethers - Cyclic allylic alcohols and ethers. OR OR OR OR OR OH OH + + + OH R=H R = Bn R = TBDMS 83 68 74 18 7 2 9-BBN OH 5 72 13 72 13 86 2 0 0 10 19 13 1 8 1 9 13 11 catechol borane/Rh(I) Evans J. Am. Chem. Soc. 1988, 110, 6917. Minor H 9-BBN reaction: OR OR H H H - Least hindered face opposite alkoxy group. H H B - Regioselectivity avoids a R2B/H 1,3-diaxial interaction. Major - Acyclic allylic alcohols and ethers OR OR 1) 9-BBN nBu 2) H2O2, HO OR + nBu R=H R = TBDMS OH nBu OH Me Me syn anti 8 11 92 89 - Reaction takes place from H-eclipsed conformation and cis to the smaller OR group. Still J. Am. Chem. Soc. 1983, 105, 2487. minor H 3C nBu nBu RO H H B major 142 H H3C RO B attack on face syn to smaller alkoxy substituent in the H-eclipsed conformation. H H B major Hydroboration-Oxidation Dale L. Boger D. Metal-Catalyzed Hydroboration - Diastereoselectivity (below) and regioselectivity (prior page) can be altered or even reversed with catecholborane and Rh(I) catalyst (i.e., Wilkinson's catalyst). O OR BH OR O nBu n Rh(I) OR + Bu OH n Bu OH Me syn Me anti 75 96 25 4 R=H R = TBDMS - Exocyclic allylic alcohols and ethers OR OR OR 1) 9-BBN OH OH + 2) H2O2, HO B H R=H 50 90 50 10 R = TBDMS 39 96 61 4 9-BBN No distinguishing steric interactions RO 9-BBN catecholborane/catalytic Rh(I) Evans J. Am. Chem. Soc. 1988, 110, 6917. B H - Olefin reactivity, chemoselectivity catecholborane/2% RhCl(PPh3)3 reaction times 2 min 4h 12 h R R R R R unreactive R R R - Review of transition metal-catalyzed hydroboration: Beletskaya and Pelter Tetrahedron 1997, 53, 4957. RhClL3 –L +L H L B Rh L O Cl B H RhClL2 L B Rh L Cl H R R R O reductive elimination R H B Rh L O Cl O –L B + RhClL3 - This was utilized in the synthesis of the unusual L-gulose sugar found in the disaccharide of bleomycin A2 key step: inversion of stereochemistry to convert readily available D-mannose to L-gulose derivative O O HO HO OBn OH OH D-Mannose O HO OBn OAc OBn BH O (Ph3P)3RhCl 82% ≥ 50:1 HO O OBn bleomycin A2 HO OAc OBn Boger J. Am. Chem. Soc. 1994, 116, 5647. 143 Modern Organic Chemistry The Scripps Research Institute E. Directed Hydroboration O Ph2PO OAc B H 1. Ph Ph P B O OAc O H 2. H2O2, NaOH 3. Ac2O > 10:1, 55% O Ph2PO OAc B H 1. Ph P Ph O B H O 2. H2O2, NaOH OAc 3. Ac2O > 50:1, 82% Evans J. Am. Chem. Soc. 1988, 110, 6917. versus OH OH OH catechol borane major OH OH catechol borane major OH F. Asymmetric Hydroboration Review: Brown J. Organometal. Chem. 1995, 500, 1. BH2 BH HB H LimBH HB ( )2 Masamune J. Am. Chem. Soc. 1985, 107, 4549. Dilongifolyborane (Lgf2BH) trans-2,5-dimethylborolane Ipc2BH IpcBH2 monoisopinocamphenylborane - Brown Tetrahedron 1981, 37, 3547; J. Org. Chem. 1981, 46, 2988; 1982, 47, 5065. OH O CO2Me Ipc BH 2 45% 95% ee O 1. MsCl 2. NaOH prostaglandins Partridge J. Am. Chem. Soc. 1973, 95, 7171. 144 BH 2 CO2Me Hydroboration-Oxidation Dale L. Boger OH NBOC 2. NaBO3–4H2O 73% 83% ee OBn NBOC NBOC 1. Ipc2BH O OBn Boger Synlett 1997, 515. Type I Type II Type IV Type III % ee for Asymmetric Hydroboration Ipc2BH IpcBH2 I 30 1.5 II 98 III LimBH borolane – – 1.4 24 78 66 95 13 73 – 59 97 IV 14 53 70 67 94 IV 22 66 62 45 97 Type Lgf2BH - Models IpcBH2 Ipc2BH H L M Me H H H H M H L L M H H H R1 Me R2 3 R B H H Me H Me Me Me minimize R1/Me interaction C2-symmetric 145 Modern Organic Chemistry The Scripps Research Institute 146 Enolate Chemistry Dale L. Boger VIII. Enolate Chemistry Enolate Alkylations: Comprehensive Org. Syn., Vol. 3, 1. Formation of Enolates: Comprehensive Org. Syn., Vol. 2, 99. Aldol Condensation: Comprehensive Org. Syn., Vol. 2, 133, 181 and 239. Reformatsky Reaction: Comprehensive Org. Syn., Vol. 2, 277. Acylation of Enolates: Comprehensive Org. Syn., Vol. 2, 796. Enol Ethers: Comprehensive Org. Syn., Vol. 2, 595 and 629. Metalloenamines: Comprehensive Org. Syn., Vol. 2, 475. Hydrazones: Comprehensive Org. Syn., Vol. 2, 503. A. Acidic Methylene Compounds (i.e., Malonates) - α-Deprotonation pKa ~20 O O base H O RX Keq alkylation formation of C–C bond - Use of a base which stoichiometrically deprotonates the ketone completely: (i.e. Keq > 100) O ONa + NaNH2 + is Keq > 100? pKa = 17 O pKa = 35 O– + NH2– NH3 + H+ H+ NH3 Ka = 10–17 Ka = 1035 O– O + NH2– + NH3 1018 Therefore, a good deprotonation (essentially all ketone deprotonated) Note: need to have pKa difference of 2 pKa units to get Keq = 100. 147 Modern Organic Chemistry The Scripps Research Institute 1. Estimation of pKa H C W = Cl W W= O inductive stabilization , NO2, etc. resonance stabilization O H CH3 pKa = 20; CH3 pKa = 45; pKa = 35–37 - an increase in acidity of H results in a faster deprotonation (kinetic effect) as well as a stabilization of anion formed (thermodynamic effect). H R R W Group (–W) pKa effect (units) alkyl ~1–2 halogen ~1–2 Note (decrease in acidity) both due to inductive effects ~5–7 ~5–7 both depend on favorable orbital overlap to allow resonance stabilization ~3–5 RS Others: NO2 > COR >SO2R > CO2R, CN > SOR, Ph Compound pKa Note O 20 CH3 O O OCH3 O O O O 13 11 ketone better enolate stabilizer than ester 9 H O O H 5 H H2O O H2C H 14 25 NR2 O CH3 148 NR H 15 ~same as acetic acid Enolate Chemistry Dale L. Boger 2. Ketone–Enol Tautomerism O R OH R OH CH3 R O E+ CH2 R CH2 - generally << 1% enol - Usually not likely to form a bond with weak electrophile (e.g., CH3I) since not present in high concentration E CH2 - However, some ketones do exist in high enol concentration and react via enol << 1% Compound Enol content O 0.0004% O < 0.002% O OH CO2Et O CO2Et O O O O OH OH CO2Et O 40% (neat) 60% (EtOH) O O CO2Et OH O OH O 100%(neat) 95% (H2O) 2–14% (cyclohexane) 10–13% (EtOH) 50% (cyclohexane) 16% (H2O) 63% (EtOH) 92% (cyclohexane) 3% (H2O) 31% (EtOH) 55% (cyclohexane) intramolecular H-bond intramolecular H-bond intramolecular H-bond 149 Modern Organic Chemistry The Scripps Research Institute - If a compound has a vinyl spacer, the reactivity parallels that of the parent compound. 1,3-Cyclohexadione in its enol form is a vinylogous carboxylic acid and it exhibits many properties of a RCOOH, including low pKa, O-alkylation. O O ~ = OH OH OH O O base O O nBu O analogous to RCOOH -> RCOOnBu + nBuBr OnBu OH 15% 37% VINYLOGY RULE O O Nu– analogous to RCOCl -> RCONu Nu Cl vinylogous acid chloride 3. Acetoacetic Ester Synthesis O O NaOCH3 OCH3 pKa = 13 NaH THF CH3OH ONa O nBuBr, ∆ O O OCH3 OCH3 nBu nBuBr stable, can be isolated pKa =16 (deprotonation equilibrium 74% K = 99.9 -> 99% deprotonated) O O OCH3 nBu ~70% NaH: strong base, operates in range up to pKa = 35. Sometimes kinetically slow, sometimes difficult to reproduce. It is insoluble and the reaction is heterogeneous. Thought that trace –OH might be active base. Therefore, deliberately add 0.05–0.1 equiv. CH3OH to obtain reproducible reaction. Henri Moissan, who received the 1906 Nobel Prize in Chemistry for his investigation and isolation of the element fluorine and for the high temperature electric furnace named after him, prepared and studied the alkali metal hydrides. 150 Enolate Chemistry Dale L. Boger - The product can be further alkylated: O O OCH3 ii) nC5H11Br nBu H O i) NaH O OCH3 nC H 5 11 nBu 80% pKa now 1–2 units higher than parent concentration of parent enolate vs. concentration of product enolate in monoalkylation reaction is very high (> 90:10) -> monoalkylation fairly clean. - Hydrolysis and decarboxylation gives α-substituted ketones: O O O NaOH CH3 R R' OCH3 then H3O+ workup CH3 H O O R O ∆ 180–220 °C R' R' CH3 R 4. Malonic Ester Alkylation R i) NaOMe, MeOH CH3O2C CO2CH3 CH3O2C ii) RX R NaOH CH3O2C CO2CH3 CO2CH3 75–90% NaOH R HO O O H R R H3O+ NaO2C R NaOH CH3O2C CO2Na CO2Na CH3O2C COONa O ∆ (–CO2) requires higher temperature than acetoacetate decarboxylation RCH2COOH R NC NC CN related stabilized enolates O CH3OOC SO2Ph CH3OOC CN can be removed reductively 151 Modern Organic Chemistry The Scripps Research Institute 250 °C no reaction HO2C O O H O O OH violates Bredts Rule, bridgehead olefin 5. Enolates: C- vs. O-Alkylation - Ketones which are more acidic tend to give more O-alkylation. e.g. O 37% O-alkylation 15% C-alkylation OH OH CH3 OCH3 NaOH OH + CH3X X=I - The more reactive the alkylating agent, the more O-alkylation observed X = OTs 66 : 33 100 : 0 O O - Rarely see O-alkylation of ketone enolates often see O-alkylation of stabilized enolates e.g., β-diketones and β-keto esters localized, harder anion - tends to react with harder electrophiles (CH3OTs, Me3OBF4 ) softer, more diffuse anion reacts with softer alkylating agents (RI, RBr) Meerwein's salt more reactive or more ionized = harder - Intramolecular constraints can affect course of C- vs. O-alkylation HO NaOH O O H OTs 152 OTs 100% Enolate Chemistry Dale L. Boger Cl N R N NaH O N H O (+)-CC-1065 OH MeO2C R N NaH O N H O N H Cl N R R DEAD–Ph3P MeO2C O N H OH OH Mitsunobu alkylation O duocarmycin SA R N MeO2C N H O OH Boger Chem. Rev. 1997, 97, 787. - Mitsunobu alkylation Mitsunobu, Yamada, Mukaiyama Bull. Chem. Soc., Jpn. 1967, 40, 935. Mitsunobu Bull. Chem. Soc., Jpn. 1967, 40, 4235. Review: Mitsunobu Synthesis 1981, 1. Hughes Org. React. 1992, 42, 335; Castro Org. React. 1983, 29, 1. - Mechanism: Ph3P OPPh3 R1 + EtO2CN NHCO2Et PPh3 X– HX EtO2CN NCO2Et + X– EtO2CNH NHCO2Et R1 R2 X SN2 displacement R2 OH R1 R2 HX: pKa typically <15 (RCO2H, phenols, imides, malonates, β-keto esters) Related reagents including Ph3P/CCl4, Ph3P/NXS are used to convert an alcohol to the corresponding halide with inversion of stereochemistry. - Factors which favor O-alkylation 1. Polar solvent: HMPA DMSO DMF O Me2N P NMe2 NMe2 CH3 polar, aprotic solvents: a. separate metal cation from enolate oxygen, making oxygen more free to react O S CH 3 b. coordinate electrophile, activate and increase their reactivity c. increase rate of reaction Me2NCHO 2. Large, noncoordinating metal cation: - again, frees up oxygen to react M+ O M R' R = R4N O-alkylation >K > Na > Li C-alkylation rate of reaction ion pair separation of charge, harder more reactive anion lithium essentially covalently coordinated to O 153 Modern Organic Chemistry The Scripps Research Institute 3. Aggregation/Solubility: Homogeneous, monomeric enolates O-alkylation Heterogeneous, aggregate enolates C-alkylation Li enolates tend to be more aggregated hard for RX to get to O atom, so reacts at C M O H R' R 4. Structure of alkylating agent a. Leaving group: (hard alkylating agents) for RX: (soft alkylating agents) X = Me3O > OTs > Cl > Br > I C-alkylation O-alkylation O O nBuX COOCH3 O-alkylation K2CO3 100 °C Polarity of solvent For C-alkylation: I > Br > Cl COOCH3 + OnBu COOCH3 nBu C- : O-alkylation rel % products Solvent X acetone Cl 90 : 10 CH3CN Cl 81 : 19 DMSO Cl 53 : 47 DMF Cl 54 : 46 DMF Br 67 : 33 DMF I >99 : 1 b. Degree of substitution of alkylating agent: O COOEt RBr no solvent O OR COOEt COOEt + R nC more sterically hindered, so "harder" 3H7Br Br Br , 154 Ph Br 97 : 3 73 : 27 mainly C-alkylation Enolate Chemistry Dale L. Boger O O X + OH O works well in polar, aprotic solvents (ie., HMPA, DMSO), or even K2CO3, acetone will work B. Enolate Structure - Actually exist as higher aggregates in solution: dimer–tetramer. - Originally suggested by House J. Org. Chem. 1971, 36, 2361 and Brown J. Organometal. Chem. 1971, 26, 57. - Supported by NMR studies: Jackman Tetrahedron 1977, 33, 2737. - Confirmed by X-ray: Dunitz Helv. Chim. Acta 1981, 64, 2617. see also: Seebach J. Am. Chem. Soc. 1985, 107, 5403. Angew. Chem., Int. Ed. Eng. 1988, 27, 1624. Lynch Tetrahadron Lett. 1989, 30, 447. ° 1.99 A O CH2 tetramer aggregates ° bond lengths, angles much 1.34 A like those of enol ether. ° 1.45 A tBu O O ° 1.37 A ° 1.35 A Li ° Li 1.94 A CH3 CH3 CH3 1.477 A° ° 1.495 A Li Sit t Bu 1.356 A° ° 1.378 A O vs ° 1.659 A BuPh2 O ° 1.407 A ° 1.304 A Li ° 1.35 A Ketone Enolates: O Ph Ph OM Keq < 1 for most metals (Li, Na, K, MgX, ZnX) M negative charge, M+ on oxygen. > 1 for M = HgI 155 Modern Organic Chemistry The Scripps Research Institute Ester Enolates: O OR M Reformatsky Ber. 1887, 20, 1210. Reviews: Shriner Org. React. 1946, 1, 423. Rathke Org. React. 1975, 22, 423. Furstner Synthesis 1989, 571. OR OM Keq > 1 for ZnBr (Reformatsky reagents) Keq < 1 for Li C. Enolate Alkylations: π-Facial Stereoselectivity 1. Stereoelectronic Effects - The attacking electrophile must obey the principle of maximum overlap of the participating orbitals by perpendicular approach to the plane of atoms which constitute the enolate (enol) function. E+ M E+ R1 H O R2 E R1 H O R2 OLi R1 H R2 - Also applies to protonation in reprotonation reaction: R1 M O H H+ R2 –H+ H R1 H H R2 O - Nucleophilic addition to carbonyl compound takes place not at 90° (perpendicular) but at an angle of 105 ± 5° Dunitz Tetrahedron 1974, 30, 1563. - Same applies to enolate alkylations LUMO of E+ electrophile angle not 90° R2 R' H O enolate HOMO 156 O R2 R1 H Enolate Chemistry Dale L. Boger - Ramifications: E tBu O O E+ OLi LDA or tBu tBu trans H tBu cis E O H O E+ H t base removal of axial proton Bu predominant trans product observed OM axial attack proceeds through a chair-like T.S. - In order to get cis, must proceed through a boat-like T.S.! H tBu O tBu cis OM E E+ - Therefore O E OM E Energy of activation for formation of the more stable cis product is higher because it involves a boat-like T.S. O E reaction coordinate Corey, Sneen J. Am. Chem. Soc. 1956, 78, 6269 (origin of axial alkylation). They also introduced the term stereoelectronic effect to describe this behavior. This was the pioneering work that led to the now widespread predictions about reactions and reaction products based on orbital alignment or overlap and provided the term "stereoelectronic" effect. 157 Modern Organic Chemistry The Scripps Research Institute - Examples of stereoelectronic control axial alkylation chair-like transition state equatorial alkylation via twist boat T.S. H O t – Bu H E+ tBu O A – tBu R E+ E+ E+ A O tBu R House J. Org. Chem. 1968, 33, 935. Caine J. Org. Chem. 1969, 34, 3070. less reactive enolates (so more selective) E O OM tBu OM E tBu R R O + tBu E E E R M R axial equatorial Li H Et3O+BF4– 51 : 49 Li H EtI 54 : 46 Li H MeI 55 : 45 Li H DOAc 70 : 30 Li Et HOAc 80 : 20 Li Me CD3I 70 : 30 Li CN CH3I 77 : 23 Li COOCH3 CH3I 83 : 17 Kuehne J. Org. Chem. 1970, 35, 161, 171. 2. Steric Effects H - Stereoelectronic effects equivalent for exocyclic enolates. - Relatively insensitive to alkylating agent and conditions. COX E+ eq X ax H eq E H E+ ax Behavior as a large reagent preferring equatorial delivery. House J. Org. Chem. 1968, 33, 943. Krapcho J. Org. Chem. 1980, 45, 3236. 158 E major product OM tBu H - Transition states for enolate alkylations are thought to be REACTANT-LIKE. tBu tBu COX minor product eq : ax X E CH3 MeI 25 °C 85 : 15 OCH3 MeI –78 °C 84 : 16 OCH3 nBuBr –78 °C 87 : 13 Enolate Chemistry Dale L. Boger OLi E+ O E E+ via R major H R OLi R E+ D. Enolate Generation 1. Soluble Bases - NaNH2, LiNH2, KNH2 strong bases, but insoluble in conventional organic solvents - Soluble secondary amine derived bases nBuLi N H pKa 45 pKa = 35 = LDA N Li readily available, soluble; amine byproduct is low MWt, volatile, and easily removed. The anion is also nonnucleophilic (relatively hindered) - Aggregates: Williard J. Org. Chem. 1993, 58, 1 (X-ray). - Other widely used bases: Lithium isopropylcyclohexylamide (LICA) = N Li very hindered base = Lithium 2,2,6,6-tetramethylpiperidide ("FAT ALBERT", LTMP) N Li Me3Si N M very hindered SiMe3 M = Li Lithium hexamethyldisilazide (LHMDS or LHDS) = Na Sodium hexamethyldisilazide (NaHMDS) =K Potassium hexamethyldisilazide (KHMDS) = Lithium toctyl-tbutylamide (LOBA) Corey Org. Syn. 1987, 65, 166; Tetrahedron Lett. 1984, 25, 491 and 495. N Li adamantyl N Li adamantyl = Lithium bis(2-adamantyl)amide (LBAA) Collum Tetrahedron Lett. 1993, 34, 5213. THF or Et2O Me3Si N LiSn Me3Si hydrocarbon solvents Me3Si Me3Si S Li N Li N SiMe3 SiMe3 S monomer dimer Me3Si Me3Si N Li SiMe3 Li N SiMe3 Me3Si N Li Me3Si Li N Me3Si SiMe3 tetramer Brown J. Organometal. Chem. 1971, 26, 57. Collum Acc. Chem. Res. 1993, 26, 227; 1999, 32, 1035 (6Li and 15N NMR). - X-ray structures Williard J. Am. Chem. Soc. 1997, 119, 11855. 159 Modern Organic Chemistry The Scripps Research Institute Reviews: Conia House Fleming Petragnani Kaiser d'Angelo Evans Collum Rec. Chem. Prog. 1963, 24, 43. Rec. Chem. Prog. 1967, 28, 98. Chimica 1980, 34, 265. Synthesis 1982, 521. Synthesis 1977, 509. Tetrahedron 1976, 32, 2979 (Methods for regiospecific enolate generation). Asymm. Synthesis, Morrison, Ed., Vol. 3, 1. Acc. Chem. Res. 1999, 32, 1035. 2. Kinetic and Thermodynamic Enolates OTMS LDA + + (TMSCl quench) O OTMS 84% kinetic enolate Et3N TMSCl DMF, ∆ 60 h 13% OTMS 7% 9% 58% 29% thermodynamic enolate H H Ph3CLi (1.05 equiv) + (TMSCl trap) TMSO H H conditions for kinetic enolate formation H O TMSO 13 : 87 53 : 47 H Ph3CLi (0.95 equiv) HMPA some ketone always present, so deprotonation–reprotonation equilibrium conditions for thermodynamic enolate formation 3. Regiospecific Enolate Generation - In the above case, the ∆2,3 enolate cannot be cleanly obtained directly, but other approaches to this have been developed. H H H Li, NH3 MeLi TMSCl O TMSO H isolated See: Stork H O H J. Am. Chem. Soc. 1961, 83, 2965; 1965, 87, 275. H Li/NH3 tBuOH –33 °C LiO H Mander Org. Syn. 1992, 70, 256. 160 LiO Me4Si H NCCO2Me Et2O –78 to 0 °C 84% O H CO2Me Enolate Chemistry Dale L. Boger - Representive enolate selectivities: O CH3CCH2Bu 100 O CH3CCH2Me 0 (LDA, –78 °C) 71 O Me MeCH2CCH Me 95 5 (LDA, 0 °C) O Ph N O Me CH3CCH Me 29 (LDA, 0 °C) O 1 (KHMDS, –78 °C) O Me CH3CCH2N 75 99 Ph 25 (LDA, –78 °C) O CH3 CH3 N C CO2CH3 H2 82 (LDA, –78 °C) 18 O Me CO2Me 99 : 1 (LDA, 0 °C) LDA: 33 : 67 (kinetic) LHMDS: 2 : 98 (thermodynamic) Ph >99 : 1 (LDA, –78 °C) Albizati J. Am. Chem. Soc. 1990, 112, 6965. O O O OCH3 NMe2 Me Bu 85 : 15 (LDA, –78 °C) CH3 O C CH3 100 : 0 (LDA, –78 °C) 98 : 2 (LDA, –78 °C) 91 : 9 (LDA, 25 °C) 98 : 2 (LHMDS, thermodynamic) Albizati J. Am. Chem. Soc. 1990, 112, 6965. CH3 O C OMe CH3 100 : 0 (LDA, –78 °C) O O O CH3 100 : 0 (LDA, –78 °C) Me O CH3 OnBu 20 : 80 (LDA, –78 °C) 100 : 0 (LHMDS, –78 °C) Me O Me 100 : 0 (LDA, –78 °C) CH3 0 : 100 (NaH, 100 °C) thermodynamic enolate formation Taken from: Evans Asymm. Synthesis, Morrison, Ed., Vol. 3, 1. 161 Modern Organic Chemistry The Scripps Research Institute - Enantio- or diastereoselective protonation of ketone enolates deprotonation: Majewski Can. J. Chem. 1994, 72, 1699. Simpkins Tetrahedron Lett. 1992, 33, 8141. 1989, 30, 7241. protonation: Fehr Angew. Chem., Int. Ed. Eng. 1994, 33, 1764. 4. Cyclic Carbonyl Compounds - site of deprotonation - enolate geometry fixed O OM CH3 CH3 Base potassium bases not as effective for kinetic enolate generation. OM CH3 + Control Selectivity LDA (0 °C, THF) kinetic 99 : 1 KHMDS (–78 °C) " 95 : 5 10 Ph3CLi (–78 °C) " 90 : Ph3CK (–78 °C) " 67 : 33 thermodynamic 10 : 90 NaH " 26 : 74 Ph3CK " 38 : 62 Ph3CLi 5. Acyclic Carbonyl Compounds - Two issues: i. site of deprotonation ii. geometry of enolate formed cis Z-enolate (Zusammen) trans E-enolate (Entgegen) OM O R CH3 R CH3 OM R CH3 - Also: the enolate has two diastereotopic faces: For E-enolate si face looking from this face R OM counterclockwise = si Me M O R Me re face 162 looking from this face MO R Me clockwise = re Enolate Chemistry Dale L. Boger - ASIDE: Geometry of enolate can be determined by Claisen rearrangement: OTMS Z-enolate R O O R O OTMS R E-enolate O - Claisen rearrangement known to proceed through chair-like T.S.: Me R OTMS OTMS H R O O Me Z-enolate relative amounts easily determined by 1H NMR Me OTMS OTMS H R O O R Me E-enolate A. Acyclic Ketones Me Me Me Me + Me OLi O Base very hindered amide base Me OLi Z E LTMP (–78 °C) 14 : 86 kinetic enolate LTMP/HMPA 92 : 8 thermodynamic enolate LDA 23 : 77 LICA 35 : 65 LHMDS 66 : 34 (PhMe2Si)2NLi 100 : 0 163 Modern Organic Chemistry The Scripps Research Institute - Thermodynamic enolate formation Me Me + Me Me Me Me HMPA + O O OLi Me Me OLi or may take place by reversible aldol addition Rathke J. Am. Chem. Soc. 1980, 102, 3959. O OLi For the effect of HMPA on R2NLi aggregation: Collum, Romesberg J. Am. Chem. Soc. 1994, 116, 9198; 1993, 115, 3475. O OLi R2 R1 R1 LiO R2 + Z-enolate Note: As R1 becomes sterically more demanding, Z-enolate increases or predominates even under kinetic conditions. Note: As R2 becomes sterically more demanding, E-enolate selectivity increases under kinetic conditions: Ph > Me. R1 R2 Et Me Et R2 R1 E-enolate Z E LDA 23 77 Me LTMP 14 86 Et Me LTMP–LiBr 2 98 iPr Me LDA 37 63 iPr Me LTMP 33 67 iPr Me LTMP–LiBr 5 95 tBu Me LDA 98 2 tBu Me LTMP 95 5 tBu Me LTMP–LiBr 95 5 Me Ph LDA 7 93 Me Ph LTMP 8 92 Me Ph LTMP–LiBr 3 97 best conditions for E-enolate (kinetic) Z-enolate only very large R1 Collum J. Am. Chem. Soc. 1991, 113, 9571. Et Me LOBA 2 98 kinetic E-enolate Corey Tetrahedron Lett. 1984, 25, 491 and 495. 164 Enolate Chemistry Dale L. Boger B. Acyclic Esters - Similar to ketones: O R1O OLi OLi R2 + R2 R1O R1O R2 Z E thermodynamic enolate (more stable) kinetic enolate R1 R2 base Z : E Me Me LDA 5 : 95 tBu Me LDA 5 : 95 Me Et LDA 9 : 91 kinetic Me Et LDA/HMPA 84 : 16 thermodynamic tBu Et LDA 5 : 95 tBu Et LDA/HMPA 77 : 23 Role of HMPA: increase rate of equilibration, break up enolate aggregation Me Et LOBA 5 : 95 Bn Me LDA 20 : 80 Bn Me LOBA 5 : 95 Corey Tetrahedron Lett. 1984, 25, 491 and 495. kinetic E-enolate thermodynamic Z-enolate OLi CO2Et OEt OLi + OEt LDA THF 94 : 6 LDA THF–45% DMPU 7 : 93 LDA THF–23% HMPA 15 : 85 Ireland, Wipf J. Org. Chem. 1991, 56, 650 and 3572. 165 Modern Organic Chemistry The Scripps Research Institute - Silyl Ketene Acetals Otera Synlett 1994, 213. O R3SiCl + OR R = tBu OR OSiR3 OSiR3 OR LDA >99 : 1 EtMe2C LDA 97 : 3 Ph3C LDA >99 : 1 LDA 99 : 1 iPr LDA 83 : 17 bornyl LDA 83 : 17 Et LDA 84 : 16 Me LDA 87 : 13 Me LDA–HMPA or DMPU 4 : 96 Et " 3 : 97 bornyl " 13 : 87 iPr " 13 : 87 EtMe2C " 26 : 74 tBu " 28 : 72 C. Acyclic Amides give only Z-enolate OLi O R1 R2N LiO R1 R2N + Z-enolate 166 R1 R2N E-enolate R R1 base Z Et CH3 LDA >97 : 3 (CH2)4 CH3 LDA >97 : 3 E Enolate Chemistry Dale L. Boger 6. Ireland Transition State Model for Deprotonation J. Am. Chem. Soc. 1976, 98, 2868. Tetrahedron Lett. 1975, 3975. b O R a - For Cyclic Ketones: a b LiNR21 H O R O Li R1 N Li R1 H R1 N 1,3-diaxial R, R1 H R1 A B OLi OLi R R R1-H interaction < R1-R interaction ketone base A vs. B 1,3-diaxial interaction LDA 99 : 1 iPr, CH3 Ph LDA >99 : 1 iPr, Ph OCH3 LDA 85 : 15 iPr, OCH3 NMe2 LDA 98 : 2 iPr, NMe2 R = CH3 - More hindered bases (tBu2NLi, LiHMDS, LTMP) would increase selectivity for kinetic enolate formation (1,3-diaxial interactions even larger in T.S. for thermodynamic enolate formation) - For Acyclic Ketones, Esters, and Amides: O X X H O N LiNR12 a Me Li R1 Me b N H R'1 Me O X H 1,3-diaxial interaction H R1 H very little A (1,2) strain A (1,2) strain (torsional strain) LiO X Li R1 H X Me O OLi Me E-enolate X in most instances, kinetically favored Me Z-enolate thermodynamically more stable enolate 167 Modern Organic Chemistry The Scripps Research Institute - Example: LiO LDA O X X LDA Me X Me Z-enolate E-enolate X OLi + Me E:Z OCH3 95 : 5 OtBu 95 : 5 Et 77 : 23 iPr 40 : 60 tBu Me/R1 1,3-diaxial interaction worse than Me/X A (1,2)-interaction 0 : 100 Ph 0 : 100 NEt2 0 : 100 X getting larger, so A (1,2) steric interaction outweighs the Me/R1 1,3-diaxial interaction E. Alkylation Reactions: Stereochemistry 1. Exocyclic Enolates i. 1,2-Stereocontrol in Exocyclic Enolates OM X E O E O X E+ X + R R H H R H major OM E+ R X R R COX OM allylic (1,3) strain E+ E X for R = CH3, X = OMe ∆G > 3.7 kcal/mol COX R OM H R X OM H X H-eclipsed conformation 168 E R Enolate Chemistry Dale L. Boger COOCH3 Me Me COOCH3 Me LDA Me COOCH3 Me + MeI COOCH3 Me : 80 Krapcho J. Org. Chem. 1980, 45, 3236. Me COOCH3 Me LDA Me COOCH3 Me + MeI : 95 COOEt Me Ph3CNa MeI 82% MeO 20 5 Me COOEt COOEt Me Me + Me MeO Hogg J. Am. Chem. Soc. 1948, 70, 161. MeO : 98 2 - Also true for other common ring sizes: CO2Me CO2Me OMe OMe LDA OMe Br >95 : 5 OMe 72% Heathcock Tetrahedron Lett. 1979, 2115. CO2Me Me CO2Me LDA Me CO2Me + MeI 92% : 85 15 Clark Syn. Commun. 1979, 325. O R O i) Li, NH3 tBuOH (0.95 equiv) H H O O H ii) RX reductive alkylation H H O H O R = CH3 65% R = Et 43% only product Weiss, Coscia Tetrahedron 1964, 20, 357. 169 Modern Organic Chemistry The Scripps Research Institute ii. 1,3-Stereocontrol CO2Me Me CO2Me MeO2C Me LDA + MeI H H R H R R major R = CH3 R = OCH3 minor : : 90 78 10 22 Krapcho J. Org. Chem. 1980, 45, 3236. E+ E+ OM H H OMe R reactive conformation OM R E+ OMe equatorial delivery of electrophile but axial R group iii. 1,4-Stereocontrol Me COOCH3 COOCH3 LDA MeI CH3OOC Me + H R H R R = tBu 84 : 16 84 : 16 OCH3 H R Krapcho J. Org. Chem. 1980, 45, 3236. E+ H H R OM ax R OR1 eq E+ OM OR1 reactive conformation Again, equatorial attack predominates due to destabilizing steric interactions for axial approach of electrophile. 170 Enolate Chemistry Dale L. Boger House J. Org. Chem. 1968, 33, 943. Ziegler, Wender J. Am. Chem. Soc. 1971, 93, 4318. CN Me CN Me CN LDA + MeI tBu tBu tBu : 71–76% LiO COOH OLi R COOH Li, NH3 0.95 equiv 24–29% RX + then H3O+ tBuOH tBu tBu tBu tBu RX Van Bekkum Recl. Trav. Chim. Pays-Bas 1971, 90, 137. E+ Me Me Me R COOH MeI 45 : 55 EtBr 88 : 12 iPrBr 93 : 7 OM OM H E+ Surprising given the distance, but Schöllkopf subsequently put such observations to effective use. pronounced effect of size of alkylating agent on stereoselectivity. Steric Effects? 2. Endocyclic Enolates a. 1,2-Stereocontrol O O OM R1 vinyl group sterically smaller, so stereoselectivity lower R2 R2 R2X + H R1 major H R1 R1 R2X nBu MeI 88 : 12 CH=CH2 MeI 75 : 25 89 : 11 Br Me H E+ Posner J. Am. Chem. Soc. 1975, 97, 107. Coates J. Org. Chem. 1974, 39, 275. R1 LiO ax axial attack preferred on stereoelectronic and steric grounds H H E+ 171 Modern Organic Chemistry The Scripps Research Institute b. 1,3-Stereocontrol O O NaOtAm CH3I 70% tBu CH3 trans delivery tBu 73 : 27 Conia Bull. Soc. Chim., Fr. 1966, 3881 and 3888. - tBu group in preferred equatorial position Rt NaO - axial attack favored on stereoelectronic basis, no steric bias for either face Bu E+ c. 1,4-Stereocontrol O OLi CH3 CD3I CH3 CD3 O + tBu tBu tBu 83 : 17 House J. Org. Chem. 1973, 38, 1000. H E+ preferred stereoelectronic approach from most stable conformation with tBu equatorial axial tBu Me OLi H d. 1,5-Stereocontrol O Ph tBuOK Me PhO Me MeI >95% one isomer Ireland J. Org. Chem. 1970, 35, 570. Ph MO Me R E+ 172 reaction from preferred conformation where Me group vs Ph adopts pseudo axial position preferred stereoelectronic approach CD3 CH3 Enolate Chemistry Dale L. Boger 3. Other Conformationally Inflexible Systems - Exocyclic Enolates of a Fixed Conformation MeI 74% H LiO H CO2Me OMe >100 : 1 more severe 1,3-diaxial interaction E+ - Exocyclic Norbornanes OMe CH3 Welsch J. Org. Chem. 1977, 42, 2879; J. Am. Chem. Soc. 1977, 99, 549. This leads to a further enhancement of the preferred equatorial delivery of electrophile. OLi E+ E+ exo LDA Me MeI endo OMe + COOMe LiO H E+ OLi O Me Ph3CNa MeI H Equilibration: Me 97 : 3 47 : 53 Corey J. Am. Chem. Soc. 1962, 84, 2611. - Confined Endocyclic Enolates R R R CD3I H O H + H E+ O CD3 + O H 83 5 via : : E+ H Me 97 : 3 strong exo preference Krapcho J. Org. Chem. 1980, 45, 3236. E+ LiO COOMe H CD3 17 (R = H) 95 (R = CH3) E+ H CH3 H severe 1,3-diaxial steric interaction But LiO LiO H stereoelectronic preference for axial alkylation H E+ preference for equatorial alkylation through twist boat Matthews J. Chem. Soc., Chem. Commun. 1970, 38 and 708. 173 Modern Organic Chemistry The Scripps Research Institute E+ Me Me –O vs. –O H H E+ - Similarly Me R H MeI LiO CN base RX O O H Me R Me + O H NC H R R = H 79 : 21 R = Me 6 : 94 Me + R O H R Me NC O 9:1 Kuehne J. Org. Chem. 1970, 35, 161. - Predict the major product for Me base O R1X R ? H Kuehne J. Org. Chem. 1970, 35, 171. Morris J. Org. Chem. 1972, 37, 789. R = CN, CO2Me Stork J. Am. Chem. Soc. 1961, 83, 2965; 1965, 87, 275. OLi O Me O Me MeI H + H : 20 H 80 axial attack H H H H equatorial attack (preferred) House, Trost J. Org. Chem. 1965, 30, 2502. H O O Me Ar O Me Ar MeI Ar + tBuOK H H H 32 H O Ar MeI : O Me 68 O Me Ar + Ar tBuOK H removes one 1,3-diaxial interaction for axial alkylation through chair-like T.S. 174 H H 90 OLi : 10 Enolate Chemistry Dale L. Boger 4. Conjugate Addition/Alkylation: Stereochemistry - There are also many examples of tandem conjugate addition/alkylation reactions and conjugate reduction/alkylation reactions that combine elements of both the conjugate addition or reduction with the subsequent alkylation. Li N N R1Li R2 N R2X S S S tBu tBu R1 tBu R1 R2X tBu H H BT t Bu R1 Li R1 R1Li axial attack N t N Bu H R2 S S Corey and Boger Tetrahedron Lett. 1978, 5, 9, and 13. F. Asymmetric Alkylations Conformational or Intraannular Chirality Transfer 1. Schöllkopf asymmetric amino acid synthesis: CH3O O N NH2 HO H2N E+ Li E then H3O+ O OH OCH3 > 90% de (S)-valine alkylation on face opposite iPr group (1,4-stereocontrol) Angew. Chem., Int. Ed. Eng. 1979, 18, 863; 1981, 20, 798 and 977. Liebigs Ann. Chem. 1981, 696 and 2407. Synthesis 1981, 966 and 969. N - Representative recent templates for asymmetric amino acid synthesis Ph MeO H O N O Ph O O O Me N O tBu N Me COR Ph Ph O X tBu N Me COR O N Me COR N Me X = NBOC, O Schollkopf Ann. Spanton J. Org. Chem. Williams J. Am. Chem. Seebach Liebigs Ann. Najera J. Heterocyclic Soc. 1991, 113, 9276. 1995, 217. 1982, 1952. 1990, 55, 5437. Chem. 2000, 37, 467. O 2. Seebach: HO O R HO OH O O R O tBu O H R O E+ tBu R tBu OLi LDA E O E OH tBuCHO relative and absolute stereochemistry of tBu group set by substrate and incorporation into 5-membered ring O H3O+ R but restored by virtue of alkylation diastereoselectively O chirality destroyed Seebach J. Am. Chem. Soc. 1983, 105, 5390. Fráter Tetrahedron Lett. 1981, 22, 4221. 175 Modern Organic Chemistry The Scripps Research Institute 3. Meyers: R R O HO O HO O R1 R2 O OH NH2 H2SO4 TsOH R R R O O LDA N O R1 LDA N R1X R2 N R2X O O R1 O Meyers J. Am. Chem. Soc. 1984, 106, 1146; J. Org. Chem. 1989, 54, 2509. Chelation Enforced Chirality Transfer 4. H OH COOR' R LDA (1st equiv) COOR' R H LDA (2nd equiv) H OLi Li OR' O H O R H OH O R E+ H R OR' E E+ = Br = nBuBr 96 : 4 O Li O Li N OR' Z-enolate (note that normally get E-enolate from esters) 97 : 3 removal of axial proton (much more sterically accessible) Seebach Angew. Chem., Int. Ed. Eng. 1981, 20, 971. Helv. Chim. Acta 1980, 63, 197, 2005. Fráter Tetrahedron Lett. 1981, 22, 425. Helv. Chim. Acta 1979, 62, 2825 and 2829; 1980, 63, 1383. Kraus Tetrahedron Lett. 1977, 18, 4575. 5. Evans' chiral imide auxiliaries: J. Am. Chem. Soc. 1982, 104, 1737. N-acyl oxazolidinones O O R N O LDA E+ from face opposite iPr group Li O O alkylation R N O from valine N O E Li R N Me from norephedrine O O O 176 R H E+ = BnBr, 120 : 1 Z-enolate - and O O O Ph LDA O N E+ Me O O R O Ph Z-enolate alkylation opposite Me and Ph group R H N O E Me Ph Enolate Chemistry Dale L. Boger new chiral centers created which have opposite absolute configuration. Access to either enantiomer - Factors responsible for high diastereoselectivity: a. exclusive formation of Z-enolate. b. chelation results in formation of rigid template, single conformation. c. π-facial selectivity results from sterics of alkylation. Other electrophiles beyond RX may be employed O alcohols ArSO2N3 Ph NSO2Ph NBS azides bromides Extraannular Chirality Transfer 6. Schöllkopf Liebigs Ann. Chem. 1981, 439. H-eclipsed H Me N Ph O R LDA N Ph R Me N Ph O H OLi H Br Me N Ph –60 °C N R N Ph >95 : 5 Stereoelectronic Steric R = CH3, BnBr, 94%, >97 : 3 R = Et, BnBr, 85%, 97.5 : 2.5 (E+ = D2O) RS RL Me OEt 10 : 1 Me OPh 10 : 1 Me t Bu 9:1 Me OtBu 8:1 Me StBu 7.5 : 1 Me OMe 7:1 Me CF3 5:1 Me Ph 3:1 Me i Pr 2.3 : 1 Me Et 1.4 : 1 RL O R R H RS E with control of enolate geometry available, reaction via H-eclipsed conformation might be facially selective. To date, this has not been extensively examined with acyclic systems. See: Mohrig J. Am. Chem. Soc. 1997, 119, 479. 7. Fraser Tetrahedron Lett. 1979, 20, 3929. Me Ph N H LDA E+ Me LiN Me Ph N H E E+ = MeI, 3.2 : 1 Ph H E+ 177 Modern Organic Chemistry The Scripps Research Institute Through Space Interactions/Blocking Groups 8. H R O H O O with certain esters of chiral alcohols, could see enantioselectivity via conformational control O O H O H O O R H and carbonyl are eclipsed in much preferred conformation Me N Ph R' re face is blocked Me R' N O Ph O H H O H OLi E+ si face alkylation E-enolate LICA THF kinetic enolate generation H's eclipsed with carbonyls in ground state conformation LICA THF–HMPA R' H Xc thermodynamic enolate generation (via equilibration) E O Me HN O Ph O R' H O H OLi + Z-enolate E 1 H E+ R' Xc (si face attack) E O 2 R' solvent E+ 1:2 yield CH2Ph THF MeI 95 : 5 95% Me THF BnBr 94 : 6 96% Me THF–HMPA BnBr 30 : 70 96% lower diastereoselectivity due to inability to generate exclusively the Z-enolate (70:30 = Z : E formed) Helmchen Angew. Chem., Int. Ed. Eng. 1981, 20, 207. Tetrahedron Lett. 1980, 21, 1137; 1983, 24, 3213. SO2Ph N Ar O O Helmchen 178 N O S O M O R E E+ N 90−99% de S O OO Oppolzer Tetrahedron Lett. 1989, 30, 5603 and 6009. R Enolate Chemistry Dale L. Boger 9. Catalytic asymmetric alkylation: Corey Tetrahedron Lett. 1998, 39, 5347. BrO Ph N OtBu Ph + RX 1 (10 mol%) Ph CsOH•H2O Ph O N OtBu H H R N O R= -(CH2)4Cl ee (%) -(CH2)2CO2CH3 99 N + H O -(CH2)2COEt 95 99 1 91 Additional examples of asymmetric alkylations may be found in the sections discussing enolate equivalents. G. Aldol Addition (Condensation) R3CHO R2 OM H R1 OH O + R3 First report: Wurtz Bull. Soc. Chim. Fr. 1872, 17, 436. 1. Nomenclature syn/anti erythro/threo Summary IUPAC Others OH O + R1 R2 syn (or threo) R3 R1 R2 anti (or erythro) J. Am. Chem. Soc. 1981, 103, 2106. (supercedes erythro/threo nomenclature) Angew. Chem., Int. Ed. Eng. 1980, 19, 557. Asymm. Synth. Vol. 3, pp 111–212. (Review of aldol diastereoselection) Pure Appl. Chem. 1976, 45, 11. Angew. Chem., Int. Ed. Eng. 1966, 5, 385. (Cahn, Ingold, Prelog) Angew. Chem., Int. Ed. Eng. 1982, 21, 654. (Seebach, Prelog) J. Org. Chem. 1982, 47, 3811. (Carey, Kuehne) 2. Generalizations R3CHO R2 OH O OM + R1 Z-enolate R3 R1 R2 syn (or threo) R 3CHO OH O OM + R3 R2 R1 E-enolate R1 R2 anti (or erythro) 1. Z-enolates give predominantly syn (or threo) aldol products (thermodynamic enolates). 2. E-enolates give predominantly anti (or erythro) aldol products (kinetic enolates). and 3. Diastereoselectivity (for syn aldol) of Z-enolates is greater than that of E-enolates (for anti). 4. Correlation for E or Z-enolate is greater when R1 is sterically demanding. 5. Correlation is stronger when R3 is large (most important for boron enolates). 6. Correlation is reversed when R2 is sterically demanding (very large). - Advances in 1H NMR, 13C NMR permitted detection, quantification and identification. - Issue of equilibration addressed. 179 Modern Organic Chemistry The Scripps Research Institute Francis W. Aston was awarded the 1922 Nobel Prize in Chemistry for his contributions to analytical chemistry and the study of atomic structure. He is primarily associated with the design and use of the mass spectrometer. Fritz Pregl received the 1923 Nobel Prize in Chemistry for his development of microanalytical techniques (accurate microbalance weighing of 1 µg−20 g) and for refinements in characterizing organic compounds (CHNSX analysis). R. R. Ernst received the 1991 Nobel Prize in Chemistry for the development of the methodology of high resolution NMR spectroscopy. 3. Examples O O OH O OH LDA + CHO E-enolate formation EtO EtO EtO syn 7–10% anti 90–93% - Steric size of R1 affects diastereoselectivity OMg OH O PhCHO syn:anti >98:2 Ph note: R1 = tBu > iPr - Z-enolate OLi OH O PhCHO syn:anti 90:10 Ph OLi OH O PhCHO syn:anti 45:55 Ph note: Z > E, stereoselectivity much lower with E-enolate OLi OH O PhCHO Ph Ph syn:anti 88:12 > 98:2 Z:E OLi CH3 OH O PhCHO Ph H3C Ar syn:anti 88:12 CH3 87:13 Z:E OLi CH3 OH O PhCHO Ph H3C CH3 92:8 E:Z Heathcock J. Org. Chem. 1980, 45, 1066. 180 Ar anti:syn 92:8 note: larger R1 helps maintain high selectivity dictated by enolate geometry and substantially enhances E-enolate diastereoselectivity Enolate Chemistry Dale L. Boger 4. Origin of Diastereoselectivity - Zimmerman–Traxler Model (J. Am. Chem. Soc. 1957, 79, 1920) - Chair-like, closed transition state: metal coordination to both carbonyls a. Z-enolates R2 HO R3 H H O O R3 R1 R3 R2 Major product (syn) O H R2 M H R3 H R2 HO H R3 R1 R2 O M O H O O R1 1,3-diaxial interaction (destabilizing) anti is minor diastereomer R2 R3 R1 O H H R1 syn (major) gauche interaction OH O R2 M OH O O M O H H H R1 R3 R1 R2 R3 R1 1,3-diaxial interaction 1. Diastereoselectivity for Z-enolate (giving syn aldol product) is maximized when R1 and R3 are sterically demanding (R1/R3 interaction is maximized). 2. Diastereoselectivity also increases as metal is changed to boron. This is attritubted to a tighter T.S. (B–O bond shorter, so R1/R3 steric interactions are magnified in T.S. for anti product). 3. When R2 is very large the R3/R2 gauche interaction > R1/R3 1,3-diaxial interaction (Why?). ° 1.92–2.00 A ° 2.01–2.03 A ° 1.92–2.16 A ° 1.92 A ° 1.36–1.47 A ° 1.62–1.73 A ° 2.15 A Li–O Mg–O Zn–O Al–O B–O Ti–O Zr–O b. E-enolates H HO O R3 2 R R1 H O R3 M B > Li > Na > K O R2 H R1 anti (major) O H R1 R2 Major Product (anti) gauche interaction R3 R2 H O M H 2 R R3 R2 R1 R3 H O M O H R1 H HO O R1 1,3-diaxial interaction syn (minor) H OH O R3 H Diastereoselection: H R2 gauche interaction OH O M O R3 R1 1,3-diaxial interaction R3 O R1 R2 syn 1. Diastereoselectivity increases as R1 and R3 become sterically large, and a switch to the boron enolate will increase selectivity. 2. Diastereoselectivity may switch when R2 is very large (Why?). 181 Modern Organic Chemistry The Scripps Research Institute 5. Cyclic Ketones - Only E-enolate and therefore anti aldol. - Aldol addition is reversible, can get very different selectivity by allowing reaction products to equilibrate (and equilibration can be very fast). O O base + CHO Dubois: H for kinetic aldol product E-enolate anti:syn LiOH KOH Me4N+OH– >95:5 >95:5 30:70 H OH syn (stabilization of adduct via coordinating countercation) thermodynamic ratio Tetrahedron Lett. 1989, 30, 5681. J. Am. Chem. Soc. 1973, 95, 3310. J. Org. Chem. 1980, 45, 1066. O OLi + + anti base - Instructive examples: Majewski House Heathcock O OH OH O Ph PhCHO Ph + 52:48 anti OH syn widely quoted - but really is the result of equilibration: Tetrahedron Lett. 1989, 30, 5681. ratio OLi O O Ar H + R THF > DME OH R=H OLi THF DME Et2O THF THF THF THF : : : : : : : OH Ph PhCHO Ar syn 84 72 76 73 78 94 74 O OH + anti R = NMe2 R = OCH3 R = Ph R = CF3 + O 16 28 24 27 28 6 26 O 75% 50% 84% 68% 68% 67% 80% OH Ph + axial attack tBu tBu tBu anti 1. E-enolate -> anti aldol. 2. Axial attack of enolate (stereoelectronic control). 182 THF 81 Et2O 75 Et2O–HMPA 68 syn : : : 19 25 32 63% 61% 68% Enolate Chemistry Dale L. Boger 6. Acyclic Enolates - Effect of R1 OLi + PhCHO syn : anti aldol R1 syn : anti ratio R1 OMe OtBu H Et iPr Ph tBu mesityl Z-enolate – – 1.0 9.0 9.0 7 70 >50 E-enolate 1.5 1.0 1.5 1.5 1.0 – – <0.02 typically: Z > E diastereoselection diastereoselection increases as size of R1 increases 7. Refined and Alternative Models - Idealized closed, chair transition state does not account for Z > E diastereoselectivity nor does it explain the switch in diastereoselectivity when R2 is sterically demanding. - It has been suggested that the transition state for addition more closely resembles an eclipsed conformation. - Dubois, Fellmann Tetrahedron Lett. 1975, 1225; Tetrahedron 1978, 34, 1349. - Heathcock J. Org. Chem. 1980, 45, 1066. - For Z-enolate R2O syn R3 H R2O M H H O H R2/R3 gauche R1 M anti O R3 R1 R1/R3 interaction even worse than in staggered interaction is further minimized Z>E diastereoselectivity - For E-enolate HO anti R3 R2 M HO H R2 O H M O syn R3 1 R R1 nearly eclipsed much worse than gauche interaction As R2 increases in size, R2/R3 interaction competes with or surpasses R1/R3 interaction E < Z diastereoselectivity diastereoselectivity reverses when R2 becomes sterically demanding - Burgi–Dunitz approach angle -skewed approach where R2/R3 come closer together than R1/R3 R1 R2 OLi H R3 109° O H 183 Modern Organic Chemistry The Scripps Research Institute - An additional alternative explanation considers the boat transition states Evans Top. Stereochem. 1982, 13, 1. - In addition to the four idealized closed chair transition states, four closed boat transition states must be considered as well. - Z-enolate R2/R3 eclipsed 2 R3 R M syn aldol R2/H eclipsed H R2 O M anti aldol O R3 H O H H O R1 H/H eclipsed R3/H eclipsed R1 - when the R2/R3 gauche interaction is large in chair TS, Z-enolate boat TS might become competitive leading to the anti aldol - E-enolate R3/H eclipsed R3 anti aldol H R2 H M H/H eclipsed H H O M syn aldol O 3 R R2 O O R2/H eclipsed R1 R1 R3/R2 eclipsed - However, the boat transition state alternative does not explain the E-enolate switch from anti to syn aldol when R2 becomes sterically more demanding. - Examples OMgBr R O CH3CHO O OH R OH 0 °C syn anti E-enolate Dubois, Fellmann C. R. Hebd. Seances Acad. Sci. Ser. C. 1972, 274, 1307. R R = Me = Et = iBu = iPr = tBu : : : : : 93.5 87.5 80 46 29 6.5 12.5 20 54 71 anti:syn ratio decreases smoothly as R becomes larger (R2 in models above) O OLi tBu tBuCHO R Et2O, 20 °C Z-enolate R = Me = Et = nPr = iBu = iPr = tBu 184 tBu OH O tBu tBu R anti 0 0 2 3 71 100 tBu R syn : : : : : : OH 100 100 98 97 29 0 Enolate Chemistry Dale L. Boger 8. Boron Enolates - Often much more diastereoselective in their aldol addition reactions - This results from a shorter B–O bond length, tighter transition state OB(Bu)2 OH O R2CHO R2 R1 OH O R1 R2 R1 Z-enolates (syn aldol) syn R1 = Me R1 = PhCH2 R1 = Ph R1 = Ph R1 = Ph R2 = Ph R2 = Ph R2 = Ph R2 = Et R2 = iPr OB(Bu)2 anti >95:5 for all cases OH O R2CHO R2 R1 E-enolates (anti aldol) OH O R1 R2 syn R1 = Me R2 = Ph 1 R = PhCH2 R2 = Ph R1 = Ph R2 = Ph R1 anti 25:75 20:80 25:75 E-enolates give lower diastereoselectivity Z > E diastereoselection Masamune Tetrahedron Lett. 1979, 1665. a. Z-enolate Preparation and Reactions R2BOTf O R1 iPr 2NEt –78 °C OBR2 R1 Z-enolate R1 = Et R1 = Et Bu2BOTf, –78 °C BOTf, 0 °C OH O PhCHO R1 Ph syn aldol >97:3 >97:3 syn/anti 82:18 84:16 syn/anti >95:5 >97:3 syn/anti >99:1 >95:5 syn/anti 2 R1 = Ph R1 = Ph 9-BBNOTf, 0 °C BOTf, 0 °C 2 185 Modern Organic Chemistry The Scripps Research Institute b. E-enolate Preparation and Reactions O Me OBR2 R2BOTf iPr 2NEt R1 OH O PhCHO Me R1 = iPr Bu2BOTf, –78 °C R1 = iPr BOTf, 0 °C R1 Ph R1 anti aldol 45:55 Z:E 44:56 syn/anti 19:81 Z:E 18:82 syn/anti 2 - originally difficult to control but: O Me OBR2 R2BOTf iPr 2NEt StBu OH O PhCHO Masamune Tetrahedron Lett. 1979, 2225. Me E-enolate Bu2BOTf, 0 °C BOTf, 0 °C StBu Ph StBu anti aldol >95:5 10:90 syn/anti >95:5 5:95 syn/anti 2 E-enolates very accessible using tbutylthiol esters c. Examples of more recent methods to control boron enolate geometry B OBBN R 9-BBN–Cl/ R Z R O B HR H OBChx2 O H RR R E H iPr R Cl–B(Chx)2/Et3N E-enolate kinetic enolate E2 elimination mechanism 2NEt (hindered base) Z-enolate thermodynamic enolate E1 elimination mechanism Cl–B(Chx)2 O BCl O OB(Chx)2 i) PhCHO 2 Et3N, 0 °C Ph ii) H2O2 workup >95:5 anti:syn >99% E O OBBN 9-BBN–Cl iPr 2NEt, Ph ii) H2O2 workup >99% Z 98:2 syn:anti -These results are difficult to achieve with boron triflates 186 OH i) PhCHO 0 °C Brown J. Am. Chem. Soc. 1989, 111, 3441. OH Enolate Chemistry Dale L. Boger - Examples BCl 2 9-BBN–Cl O 99:1 (Z:E) <1:99 (Z:E) >99:1 15:85 98:2 (via equilibration) <1:99 96:4 (via equilibration) <1:99 99:1 (via equilibration) 21:79 O O O O Z-enolate is easy to access: thermodynamic enolate E-enolate is less stable, more difficult to generate without equilibration (also still difficult to prepare unless alkyl groups are bulky). - see also Brown J. Org. Chem. 1992, 57, 499 and 2716. Brown J. Org. Chem. 1994, 59, 2336. O R Chx2BX OEt R = CH3 R = CH3 R = Et R = iPr R = tBu R = Ph O OR iPr 2NEt or Et3N CCl4 X=I X = Br X=I X=I X=I X=I OBChx2 OBChx2 OEt OEt R R Z >97 84 95 <3 <3 <3 : : : : : : E 3 17 5 >97 >97 >97 Chx2BI OBChx2 OBChx2 CCl4 OR OR Z R = CH3 R = Et R = iPr R = tBu Et3N iPr NEt 2 Et3N iPr NEt 2 Et3N iPr NEt 2 Et3N iPr NEt 2 >97 >97 >97 >97 86 64 59 3 E : : : : : : : : <3 <3 <3 <3 14 36 41 97 9. Aldol Condensation with Chiral Aldehydes a. Felkin Addition - Two faces of aldehyde are diastereotopic. - Nucleophilic addition of enolate follows Cram's empirical generalization (Felkin–Anh addition). 187 Modern Organic Chemistry The Scripps Research Institute Nu– H H Nu Nu– RL H R O M Felkin model - Example: H H H RMOH O OH RL RM OM R Ph R MO O R R H Me H O H O R R O 1 syn H H MeOH Me Ph Ph Me MO : R Ph Ph anti syn 3 major H Ph OH O O H Me O R + Ph OH O invariant diastereoselectivity with different size of R H H Nu RL RL + CHO Ph RM major H Ph O minor H Me OH anti CH2COR H - Can combine all selectivities to give 3 contiguous chiral centers, if the chiral aldehyde and enolate partners are both highly diastereoselective. Z-enolate OLi tBu + Ph CHO tBu Ph OH O - A & B represent 2,3 syn products (from Z-enolate with large R group) - A & C represent 3,4 syn products (from Cram/Felkin–Anh addition to aldehyde) OH O A tBu Ph OH O tBu Ph B tBu Ph OH O C D experimental: A:B:C:D = 86:14:0:0 Heathcock J. Org. Chem. 1980, 45, 1066. - syn aldol reaction proceeds with >98% syn selectivity - Cram/Felkin–Anh addition proceeds with 86:14 syn selectivity E-enolate H MOMO O O Felkin addition OLi OAc O O O StBu StBu MOMO O O OAc Woodward J. Am. Chem. Soc. 1981, 103, 3210, 3213, 3215. 188 E-enolate anti aldol O O OH O erythromycin Enolate Chemistry Dale L. Boger b. Chelation Control OLi + R CHO R + OTBDMS OTBDMS R OH O OTBDMS OH O syn, anti syn, syn R = Ph : 81 Z-enolate (with large R group) gives clean syn aldol product for both. 19 >98% syn aldol, 81:19 Cram addition : 21 79 R = CH2OTBDMS >98% syn aldol, 79:21 chelation-controlled addition to RCHO Heathcock J. Org. Chem. 1980, 45, 1066. Explanation of Chelation Control 1. without chelation control OLi O Ph H H Me OTBDMS O Me OLi Me syn, syn aldol condensation H H OTBDMS H Nu– Nu– Nu Me H H Me O H Ph H Me OH 3,4 syn Ph Ph 4 3 OTBDMS OH O 2. with chelation control + Li O O M M O O OTBDMS Me TBDMSO H + Li OTBDMS Me syn, anti aldol TBDMSO H syn, syn aldol H H Me nucleophilic addition opposite to larger (Me) substituent H H Me severe Me/Me interaction backside attack -drawn another way H O H Me OR H Me H minor Li O OR H RO major Me Me H Li O RO Nu OH 3,4 anti 189 Modern Organic Chemistry The Scripps Research Institute 10. Aldol Condensation with Chiral Enolates Evans' Chiral N-Acyl Oxazolidinones O O O O O R N Bu2BOTf iPr 2NEt O B O O OH R1 N O N R R1CHO R or O O O OH R1 N R only Z-enolate (independent of conditions) two possible syn aldol products (relative to chiral center on aux.) 1. Experimental results O O O O Me Bu2BOTf N R1CHO R1 = nBu R1 = iPr R1 = Ph O O O OH R1 N O Me O OH R1 N Me 99.3 99.8 >99.8 : : : 0.7 0.2 <0.2 * no anti adducts Evans J. Am. Chem. Soc. 1981, 103, 2127, 2876, and 3099. 2. Origin of diastereoselectivity - Z-enolate (boron enolate/amide) gives syn aldol (minor syn aldol product) B O O Xc O O CH3 N H H H O H O 190 R H Me O Me Aldehyde R group equatorial (axial would give anti aldol) O O N OH R - chiral auxiliary rotates - non-chelated enolate: opens coordination site on boron required to complex and activate aldehyde - dipoles non-aligned, more favorable B O H R observed syn aldol product Xc O R O OH Me CH3 N O - H–H interaction - steric interaction with iPr (facial selectivity) - aligned dipoles less favorable O O O H HN R B H Chair transition state non-chelated Z-enolate H B O H R Me O Enolate Chemistry Dale L. Boger 3. For the alternative enantiomer B O Auxiliary with the opposite absolute configuration or the more accessible O O O Ph RCHO Me N O O OH N R Me Ph Me nBu syn : <0.2 : <0.2 : <0.2 >99.8 >99.8 >99.8 R= R = iPr R = Ph Me anti : 0 0 : 0 0 : 0 0 : : : O - Note: selectivity not good for H Xc O - Solution: use removable substituent SMe Xc Evans aldol overrides any chiral aldehyde directing preference: i.e. Felkin–Anh preference. As before - two possible transition states for syn aldol product formation B O O Me Ph H R H R - anti carbonyl conformation O H Ph OH Me O observed syn aldol product B O O O O CH3 N O Xc Xc O CH3 N H H Me H OH Me R R - syn carbonyl conformation - steric interactions between H's (minor syn aldol product) S Note: Availability of oxazolidinone alternatives Fujita J. Org. Chem. 1986, 51, 2391. Crimmins J. Am. Chem. Soc. 1997, 119, 7883. X O R N X=O X=S Advantages: S > O for chelation and more readily cleaved 4. Ti enolate promoted Evans aldol (non-Evans syn aldol) Ti O O O O N R LDA ClTi(OiPr) O O O N R O OH R1CHO O R1 N 3 R or TiCl4 Et2O vs. THF as solvent Z-enolate and chelated enolate higher coordination sphere of Ti 8 syn : 87 : 5 anti : 0 191 Modern Organic Chemistry The Scripps Research Institute syn aldol product but opposite absolute stereochemistry (non-Evans syn aldol). Thornton J. Am. Chem. Soc. 1989, 111, 5722; 1991, 113, 1299. Evans J. Am. Chem. Soc. 1991, 113, 1047. Thornton J. Org. Chem. 1991, 56, 2489. Heathcock J. Org. Chem. 1991, 56, 5747. 5. Origin of diastereoselectivity - chelated Z-enolate O Ti O O H O O H H H O R H H Closed, chair transition state with chelated Z-enolate O H CH3 N O Me O O syn Ti O H R R Ti O O HN CH3 N Chelation orients chiral auxiliary in opposite orientation O anti RN H Ti O H H O Me steric interaction 6. Chelated and non-chelated Ti enolates OH O R S N O S N O 2.5 equiv TMEDA 2NEt O 2 equiv TiCl4 R Me or sparteine Bn RCHO Evans syn via non-chelated Z-enolate N O Bn non-Evans syn via chelated Z-enolate O S N Bn Cl Cl Cl Ti O Cl O S Me RCHO Bn O H OH O iPr 1 equiv TiCl4 H +Cl– H H –Cl– R S Bn H N H R O O Cl Ti Cl Cl Me Me Crimmins J. Am. Chem. Soc. 1997, 119, 7883. 7. Anti-selective additions - see also Heathcock Aldrichimica Acta 1990, 23, 99; J. Org. Chem. 1991, 56, 5747. Se OH O Pr N 1.1 equiv TiCl4 O 1.15 equiv iPr2NEt Me 90%, > 98% syn non-Evans syn 192 PrCHO Se O BnO N 1.1 equiv TiCl4 O 1.15 equiv iPr2NEt BnOCH2CHO−TiCl4 Silks J. Am. Chem. Soc. 2000, 122, 386. OH Se O BnO N O Me 90%, > 99.9% anti via chelated Z-enolate Enolate Chemistry Dale L. Boger 11. Asymmetric Aldol Reactions - Review: Paterson Org. React. 1997, 51, 1. Corey J. Am. Chem. Soc. 1990, 112, 4976. Corey J. Am. Chem. Soc. 1989, 111, 5493. F3C CF3 Ph Ph F3C N O S O Et3N O OBR*2 R*2BBr OtBu CF3 N S B O O Br Corey OH O RCHO OtBu R OtBu Me Me E-enolate (kinetic enolate) anti aldol anti:syn toluene–hexane R = Ph 93% 98:2 94% ee CH2Cl2 R = Ph 90% 96:4 89% ee in plane lone pair oriented away from ester via: B Br H + O tBu O Me E-enolate E2 elimination H Et3N non-hindered base iPr 2NEt O Me OBR*2 R CH2Cl2 SPh SPh R = Ph B SPh+ B H Br O –Br– Me Me SPh Me syn aldol anti:syn 93% 1:99 97% ee Z-enolate via: OH O RCHO SPh+ O Z-enolate (thermodynamic) H E1 elimination H H i Pr2NEt hindered base Facial selectivity: Ar Me R O O H S H Ar Ph SO2 N B N SO2 Ph Ph Ph Orientation determined by the phenyl groups Ph Ar S N N SO2 B O2 Ar O O Me SPh R H H - Chair transition state - Boron enolate - Z-enolate 193 Modern Organic Chemistry The Scripps Research Institute Examples Corey Tetrahedron Lett. 1993, 34, 1737. O OBR*2 R2*BBr X Ph X Yield 82% 78% 82% 94% iPr X = SPh X = OtBu X = StBu X = StBu CH2Cl2, 2NEt CH2Cl2, iPr2NEt CH2Cl2, iPr2NEt toluene, Et3N OBR*2 O X ee 64% 80% 73% 52% OH O X 1 Ph Me OH O PhCHO OBR*2 Ph X Yield 90% 78% 89% 64% 73% 78% 79% 84% 73% 86% CH2Cl2, iPr2NEt toluene, Et3N CH2Cl2, iPr2NEt toluene, Et3N CH2Cl2, iPr2NEt toluene, Et3N CH2Cl2, iPr2NEt toluene, Et3N CH2Cl2, iPr2NEt toluene, Et3N X = SPh X = SPh X = OtBu X = OtBu X = OBn X = OBn X = SBn X = SBn X = StBu X = StBu Config. S S S S PhCHO X R2*BBr X Note: Z-enolate E-enolate OH O PhCHO OH O X Ph X Me Me 2a 2b syn:anti Major Prod. 99:1 1 94:6 1 4:96 2a 2:98 2a 84:16 1 15:85 2a 70:30 1 9:91 2a 71:29 1 6:94 2b (+ 2a) ee 97% 95% 94% 94% 97% 97% 81% 94% 50% 46% see also: Corey Tetrahedron Lett. 1992, 33, 6735. - Mukaiyama Chem. Lett. 1973, 1011; review Org. React. 1982, 28, 203. - Carreira's catalytic asymmetric aldol O + tBu R1 H OSiMe3 OMe 1.1 (2-5 mol%) OH O –10 °C R1 OMe 2. Bu4NF Aldehyde N O Ti O O O Br O Me Ph tBu 1 Me tBu Ph CHO 97% CHO 95% CHO 97% CHO 94% C6H11CHO 95% PhCHO 96% Carreira J. Am. Chem. Soc. 1994, 116, 8837. 194 ee: Enolate Chemistry Dale L. Boger - Evans C2-symmetric bisoxazoline catalysts OSiMe3 2 (10 mol%) R2 OH O –78 °C 1 R O StBu StBu 1N HCl O ee: 99% 99% 99% 94% 94% 36% O R1O O O N Me3C N Cu R2 O R1 Me Bn tBu Me Me Et 2 –OTf CMe3 2 + R2 Me Me Me Et iBu iBu Evans J. Am. Chem. Soc. 1997, 119, 7893. OSiMe3 3 (10 mol%) –78 °C EtO SR2 1N HCl O EtO O O N Bn TfO Sn + H O R1 N 3 H Me Et iPr iBu iBu iBu - review of catalyzed enantioselective aldol reaction Tetrahedron Asymm. 1998, 9, 357. SR2 R1 O R1 R2 OTf Bn OH O anti:syn ee – 90:10 92:8 93:7 92:8 96:4 92:8 98% 95% 95% 95% 98% 96% 92% Ph Ph Ph Ph Ph tBu Et Evans J. Am. Chem. Soc. 1997, 119, 10859. O O + H N H CO2H 97% O (H)HO R 96% ee List, Lerner, and Barbas J. Am. Chem. Soc. 2000, 122, 2395. O O + 62% O OH H 99% ee OH List J. Am. Chem. Soc. 2000, 122, 7386. H OH OH H N O H Me O O regioselectivity > 20:1 diastereoselectivity > 20:1 enantioselectivity > 100:1 195 Modern Organic Chemistry The Scripps Research Institute 12. Enzyme-Catalyzed Aldol - Wong aldolase based synthesis of carbohydrates and aza-sugars O OP = DHAP HO O FDP aldolase OH PO R DHAP OH OH O 1. Phosphatase 2. H2 / Pd–C OH H N HO HO R = N3 HO OH H R R = OH OH Rham-1-P aldolase O OH PO DHAP HO OP HO OH L-Fructose 1-P R OH OH H2 / Pd–C R = N3 HO H3C - Review: Wong Pure Appl. Chem. 1993, 65, 803. - wide range of donors and acceptors utilized - commercially available Donor O H N HO OH Niels K. Jerne, Georges F. Kohler, and Cesar Milstein shared the 1984 Nobel Prize in Medicine for the preparation of monoclonal antibodies. - Lerner catalytic antibodies Acceptor O Product 38C2 ee 33F12 ee >99% >99% >98% 89% >95% >95% OH O O H O O H O OH OH OH O O O O O Lerner, Barbas J. Am. Chem. Soc. 1998, 120, 2768. Org. Lett. 1999, 1, 59. Kinetic resolution Me OH O Me OH O 38C2 50% MeO MeO > 99% ee catalyzes retro aldol of only one enantiomer Lerner, Barbas J. Am. Chem. Soc. 1999, 121, 7283. 196 Enolate Chemistry Dale L. Boger H. Aldol Equivalents 1. Chiral Organoboranes Brown: 2. OH–, H2O2 2 95 78 99 95 75 OH 1. CH3CHO, –78 °C 2 99 CH3 oxidative cleavage gives typical aldol product B ee% yield% OH 1. CH3CHO, –78 °C B de% 2. OH–, H2O2 CH3 Brown J. Am. Chem. Soc. 1986, 108, 293 and 5919. J. Org. Chem. 1989, 54, 1570. The relative configuration, syn or anti, of the product is determined by the configuration of the olefin. H OH B Et O Et E H anti OH B Et O Et Z OH syn B B 2 2 OH BnO BnO BnO syn : 92 Z OH CHO OH BnO anti E BnO 8 : 98 2 The reagent controls facial selectivity of addition and determines the absolute configuration of product. Roush: O iPrO iPrO O 2C de% ee% yield% 80 84 OHC 2C O Me O B toluene, –78 °C ° sieves 4A O O 80 OH Roush and Halterman J. Am. Chem. Soc. 1986, 108, 294. H Me R O O H OR O A B B O CO2R O CO2R H Me R H B O OR O O - asymmetric induction is a consequence of n/n electronic repulsive interactions disfavoring transition state B relative to transition state A 197 Modern Organic Chemistry The Scripps Research Institute 2. Allylsilanes Reviews: Fleming Org. React. 1989, 37, 57. Panek Chem. Rev. 1995, 95, 1293. A. Chiral allylsilanes yield E-olefins selectively R3Si H H H R + H R H H H H H R3Si H H Anti-SE' E H R H E H H H H R H R3Si H +R H H H Anti-SE' H E H R3Si E R A 1,3 -strain - Chiral allylsilanes add to carbonyls in syn fashion (either synclinal or antiperiplanar T.S.) (Unless chelation control is utilized) LA LA O Me H H R Me O H Me R H Me R R OH OH SiR3 (E)-silane reagent SiR3 (Z)-silane reagent syn-homoallylic alcohol syn-homoallylic alcohol B. Additions to Aldehydes (Opposite face of silane) O BnO Me H O F3B BF3•OEt2 (–78 °C) H H BnO CO Me SiMe3 2 Br SiMe3 O O Mg H Br H O H Synclinal T.S. MeO2C O Me CO2Me SiMe2Ph BnO 198 CO2Me SiMe2Ph H Me O R Me OH + BnO anti-homoallylic alcohol TiCl4 –78 °C R R = Me 64%, 10:1 CO2Me R = Et 35%, 15:1 BnO Me H Me TiCl4 –78 °C CO2Me oxidative cleavage provides aldehyde, carboxylic acid (R = H) or ketone (R = Me, Et) aldol addition products C. Additions to Chiral Aldehydes - BnO chelation, anti R3SiO no chelation, syn + OH BnO 12.2 : 1 Denmark J. Org. Chem. 1994, 59, 5130. R CO2Me Me H Me3Si MgBr2•OEt2 (–25 °C) OH 6.5 : 1 syn-homoallylic alcohol Bn CO2Me BnO Antiperiplanar T.S. BnO Me OH R R=H CO2Me R = Et BnO Me Me 85%, >30:1 69%, 10:1 Enolate Chemistry Dale L. Boger O R Me CO2Me + Ph2tBuSiO SiMe2Ph H Me O CO2Me + Ph2tBuSiO SiMe2Ph TiCl4 –78 °C H R R = H 90%, >30:1 CO2Me R = Me 79%, >30:1 R = Et 74%, 15:1 R3SiO Me R Me OH TiCl4 –78 °C Me OH R R = Me 98%, 8:1 CO2Me R = Et 79%, 10:1 R3SiO Me Me Me Jain and Panek J. Am. Chem. Soc. 1996, 118, 12475. 3. Allylstannanes A. Asymmetric addition via optically active catalyst + Bu3Sn 10 mol% BINOL−TiCl2 O H OH CO2Me 64% CO2Me 84% syn, 86% ee Aoki Tetrahedron 1993, 49, 1783. Keck J. Am. Chem. Soc. 1993, 115, 8467; J. Org. Chem. 1993, 58, 6543. - Also applicable to allylsilanes. I. Enolate-imine Addition Reactions - Review: Hart Chem. Rev. 1989, 89, 1447. R1 Ph R1 CO2Et 1. LDA 2. PhCH=NSiMe3 3. HCl, H2O H H NH O yield 0% 3% 0% 1% 0% OH H Ph OH H H 1. LDA 2. PhCH=NPh H Georg Tetrahedron Lett. 1985, 26, 3903. O N H2N CO2Et Ph 16% NHBOC CONH2 N N Ph 25% NHBOC N Ph + N O + H NH yield 14% 41% 72% 80% 40% R H Me Et i Pr tBu Hart J. Am. Chem. Soc. 1984, 106, 4819. CO2Et R + O 1 OH H Ph 1 MeS OTf Sn O O Xc THF, 0 °C N Me O CH3 CONH2 NH MeS N 85% Ph O Boger J. Am. Chem. Soc. 1994, 116, 5619. O CONH2 NH MeS CO2Et CH3 Xc + N H2N NHBOC N N H2N 7:1 anti:syn (>16:1) CO2Et CH3 199 Modern Organic Chemistry The Scripps Research Institute J. Claisen Condensation O EtO ONa O OEt CH3CO2Et + NaOH (or NaOEt) ONa OEt H2C OEt Claisen Chem Ber. 1887, 20, 651. NaO reaction driven to completion by forming product which is stable to the reaction conditions. O OEt pKa = 13 - Weinreb Amide Turner J. Org. Chem. 1989, 54, 4229. O OMe Li CN N + Me + O OEt pKa = 13 O CN 62% O O OLi OR' OR' 63–89% R + O irreversible R O O O NNMe2 OLi 47% NNMe2 + Li 98% - Tetrahedral intermediate is stabilized - Breaks down upon workup, not in reaction - Generality of Weinreb amide - Weinreb Tetrahedron Lett. 1981, 22, 3815. O R Ph Li O N Me Me - Knoevenagel–Doebner and Stobbe Condensation CHO CO2Et + CO2H OMe OMe OMe OMe CO2Et Ph O + Ph CHO + O (MeO)2P NaH Ph CO2Et CO2Et CO2Et R O OH 200 O Stobbe condensation Stobbe Chem. Ber. 1893, 26, 2312. Review: Org. React. 1951, 6, 1. CO2tBu N R Knoevenagel–Doebner condensation Knoevenagel Chem. Ber. 1896, 29, 172. Doebner Chem. Ber. 1900, 33, 2140. Review: Org. React. 1967, 15, 204. CO2Et R NaH 75–100% CO2tBu R = H, Br, OCH3 R CO2Et Ph CO2Et - Example R CO2Et piperidine 1. TFA 2. Ac2O Boger J. Org. Chem. 1996, 61, 1710. 1996, 61, 4894. Enolate Chemistry Dale L. Boger K. Dieckmann Condensation - Org. React. 1967, 15, 1. - Examples O OEt EtO ONa NaOEt O H+ CO2Et CO2Et 80% O O CO2Et CO2Et O CO2Et NaOEt H2O 84–89% 180 °C 64–68% EtO2C O O - Org. Syn. Coll. Vol. 2, 288. KOtBu MeO2C THF CN Thorpe–Ziegler condensation O 70% H CN Dinitrile is Ziegler condensation Ziegler Chem. Ber. 1934, 67, 139. Stevens J. Am. Chem. Soc. 1977, 99, 6105. CO2Et O Na CO2Et EtOH CO2Et Dieckmann Ber. 1894, 27, 965. Fehling Ann. 1844, 49, 192. (1st example - product not identified) R CO2Et O R R CO2Et CO2Et 2 R O O– CO2Et CO2Et 1 - products interconvert under reaction conditions equilibration driven to 1 by formation of enolate. The analogous intramolecular keto ester condensation may be described as "occurring under Dieckmann conditions" see: Org. React. 1959, 8, 79. CO2Et NNMe2 1. LiCu 2 2. H3O+ O CO2Et O NaH benzene O cat. MeOH conjugate 1,4-addition Boger and Corey Tetrahedron Lett. 1978, 4597. 201 Modern Organic Chemistry The Scripps Research Institute OMe OMe MeO KOtBu N MeO OMe MeO 98% H+ N MeO aq. dioxane 89% CN MeO2C MeO MeO2C N MeO O NH2 OMe OMe MeO MeO N MeO R=H rufescine R = OCH3 imeluteine N MeO imerubrine R O OMe MeO Boger and Brotherton J. Org. Chem. 1984, 49, 4050. Boger and Takahashi J. Am. Chem. Soc. 1995, 117, 12452. MeO2C N MeO2C OMe N LDA CO2Me OMe MeO2C OMe 68–85% O O– Me Nat. and ent Fredericamycin A OH CO2Me O N Boger J. Org. Chem. 1992, 57, 3974. Boger J. Am. Chem. Soc. 1995, 117, 11839. - Asymmetric Dieckmann-like condensation TBDMSO HN Me Kinetic control: 5–7:1 diastereomers NBOC XcOC N BOC OBn Thermodynamic control: single diastereomer TBDMSO NC Me LDA N THF O 58% O –78 °C, 30 minO NBOC N BOC OBn CO2tBu > CHO LDA anti-carbonyls O N N O Li O O O Me R iPr N Me Me NH Li O N R N O iPr N R O O ∆E = 0.76 Kcal/mol Boger J. Am. Chem. Soc. 1997, 119, 311. 202 NBOC THF Me N 78% BOC OBn –40 °C, 3 h (reversible and equilibration) Chelated Z-enolate N N HN XcOC (+)-Duocarmycin A epi-(+)-Duocarmycin A iPr TBDMSO O iPr O N O NH Me N R Enolate Chemistry Dale L. Boger L. Enolate Dianions dianion O O NaH OMe OMe or LDA O– O– –78 °C OMe 1. OH– 2. ∆ (–CO2) O R nBuLi ONa O RX Me O O R O– H+ O R OMe OMe 1. NaH R R' O 2. R'X dianion useful for slow alkylations (i.e. ketone enolate + epoxide slow but dianion reacts quickly). 3. OH– 4. ∆ Weiler J. Am. Chem. Soc. 1974, 96, 1082. Weiler Tetrahedron Lett. 1983, 24, 253. Harris Org. React. 1969, 17, 155–212. (review) M. Metalloimines, Enamines and Related Enolate Equivalents Metalloimines: Stork J. Am. Chem. Soc. 1963, 85, 2178. - Stork J. Am. Chem. Soc. 1971, 93, 5938. (Metalloimines, dimethylhydrazones) - Corey, Enders Tetrahedron Lett. 1976, 3 and 11. Chem. Ber. 1978, 111, 1337 and 1362. (Dimethylhydrazones) O O OLi R RX LDA O via enolate equilibration O OLi O OLi R R R R R O R R R R - Simple alkylation of enolates not always straightforward. - Can get polyalkylation mixtures. 203 Modern Organic Chemistry The Scripps Research Institute - Solutions O O O NaH EtO O NaH OEt OEt O R OEt RX O OH– R ∆ (–CO2) O N NMe2 N NMe2 NaH, HMPA Na NMe2 N BuI O H3O+ Bu Bu Stork J. Am. Chem. Soc. 1971, 93, 5938. O N Me2NNH2 pKa = 20 NMe2 pKa = 30 O N Me2NNH2 NMe2 N nBuLi N MeI Li NMe2 - Higher pKa so anion is more reactive - Alkylation much faster and polyalkylation is not a problem NMe2 N n BuLi NMe2 Li N MeI NMe2 or LDA pKa = 20 H3O+ or NaIO4 or CuCl2 pKa = 30 Advantages: O - monoalkylation (more reactive than ketone enolate). - no enolate anion equilibration. - regioselective (deprotonation at least substituted site). - alkylation is diastereoselective. Corey Tetrahedron Lett. 1976, 3 Note: preference for trans product is thermodynamic in origin. Cis (kinetic) product can also be obtained selectively (Collum J. Am. Chem. Soc. 1984, 106, 4865). - Examples: O tBu O LDA MeI Me 55 N MeI 90 H3O+ Enamine (Stork J. Am. Chem. Soc. 1963, 85, 207) tBu NNMe2 t 1. LDA Bu 2. MeI Dimethylhydrazone 3. CuCl2 H2O, pH = 7 204 O + tBu 97 tBu Me : 45 : 10 : 3 (Corey Tetrahedron Lett. 1976, 3 Chem. Ber. 1978, 111, 1337) Enolate Chemistry Dale L. Boger -also useful in acyclic cases O OLi LDA C4H9 C4H9 –78 °C no problem to make kinetic enolate, but if alkylation is slow, an equilibration may compete in product formation. Me2NNH2 N NMe2 LDA N C4H9 NMe2 C4H9 MeI N Li C4H9 NMe2 Me - very good as aldehyde enolate equivalents but H R N Me2NNH2 H R R O NMe2 nBuLi LDA OLi - aldehyde enolates difficult to generate and alkylate cleanly. 1. LDA 2. R'X R' R CN polycondensation self condensation H R N H NMe2 Review of methods for dimethylhydrazone cleavage: Enders Acc. Chem. Res. 2000, 33, 157. Oxidative methods: O3, 1O2, NaIO4, NaBO3, (Bu4N)2S2O8, HTIB/BTI, MMPP, m-CPBA, CH3CO3H, H2O2/SeO2, H2O2, MeReO3/H2O2, DMDO. Note: aldehyde dimethylhydrazones provide the nitrile upon oxidative cleavage. Hydrolytic methods: CuCl2, Cu(OAc)2, (CO2H)2, (NH4)H2PO4, MeI−HCl, HCl, SiO2−H2O, BiCl3/µW, Pd(OAc)2/SnCl2, BF3•OEt2 Reductive methods: =NNMe2 =NH =O, TiCl3, SnCl2, Cr(OAc)2, VCl2 - Enders chiral hydrazones (SAMP and RAMP) OMe H N NH2 SAMP N H N H OMe LDA or sBuLI MeI N H N MeO H H N NH2 RAMP - alkylation from the least hindered face of chelated anion. OMe MeI, HCl 80% O H 90% de Review: Asymm. Synth. Vol. 3, 275. 205 Modern Organic Chemistry The Scripps Research Institute - Meyers chiral oxazolines - Phenyl group shields top face to E+ attack Me O N Ph Me LDA Ph O N H Me H R Li R–X OCH3 Ph O N R–X OCH3 Me H CO2H R OCH3 Z-azaenolate (95:5 Z:E) –95 to –105 °C 72–82% de S-enantiomer Review: Asymm. Synth. Vol. 3, 213. N. Alkylation of Extended Enolates ONa O R–X NaH OCH3 OCH3 R O α-alkylation OCH3 two possible sites of alkylation - For alkylation in the γ position - can use a dianion O O O– LDA (2 equiv) O– or OCH3 R–X O O H3O+ OCH3 OCH3 1. NaH, 0 °C R 2. nBuLi, –78 °C - In cyclic systems O OLi O R'X LDA (1.05 equiv) –78 °C OR NaBH4 R' then OR OR R = Me, iPr H3O+ kinetic enolate Danheiser, Stork J. Org. Chem. 1973, 38, 1775. Cargill J. Org. Chem. 1973, 38, 2125. O OLi O R'X LDA or nBuLi N N N R' Yoshimoto, Ishida, Hiraoka Tetrahedron Lett. 1973, 39. Bryson, Gammill Tetrahedron Lett. 1974, 3963. 206 R' O Metalation Reactions Dale L. Boger IX. Metalation Reactions A. Directed Metalation - Kinetic acceleration of deprotonation of a relatively non-acidic site. - Synthesis 1983, 95. - Acc. Chem. Res. 1982, 15, 306. lateral lithiation: Org. React. 1995, 47, 1. - Org. React. 1979, 26, 1. H H Li LB nBuLi LB H LB or H Li - Usually requires very strong base (nBuLi, sBuLi or tBuLi, sometimes LDA). - Sometimes requires additives (TMEDA, DABCO) to break up Li aggregates (make bases more reactive). NMe2 N TMEDA DABCO N NMe2 - Examples: OCH3 OCH3 nBuLi H OCH3 OCH3 E+ Li OCH3 E OCH3 - All aromatic H's have approximately the same pKa nBu OH nBuLi Li H (2 equiv) O Li Li O Li hexane TMEDA 1. CO2 2. H+ - TMEDA breaks up RLi aggregates HO2C O Li - Not limited to aromatic substrates H H2C CH3 NR2 O LDA Li H2C NR2 O CH3 - Kinetic acceleration of deprotonation even in the presence of a more acidic proton. 207 Modern Organic Chemistry The Scripps Research Institute - Directed Metalation Groups carbon based heteroatom based Strong: Strong: CON–R CSN–R CONR2 CON(R)CH(Z)TMS, Z = H,TMS CH=NR (CH2)nNR2, n = 1,2 CH(OH)CH2NR2 CN O N Moderate: CF3 O NR2 Weak: C(OTMS)=CH2 CH(OR)2 C≡C– Ph R N N R N N–COR N–CO2R OCONR2 OPO(NR)2 OCH2OMe OTHP OPh SO3R SO2N–R SO2NR SO3– SO2tBu SOtBu Moderate: NR2 N≡C OMe OCH=CH2 OPO(OR)2 O(CH2)2X, X = OMe, NR2 F Cl PO(NR)2 PS(Ph)NR2 Weak: N O– S– Snieckus Chem. Rev. 1990, 90, 879. - Examples (cooperative effect) OMOM NBOC H nBuLi TMEDA ICH2CH2Cl –25 °C, 80% OMOM I NBOC H O N O Boger and Garbaccio, J. Org. Chem. 1997, 62, 8875. 208 R Metalation Reactions Dale L. Boger - Representative Organolithium Compounds by Directed Metalation OCH3 + nBuLi OCH3 Li Et2O, 35 °C 2h major Shirley J. Org. Chem. 1966, 31, 1221. O NEt2 O + nBuLi Li OCH3 + minor NEt2 Li THF, –78 °C TMEDA, 1 h Beak J. Org. Chem. 1977, 42, 1823. Beak J. Org. Chem. 1979, 44, 4463. CH3 CH3 N N CH3 + nBuLi N ether, 25 °C TMEDA, 7 h Li N CH3 Harris J. Org. Chem. 1979, 44, 2004. + nBuLi S THF, 30 °C 1h Li S Jones and Moodie Org. Synth. 1988, 6, 979. CH2=CHOCH3 + tBuLi OCH3 THF, 0 °C H2C Li Baldwin J. Am. Chem. Soc. 1974, 96, 7125. CH2=CHCH2OTMS + sBuLi H THF, HMPA –78 °C, 5 min H H2C Li Still J. Org. Chem. 1976, 41, 3620. O + nBuLi Ph3Si THF, –78 °C 4h OTMS Ph3Si O Li Eisch J. Am. Chem. Soc. 1976, 98, 4646. S nBuLi S Li S S Corey, Seebach J. Org. Chem. 1975, 40, 231. 209 Modern Organic Chemistry The Scripps Research Institute B. Organolithium Compounds by Metal–Halogen Exchange Jones and Gilman Org. React. 1951, 6, 339. 2 equiv tBuLi Ph Ph –120 °C Br - configurationally stable - retention of configuration Li Note: 2 equiv of reagent are required MeO 1 equiv nBuLi –78 °C Br Li MeO Li Seebach Tetrahedron Lett. 1976, 4839. Hoye J. Org. Chem. 1982, 47, 331. Br tBuLi nBuLi -> nBuBr - slower elimination but such products may still compete with desired electrophile for reaction with the generated organolithium reagent. - Additional examples CH3 H H Br + tBuLi –120 °C CH3 H H Li Seebach Tetrahedron Lett. 1976, 4839. + nBuLi Br –70 °C Li Linstrumelle Synthesis 1975, 434. + tBuLi CH3O Br CH3O Li Corey Tetrahedron Lett. 1975, 3685. nBu H TMS + sBuLi nBu –70 °C Br H TMS Li Miller J. Org. Chem. 1979, 44, 4623. NC Br + nBuLi NC –100 °C Li note: metalation in presence of reactive groups. Parham J. Org. Chem. 1976, 41, 1187. O2N Br O2N + nBuLi –100 °C Br Br Parham J. Org. Chem. 1977, 42, 257. 210 Li Metalation Reactions Dale L. Boger Corey and Boger Tetrahedron Lett. 1978, 5, 9, and 13. O R1 CHO R O N R O S R Me N n BuLi –78 °C Li S O H O O O N O Li R S R OMe MeO nBuLi, MeO OMOM Br OMe THF, 15 min N MeO MeO –78 °C MeO –78 °C MeO OMOM Li Boger nBuLi, OMOM Li Et2O, 15 min N Br R OMOM Boger J. Org. Chem. 1991, 56, 2115. J. Am. Chem. Soc. 1995, 117, 11839. J. Org. Chem. 1984, 49, 4050. J. Am. Chem. Soc. 1995, 117, 12452. C. Organolithium Compounds by Metal–Metal Exchange - Reactions of organotin reagents with alkyllithium reagents are particularly significant. CH2OTHP CH2OTHP nBuLi Proceeds in direction of placing the more electropositive metal on the more electronegative (acidic) carbon. Li Bu3Sn Corey J. Org. Chem. 1975, 40, 2265. OR R SnBu3 n OR BuLi R –78 °C n R2NCH2SnBu3 Li Still J. Am. Chem. Soc. 1978, 100, 1481. J. Am. Chem. Soc. 1980, 102, 1201. McGarvey J. Am. Chem. Soc. 1988, 110, 842. Macdonald Peterson BuLi 0 °C R2NCH2Li J. Am. Chem. Soc. 1971, 93, 4027. - transmetalation with retention and maintenance of configuration D. Organolithium Compounds from the Shapiro Reaction N-NHTs Et Me Bamford, Stevens Shapiro Bond Chamberlin 2 equiv nBuLi TMEDA Li Et Me J. Chem. Soc. 1952, 4735. Org. React. 1976, 23, 405. J. Org. Chem. 1981, 46, 1315. Org. React. 1990, 39, 1. 211 Modern Organic Chemistry The Scripps Research Institute E. Key Organometallic Reactions Enlisting Metalation and Transmetalation Reactions Heck Reaction R' ArX (RX) + R' Pd(0) H (Ar)R Heck J. Am. Chem. Soc. 1974, 96, 1133. Org. React. 1982, 27, 345. Acc. Chem. Res. 1979, 12, 146. Stille Coupling Reaction RX + RCOCl, R'SnR3 Pd(0) R−R' Stille J. Am. Chem. Soc. 1978, 100, 3636. Farina Org. React. 1997, 50, 1. Stille Angew. Chem., Int. Ed. Eng. 1986, 25, 508. X, ArX, XCH2CO2R 1) oxidative addition (R−Pd−X), generally rate determining step 2) transmetalation (R−Pd−R' + XSnR3 or XB(OH)2) 3) reductive elimination (R−R' + Pd(0)) Suzuki Reaction RX + R'B(OH)2 Pd(0) R−R' I > OTf > Br >> Cl: generally the initial oxidative addition is the rate determining step. Suzuki J. Chem. Soc., Chem. Commun. 1979, 866. Suzuki Chem. Rev. 1995, 95, 8457. 212 Key Ring Forming Reactions Dale L. Boger X. Key Ring Forming Reactions A. Diels–Alder Reaction 1. Reviews 1. General reference: Onishchenko, A. S. Diene Synthesis; Daniel Davy: New York, 1964. 2. General reference: Wasserman, A. Diels–Alder Reactions; Elsevier: New York, 1965. 3. General review: Alder, K. Newer Methods of Preparative Organic Chemistry, Vol. 1, Wiley: New York, 1948, pp 381–511. 4. General review: Huisgen, R.; Grashey, R.; Sauer, J. in Chemistry of Alkenes; S. Patai, Ed.; Wiley: New York, 1964, pp 878–953. 5. General review: Wollweber, H. in Houben–Weyl, Methoden der Organischen Chemie; E. Muller, Ed.; Georg Thieme: Stuttgart, 1970, pp 977–1210. 6. General reference: Wollweber, H. Diels–Alder Reaction; Georg Thieme: Stuttgart, 1972. 7. General reference: Fleming, I. Frontier Orbitals and Organic Chemical Reactions; Wiley: New York, 1977. 8. Diels–Alder reactions with maleic anhydride: Kloetzel, M. C. Org. React. 1948, 4, 1. 9. Diels–Alder reactions with ethylenic and acetylenic dienophiles: Holmes, H. L. Org. React. 1948, 4, 60. 10. Diels–Alder reactions with quinones: Butz, L. W.; Rytina, A. W. Org. React. 1949, 5, 136. 11. Diels–Alder reaction: preparative aspects: Sauer, J. Angew. Chem., Int. Ed. Eng. 1966, 5, 211. 12. Diels–Alder reaction: mechanism: Sauer, J. Angew. Chem., Int. Ed. Eng. 1967, 6, 16. 13. Stereochemistry of the Diels–Alder reaction: Martin, J. G.; Hill, R. K. Chem. Rev. 1961, 61, 537. 14. Regiochemistry of the Diels–Alder reaction: Titov, Y. A. Russ. Chem. Rev. 1962, 31, 267. 15. Mechanism of the Diels–Alder reaction: Seltzer, S. Adv. Alicycl. Chem. 1968, 2, 1. 16. Diels–Alder reaction of heteroatom-substituted dienes: Petrzilka, M.; Grayson, J. I. Synthesis 1981, 753. 17. Preparation and Synthetic Aspects: Wagner-Jauregg, T. Synthesis 1976, 349; Synthesis 1980, 165, 769. 18. Diels–Alder reaction of azadienes: Boger, D. L. Tetrahedron 1983, 39, 2869. 19. Review on "Danishefsky's diene" and related dienes: Danishefsky, S. Acc. Chem. Res. 1981, 14, 400. 20. Intramolecular Diels–Alder reaction: Carlson, R. G. Ann. Rep. Med. Chem. 1974, 9, 270. 21. Intramolecular Diels–Alder reaction: Oppolzer, W. Angew. Chem. 1977, 16, 10. 22. Intramolecular Diels–Alder reaction of o-quinodimethanes: Oppolzer, W. Synthesis 1978, 793. 23. Intramolecular Diels–Alder reaction: Brieger, G.; Bennett, J. N. Chem. Rev. 1980, 80, 63. 24. Intramolecular Diels–Alder reaction: Ciganek, E. Org. React. 1984, 32, 1. 25. Intramolecular Diels–Alder reaction: Fallis, A. G. Can. J. Chem. 1984, 62, 183. 26. Intermolecular Diels–Alder reaction: Oppolzer, W. in Comprehensive Organic Synthesis, Vol. 5; pp 315–399. 27. Intramolecular Diels–Alder reaction: Roush, W. R. in Comprehensive Organic Synthesis, Vol. 5; pp 513–550. 28. Retrograde Diels–Alder reactions: Sweger, R. W. in Comprehensive Organic Synthesis, Vol. 5; pp 551–592. 29. The Retro Diels–Alder reaction: Rickborn, B. Org. React. 1998, 52, 1. 30. Heterodienophile Diels–Alder reactions: Weinreb, S. M. in Comprehensive Organic Synthesis, Vol. 5; pp 401–449. 31. Heterodiene Diels–Alder reactions: Boger, D. L. in Comprehensive Organic Synthesis, Vol. 5; pp 451–512. 32. Hetero Diels–Alder reaction: Boger, D. L.; Weinreb, S. M. Hetero Diels–Alder Methodology in Organic Synthesis; Academic: San Diego, 1987. 33. Catalytic Asymmetric Diels–Alder reactions: Kagan, H. B.; Riant, O. Chem. Rev. 1992, 92, 1007. 34. Asymmetric Hetero Diels–Alder reaction: Waldermann, H. Synthesis 1994, 535. 213 Modern Organic Chemistry The Scripps Research Institute 2. Discovery Wieland (Ber. 1906, 39, 1492) described the 1:1 dimerization of conjugated dienes in what was probably the first report of a Diels–Alder reaction. Wieland received the 1927 Nobel Prize in Chemistry for his steroid work unrelated to these observations. Albrecht (Thiele) Reaction: Ann. 1906, 348, 31. O O C5H5 Misassigned structure O Staudinger Structure: Die Ketene, Stuttgart 1912, 59. O O O O O Structure established by Diels and Alder, and they went on to define scope and mechanism of the reaction. For this, they received the 1950 Nobel Prize in Chemistry. Diels and Alder Ann. 1928, 460, 98. In fact, von Euler had correctly, but tentatively, identified the 2:1 adduct of isoprene with p-benzoquinone before Diels and Alder's work. von Euler, Josephson Ber. 1920, 53, 822. O O O or O O O von Euler received the 1929 Nobel Prize in Chemistry for his investigations on fermentations of sugars and the fermentative enzymes. He had trained with Landolt, Nernst, van't Hoff, Arrhenius, Hantzsch, and Thiele and was remarkable in his scientific pursuits. By 1910, he had already initiated his monumental studies of enzyme structure, kinetics, and mechanism and his occasional forays into pure organic chemistry were just as remarkable. For an engaging description of the discovery of the Diels–Alder reaction, the competition for its exploration and applications, and the missed opportunities, see: Berson Tetrahedron 1992, 48, 3. Even in their first disclosure, Diels and Alder recognized the potential the reaction might hold for synthesis: "Thus, it appears to us that the possibility of synthesis of complex compounds related to or identical with natural products such as terpenes, sesquiterpenes, perhaps also alkaloids, has moved to a near prospect." They also felt this could be reserved: "We explicitly reserve for ourselves the application of the reaction discovered by us to the solution of such problems." Fortunately, this was not the case and an extraordinary group of investigators helped define the scope and mechanism of the Diels–Alder reaction. The first applications in total synthesis include: Cortisone by Woodward, Sondheimer J. Am. Chem. Soc. 1951, 73, 2403; Sarett (Merck) J. Am. Chem. Soc. 1952, 74, 4974. Cantharidin by Stork, Burgstahler, van Tamelen J. Am. Chem. Soc. 1951, 73, 4501. 3. Mechanism, FMO Treatment [π2s + π4s] Cycloaddition HOMOdiene LUMOdienophile Alternatively: This is the dominant interaction in a normal Diels–Alder reaction. LUMOdiene HOMOdienophile Dominant interaction in an inverse electron demand Diels–Alder reaction. 1. Large Ea for the reactions. 2. Driving force is formation of two new σ bonds accompanying the loss of two π bonds. 214 Key Ring Forming Reactions Dale L. Boger 4. Diastereoselectivity a. cis Principle: Geometry of dienophile and diene are maintained in the [4 + 2] cycloadduct. e.g. CO2CH3 CO2CH3 CO2CH3 CO2CH3 CO2CH3 CO2CH3 CH3O2C CO2CH3 Stereospecific R R X X X X R R b. Alder's Endo Rule: Stereoselective Endo product and endo transition state predominate even though exo products are usually more stable; endo is the kinetic product. e.g. H H COOCH3 COOCH3 CO2CH3 CO2CH3 COOCH3 COOCH3 H H endo exo Major Minor Endo, boat transition state Endo T.S. CH3OOC CH3OOC H H Result: Both cis rule and endo rule Exo T.S. H H COOCH3 COOCH3 Diels–Alder reaction very useful, diastereoselective 215 Modern Organic Chemistry The Scripps Research Institute c. Factors influencing endo selectivity of the Diels–Alder reaction OAc OAc CHO CHO Me R Me R via R AcO H H OHC H H CH3 i. Endo transition state is favored by stabilizing secondary orbital interactions. ii. Endo selectivity often increases with the use of Lewis acid catalysis. iii. Endo selectivity often increases with increase in pressure of reaction. Endo selectivity ∆∆V = –4 to –8 cm3/mol (endo/exo) , pressure R H H OHC H H endo T.S. R CHO exo T.S. Raistrick J. Chem. Soc. 1939. 1761, 1770. Jones Tetrahedron 1962, 18, 267. Dauben demonstrated pressure-promoted reactions are viable: J. Am. Chem. Soc. 1974, 96, 3664. J. Am. Chem. Soc. 1976, 98, 1992. J. Org. Chem. 1977, 42, 282. is negative (–25 to –38 cm3/mol). So increase pressure, increase rate of reaction. -∆V -And endo T.S. is more compact, so ∆∆V (i.e., diastereoselectivity increases) for endo:exo also negative. O Example of Boger J. Am. Chem. Soc. 1988, 108, 6695 and 6713. O iv. Endo selectivity also increases with decreases in temperature at which the reaction is conducted e.g. COOH COOH COOH COOH Endo selectivity 216 , temperature temp. endo 75 °C only endo COOH COOH exo 90 °C 7 : 1 100 °C 4.5 : 1 110 °C 2 : 1 130 °C 1 : 1 Key Ring Forming Reactions Dale L. Boger CHO + CHO + OBn CHO OBn exo OBn endo conditions Lewis acid-catalyzed 10 days, 0 °C 66 : 34 6 h, 200 °C 34 : 66 90 : 10 BF3•OEt2, 5 min, –20 °C Furukawa J. Am. Chem. Soc. 1970, 92, 6548. Ph Ph Ph Ph O + O H H O Ph O Ph + O O HH temp. endo exo 25 °C 100 : 0 140 °C 29 : 71 O O O Some Diels–Alder adducts are thermally unstable (reversible) and subject to equilibration via retro Diels–Alder reaction to provide the most stable product: Ripoll Tetrahedron 1978, 34, 19. O O + O O O O O HH 100% exo O see also: Rickborn Org. React. 1998, 52, 1. 5. Regioselectivity a. 1-Substituted dienes react with substituted dienophiles to give the ortho product: X X X Y + Y + Y usually around 9:1 217 Modern Organic Chemistry The Scripps Research Institute For example: CH3 CH3 CH3 W W + + W W = CN = COOR 100 °C, 12 h, 30% 9 : 1 200 °C, 2 h, 85% 6.8 : 1 higher temperature decreases regioselectivity regioselectivity lower, because COOR not as strongly electron-withdrawing as CN -Device for predicting regioselectivity: draw out "zwitterionic" representations (resonance structures) for the reactants. CN CN CN more stable resonance forms CH3 CN CN Reaction: 100 °C, 12 h 30%, 9:1 regioselectivity b. 2-Substituted dienes give predominantly the para product: Y X X X + Y + Y Y = COOCH3 6 : 1 = OCH3 = COOCH3 10 : 1 = CN = COOCH3 10 : 1 X = CH3 218 higher regioselectivity because OCH3 better donating group than CH3. Key Ring Forming Reactions Dale L. Boger c. Complementary substitution usually provides even greater regioselectivity -1,3-Disubstituted Dienes X X Y ortho to X group para to X' group Y + X' X' But noncomplementary substitution may cause problems (lower regioselectivity) -1,2-Substituted Dienes X X X Y X' X' X' Y + + Y relative amounts of each depend on electron donating strength of substituents X and X' NHCO2R > SR > OR > alkyl > H SPh SPh O O CH3O CH2Cl2 + CH3O 25 °C 85% 100:0 Cohen J. Org Chem. 1982, 47, 4005. O O CH3O toluene + ∆, 2 h 75% PhS CH3O CH3O + PhS PhS O >5 Trost J. Am. Chem. Soc. 1980, 102, 3548. NHCO2Bn O + 56 °C Ph : 1 NHCO2Bn COPh 26 h, 86% SPh SPh Overman J. Am. Chem. Soc. 1983, 105, 6335. d. Apparent regioselectivity can be altered by adding a controlling group that is subsequently removed -Dienophile OAc OAc SO2Ph SO2Ph CO2CH3 CO2CH3 + -endo addition -CO2CH3 is in meta position -SO2Ph > CO2CH3 in controlling regioselectivity Parsons J. Chem. Soc., Chem. Commun. 1987, 1836. 219 Modern Organic Chemistry The Scripps Research Institute - Diene O O H 90 °C, 40 h + O2N NO2 O In addition to altering regioselectivity, it also serves as an equivalent of an inaccessible cyclic alkyne dienophile. nBu 3SnH DBN 0 °C, 1 h O O (86%) (83%) Corey Tetrahedron Lett. 1981, 22, 603. Ono J. Chem. Soc., Perkin Trans. 1 1987, 1929. Tanis Syn. Commun. 1986, 16, 251. Rate of reaction generally insensitive to solvent polarity, but... 6. Lewis Acid Catalysis 140 °C O + O 8–10 h 75% AlCl3 25 °C,1 h 75% Addition of Lewis Acid Catalysts: O AlCl3 δ– δ+ Al O i. Lowers LUMO of dienophile, so increases rate of reaction. ii. Increases the difference in magnitude of coefficients of dienophile -----so increases regioselectivity. iii. Changes coefficient at dienophile substituent, so increases opportunity of secondary orbital interactions .....often increases endo stereoselectivity. Increases: 1. Reaction Rate 2. Reaction Regioselectivity 3. Reaction Endo Diastereoselectivity 220 Key Ring Forming Reactions Dale L. Boger -Examples O O + + O toluene, 120 °C, 24 h 71 : 29 Yates J. Am. Chem. Soc. 1960, 82, 4436. SnCl4, benzene, 25 °C, 1 h 93 : 7 Lutz J. Am. Chem. Soc. 1964, 86, 3899. 1st example: 100 °C, 3 d, dioxane vs AlCl3, 25 °C, 5 min Diethyl fumarate CO2Et EtO2C CO2CH3 CO2CH3 + AlCl3: ∆G 9.3 kcal/mol lower than uncatalyzed reaction Inukai, Kojima J. Org. Chem. 1967, 32, 872. ∆E endo/exo: CO2CH3 + CO2CH3 CO2CH3 + uncat. reaction: 0.2 kcal/mol; AlCl3 cat. reaction: 1.8 kcal/mol Spellmeyer , Houk J. Am. Chem. Soc. 1988, 110, 3412. Jensen, Houk J. Am. Chem. Soc. 1987, 109, 3139. Calculations: s-cis > s-trans ∆E for: OCH3 O O catalyzed reaction: 1.9 kcal/mol for endo 2.7 kcal/mol for exo uncatalyzed reaction: 0.6 kcal/mol for endo 1.7 kcal/mol for exo CH3O Birney, Houk J. Am. Chem. Soc. 1990, 112, 4127. 221 Modern Organic Chemistry The Scripps Research Institute -Lewis Acid catalysis can also alter regioselectivity O O O CH3 + CH3O CH3O O O + CH3O H O 1 : 1 80% BF3•OEt2, –16 °C 4 : 1 >85% cat. SnCl4, –16 °C 1 : 20 >85% 100 °C Rationalization: monodentate vs. bidentate coordination most Lewis basic carbonyl δ– F3B versus + O δ bidentate coordination CH3 CH3O Sn CH3O O O CH3 O δ+ -Hydrophobic effect: H2O solvent acceleration: Breslow J. Am. Chem. Soc. 1980, 102, 7816. Breslow, Rideout Tetrahedron Lett. 1983, 24, 1901. also: Sternbach J. Am. Chem. Soc. 1982, 104, 5853. Grieco Tetrahedron Lett. 1983, 24, 1897. Jorgensen - Hydrogen-bonding of H2O serves in the same capacity as a mild Lewis acid. δ+ O H O H requires H-bonding carbonyl requires H-bonding solvent Jorgensen J. Am. Chem. Soc. 1991, 113, 7430. J. Org. Chem. 1994, 59, 803. 222 H Key Ring Forming Reactions Dale L. Boger 7. Detailed FMO Analysis -Using simple computational tools now available, one can quickly and easily predict regioselectivity and comparatively assess rate and diastereoselectivity of a Diels–Alder reaction by examining the frontier molecular orbitals (FMO). Each of the calculations that follow took < 1 min to run. Classification of Diels–Alder Reactions. NORMAL HOMOdiene-controlled NEUTRAL INVERSE LUMOdiene-controlled EWG EDG EDG EWG LUMO smallest ∆E, dominant molecular orbital interaction LUMO LUMO LUMO E HOMO HOMO HOMO smallest ∆E, dominant molecular orbital interaction HOMO J. A. Pople (computational methods in quantum chemistry) and W. Kohn (density-functional theory) received the 1998 Nobel Prize in Chemistry for their pioneering contributions to theoretical and computational methods for defining properties and chemical behavior. Common Computational Tools: Semiempirical MNDO: Dewar J. Am. Chem. Soc. 1977, 99, 4899. AM1: Dewar J. Am. Chem. Soc. 1985, 107, 3902. Ab Initio Gaussian: Pople, Carnegie-Mellon Quantum Chem. Pub. Unit, Pittsburgh, PA. 223 Modern Organic Chemistry The Scripps Research Institute AM1 Theoretical Highest Occupied π Orbital (HOMO) and Lowest Unoccupied π Orbital (LUMO) π system E Coefficients H2C=CH–CH=O E LUMO E HOMO O-1 C-2 C-3 C-4 0.0 eV –10.9 eV LUMO: HOMO: 0.42 0.35 –0.50 0.05 –0.43 –0.68 0.63 –0.65 –7.0 eV –16.6 eV LUMO: HOMO: 0.36 0.36 –0.73 0.23 –0.03 –0.73 0.58 –0.53 C-1 C-2 C-3 C-4 H2C=CH–CH=OH+ E LUMO E HOMO H2C4=CH–C(CH3)=C1H2 E LUMO E HOMO 0.5 eV –9.2 eV LUMO: HOMO: 0.57 0.60 –0.43 0.45 –0.37 –0.41 0.51 –0.55 0.4 eV –9.1 eV LUMO: HOMO: 0.51 0.67 –0.41 0.42 –0.44 –0.28 0.58 –0.41 C-1 C-2 OCH3 0.72 0.48 –0.66 0.69 0.21 –0.51 H2C4=CH–C(OCH3)=C1H2 E LUMO E HOMO H2C2=CH–OCH3 E LUMO E HOMO 224 1.4 eV –9.5 eV LUMO: HOMO: Key Ring Forming Reactions Dale L. Boger AM1 π-MO's Thermal reaction Model for Lewis acid-catalyzed reaction H H O 2.2 eV O H 2.2 eV 1.9 eV 0.5 eV 0.5 eV 0.0 eV E E –4.0 eV 9.2 eV 11.4 eV 2.2 eV –7.0 eV –9.2 eV –9.2 eV –10.9 eV –14.3 eV –14.6 eV –14.3 eV –16.6 eV HOMOdiene – LUMOdienophile energy difference is controlling factor for normal Diels-Alder reaction making this E difference smaller will increase rate of reaction. For uncatalyzed reaction, ∆E = 9.2 eV For catalyzed reaction, ∆E = 2.2 eV –21.6 eV Rate: -Lewis acids catalyze reaction by lowering energy of π MO's of dienophile. -Importantly, the LUMO of the dienophile becomes much lower in energy. Rate increase by Lewis acid catalysis due to lowering of E of LUMOdieneophile. 225 Modern Organic Chemistry The Scripps Research Institute Regioselectivity: Thermal Lewis acid-catalyzed HOMO HOMO LUMO 0.51 0.60 ∆ = 0.09 LUMO 0.43 CHO 0.51 0.63 0.60 0.03 O ∆ = 0.20 H 0.58 ∆ = 0.09 ∆ = 0.55! Enhanced polarization of dienophile leads to enhanced regioselectivity. Diastereoselectivity (endo cycloaddition): Lewis acid-catalyzed Thermal stabilizing 2° orbital interactions 1° (bonding) orbital interactions 0.41 H 0.50 H 0.73 0.41 O O HOMOdiene HOMOdiene LUMOdienophile HOMOdiene LUMOdienophile LUMOdienophile greater endo stereoselectivity NOTE comparison of vs. MeO > rate of reaction, MeO > regioselectivity, MeO stereoselectivity, < MeO gives rise to Me Me Me Me due to smaller (relative) coefficient at C3 of diene. 226 increase in coefficient at complexed carbonyl carbon HOMO–LUMO ∆E difference Key Ring Forming Reactions Dale L. Boger AM1 Results Lewis acid-catalyzed HOMOdiene-controlled Diels–Alder reaction HOMOdiene-controlled Diels–Alder reaction H CH3O H O CH3O 2.2 eV O H 2.2 eV 1.9 eV 0.4 eV 0.4 eV 0.0 eV E E 17.0 eV 9.1 eV –4.0 eV HOMO 2.1 eV 11.3 eV –7.0 eV –9.1 eV –9.1 eV –10.9 eV –12.7 eV –12.7 eV –14.6 eV –16.6 eV –21.6 eV Note: 1 eV = 23.06 kcal/mol, so difference of 0.1 eV is 2.3 kcal/mol and is significant in ∆∆G‡. 227 Modern Organic Chemistry The Scripps Research Institute ∆E (E LUMOdienophile – E HOMOdiene) = 9.1 eV Rate: versus ∆E (E LUMOdiene – E HOMOdienophile) = 11.3 eV 0.42 0.67 HOMOdiene MeO –0.28 –0.41 0.42 0.63 O LUMOdienophile –0.50 –0.43 stabilizing secondary orbital interaction: endo selectivity dominant HOMOdiene–LUMOdienophile orbital interaction: regioselectivity 0.42 MeO 0.67 HOMOdiene –0.28 –0.41 0.36 + H O –0.73 0.58 LUMOdienophile –0.03 ∆E (E LUMOdienophile – E HOMOdiene) = 2.1 eV Rate: versus ∆E (E LUMOdiene – E HOMOdienophile) = 17.0 eV Thermal and (Lewis) acid-catalyzed HOMOdiene-controlled Diels–Alder reaction of acrolein and 2-methoxybutadiene, AM1 results 228 Key Ring Forming Reactions Dale L. Boger AM1 Results Lewis acid-catalyzed LUMOdiene-controlled Diels–Alder reaction LUMOdiene-controlled Diels–Alder reaction H OCH3 H OCH3 O O H 1.9 eV 1.4 eV 1.4 eV 0.0 eV E E 18.0 eV 9.5 eV –4.0 eV HOMO 2.5 eV 12.3 eV –7.0 eV –9.5 eV –9.5 eV –10.9 eV –14.6 eV –16.6 eV –21.6 eV 229 Modern Organic Chemistry The Scripps Research Institute Rate: ∆E (E LUMOdienophile – E HOMOdiene) = 12.3 eV versus ∆E (E LUMOdiene – E HOMOdienophile) = 9.5 eV –0.43 –0.50 O 0.42 Me 0.69 HOMOdienophile O –0.51 –0.48 stabilizing secondary orbital interaction: endo selectivity dominant LUMOdiene–HOMOdienophile orbital interaction: regioselectivity –0.03 –0.73 Me 0.63 LUMOdiene O 0.36 + H O 0.58 LUMOdiene 0.69 HOMOdienophile –0.51 –0.48 Rate: ∆E (E LUMOdienophile – E HOMOdiene) = 18.0 eV versus ∆E (E LUMOdiene – E HOMOdienophile) = 2.5 eV Thermal and (Lewis) acid-catalyzed LUMOdiene-controlled Diels–Alder reaction of acrolein and methyl vinyl ether, AM1 results 230 Strained Olefins Participate in Accelerated Normal or Inverse Electron Demand Diels–Alder Reactions: FMO Basis HOMOdiene-controlled Neutral Diels–Alder reaction Diels–Alder reaction LUMOdiene-controlled Diels–Alder reaction CH3CO2 CH3O H CH3O O 2.3eV 2.3eV 1.9 eV 1.4 eV 1.4 eV 1.0eV 1.3 eV 1.0eV 0.5 eV 0.5 eV 0.0 eV E –0.5 eV ∆E = 9.8 eV ∆E = 8.8 eV ∆E = 10.3 eV ∆E = 11.4 eV ∆E = 11.0 eV ∆E = 10.8 eV ∆E = 11.4 eV ∆E = 10.9 eV ∆E = 9.0 eV ∆E = 9.3 eV –8.8 eV –9.5 eV –9.9 eV –12.4 eV –14.6 eV 231 Key Ring Forming Reactions Dale L. Boger –12.0 eV –9.8 eV HOMO HOMO HOMO –10.5 eV HOMO –10.9 eV HOMO –11.4 eV –9.4 eV HOMO HOMO HOMO –9.8 eV Modern Organic Chemistry The Scripps Research Institute 8. Cation–Radical Diels–Alder Reaction Me cat. H H N SbCl6– Br H 20% 3 40% CH2Cl2, 0 °C, 0.25 h SPh SPh SPh SPh reaction via radical cation Bauld J. Am. Chem. Soc. 1981, 103, 718; 1982, 104, 2665; 1983, 105, 2378. 9. Ionic Diels–Alder Reaction H+ O O O OH O + much more reactive, much more electron deficient cat. CF3SO3H O CH2Cl2 67% O O Gassman J. Am. Chem. Soc. 1987, 109, 2182. J. Chem. Soc., Chem. Commun. 1989, 837. 10. Dienophiles a. Effect of electron-withdrawing group X X relative rates: X X X = COCl > PhSO2 > PhCO > COCH3 > CN ~ COOCH3 6700 155 18 4 1.1 1.0 b. Alkyl groups on dienophile can slow Diels-Alder reaction (steric effect) c. Strain in dienophile ~ 232 > Key Ring Forming Reactions Dale L. Boger PhS benzyne bridgehead olefins Keese, Krebs Angew. Chem., Int. Ed. Eng. 1972, 11, 518. Wiberg J. Am. Chem. Soc. 1960, 82, 6375. O O H O Kraus J. Org. Chem. 1988, 53, 1397. Corey J. Am. Chem. Soc. 1965, 87, 934. H H hν H O H H Photochemical isomerization to strained trans enone (7-membered: Corey J. Am. Chem. Soc. 1965, 87, 2051. 8-membered rings: Eaton J. Am. Chem. Soc. 1965, 87, 2052) followed by inter- or intramolecular Diels−Alder reaction. intermolecular: Eaton Acc. Chem. Res. 1968, 1, 50. intramolecular: Rawal J. Am. Chem. Soc. 1999, 121, 10229. -Normal and inverse electron demand Diels–Alder reactions of cyclopropenone ketals exo adduct due to destabilizing steric R O R interactions in preferred endo T.S. O O 25 oC O 72% R = OMe 69% R = H 65% R = CO2Me Boger Tetrahedron 1986, 42, 2777. Boger J. Am. Chem. Soc. 1986, 108, 6695. OMe OMe MeO MeO N MeO OMe OMe MeO O N MeO MeO MeO N N MeO O O OH O O OMe Grandirubrine Imerubrine Boger J. Am. Chem. Soc. 1995, 117, 12452. O MeO OMe N O O N MeO OMe H O 25 °C 96% O O OMe O Isoimerubrine O N OH O H O O Boger J. Am. Chem. Soc. 2000, 122, 12169. O OH Rubrolone aglycon 233 Modern Organic Chemistry The Scripps Research Institute d. Quinones are outstanding dienophiles O O e. Number and position of electron-withdrawing groups dienophile Dienophile NC Diels–Alder or + Reaction Relative Rates CN NC CN NC CN 1.3 x 109 4.3 x 107 5.9 x 105 4.8 x 105 1.3 x 104 4.5 x 104 0.09 1 CN NC CN CN NOT as large an increase upon addition of one more noncomplementary EWG COOCH3 215 74 140 31 NOTE: large increase in rate by addition of one more complementary EWG CH3OOC CH3OOC COOCH3 f. cis vs. trans Dienophiles -In polar (or radical) processes, cis isomer reacts faster than trans, but in Diels–Alder reaction: COOCH3 CH3OOC COOCH3 COOCH3 Due to E E E E one additional destabilizing steric interaction -The relative rates of such cis vs. trans reactions are sometimes used to distinguish between concerted cycloadditions vs. nonconcerted stepwise reactions. 234 Key Ring Forming Reactions Dale L. Boger g. Heterodienophiles: typically electron-deficient e.g. O CH3OOC HOMOdiene-controlled Diels–Alder reaction. COOCH3 2π component h. Heterodienes: typically electron-deficient e.g. H O LUMOdiene-controlled Diels–Alder reaction. 4π component introduction of heteroatom makes diene electron-deficient. Note: Dienophiles can also be generated in situ: OCH3 OCH3 CH3O OCH3 OCH3 CH3O OCH3 Boger J. Org. Chem. 1984, 49, 4050. catalytic amount O electron-deficient diene N H N N N N N N N N –N2, retro Diels–Alder reaction N N N H N Catalytic Diels–Alder reaction Boger J. Org. Chem. 1982, 47, 895. i. Dienophiles which are not electron-deficient (1) Participate in inverse electron demand Diels–Alder reactions: Cl Cl O Cl Cl Cl O O Cl krel = 12 2 O 1 McBee J. Am. Chem. Soc. 1954, 77, 385. Jung J. Am. Chem. Soc. 1977, 99, 5508. (2) Can be used in cation–radical Diels–Alder reactions. (3) Also include the behavior of strained olefins. 235 Modern Organic Chemistry The Scripps Research Institute j. Dienophile equivalents -Many specialized dienophiles have been developed which react well in the Diels–Alder reaction and which serve to indirectly introduce functionality not otherwise directly achievable. inaccessible dienophile equivalent dienophile OH O OsO4 O O OH OCH2Ph OCH3 OAc OCH3 AgOAc/I2 acetylene acetylene J. Am. Chem. Soc. 1958, 80, 209. J. Org. Chem. 1988, 53, 5793. J. Org. Chem. 1984, 49, 4033. OH m-CPBA; H+, H2O acetylene AcO HO OH O AcO CN + OH– or OCH2Ph BR2 R2B Cl COCl Me3Si + NaN3/ HOAc, H2O CH2 Chem. Ber. 1964, 97, 443. J. Org. Chem. 1988, 53, 5793, 3373. Tetrahedron Lett. 1994, 35, 509. OMe MeO OMe PPh3 J. Am. Chem. Soc. 1956, 78, 2473. J. Am. Chem. Soc. 1971, 93, 4326. J. Org. Chem. 1977, 42, 4095. Review: Synthesis 1977, 289. Review: Tetrahedron 1999, 55, 293. OH O MeO or OMe J. Org. Chem. 1984, 49, 4033. OH OMe OH COCH3 N O N COCH3 NH2 NH2 Tetrahedron Lett. 1981, 2063. R N NH2 Tetrahedron Lett. 1977, 3115. Ann. 1976, 1319. O O OH R = H, COCH3 O 236 Br CHO + BH4–; MeO– Br CHO + BH4–; TsCl; HO– J. Am. Chem. Soc. 1972, 94, 2549. BR2 Key Ring Forming Reactions Dale L. Boger inaccessible dienophile O O equivalent dienophile O RS or J. Am. Chem. Soc. 1977, 99, 7079. O COOR CH2 O O Cl MeO O OMe J. Am. Chem. Soc. 1977, 99, 7079. O O Cl O MeO OMe O + m-CPBA O O Me + PCl5; HO– Chem. Ber. 1964, 97, 443. CO2H J. Org. Chem. 1973, 38, 1173. O O O + H2O; Pb(OAc)4 S O O H O Ph + (RO)3P + nBuLi O OR SO2Ph N NR2 O R = Et, Ac SO2Ph SO2Ph enamines J. Am. Chem. Soc. 1973, 95, 7161. J. Org. Chem. 1984, 49, 4033. R BR2 SO2Ph COR SO2Ph J. Am. Chem. Soc. 1980, 102, 853. J. Am. Chem. Soc. 1990, 112, 7423. R = H, R COR O2N O2N reversed regioselectivity COR PhS R COR PhO2S PPh3 CH3 COR SOPh J. Am. Chem. Soc. 1978, 100, 2918. Tetrahedron Lett. 1981, 22, 603. J. Org. Chem. 1979, 44, 1180. J. Org. Chem. 1977, 42, 2179. J. Am. Chem. Soc. 1978, 100, 1597. J. Org. Chem. 1981, 46, 624. J. Am. Chem. Soc. 1978, 100, 1597. J. Org. Chem. 1977, 42, 4095. J. Chem. Soc., Chem. Commun. 1991, 1672. O EtO2C O CO2Et J. Org. Chem. 1977, 42, 4095. O 237 Modern Organic Chemistry The Scripps Research Institute 11. Diene -Dienes must adopt an s-cisoid (s-Z) conformation to react. H H H H H H (~2.3 kcal/mol) s-E (transoid) s-Z (cisoid) Cisoid conformation of diene is favored with: (a) 2- and/or 3-substitution CH3 CH3 H H CH3 H (b) 1-Substituted dienes H CH3 CH3 CH3 R R E-diene But R R H not very reactive Z-diene R 105 rate difference for cis and trans can be used to separate cis and trans isomers of dienes (c) And, by locking the diene into cisoid conformation > > reaction rates for cyclic dienes are faster O O : MeO Cl O krel = 1348 238 110 12 5 3.3 2.2 2 1 0.1 Key Ring Forming Reactions Dale L. Boger 12. Functionalized Dienes Review: Petrzilka, Grayson Synthesis 1981, 753. -Diels–Alder reaction with introduction of useful functionality O O O H3O+ RO 160 oC RO O Danishefsky J. Am. Chem. Soc. 1979, 101, 6996. -Danishefsky: OCH3 H CHO OCH3 CHO TMSO H3O+ (–CH3OH) Si O So an alternative disconnection for α,β-unsaturated enones CHO O looks like a Robinson annulation product R Y Y R Y R O O OCH3 TMSO Example: OCH3 O R TMSO O R = Me i) 200 °C 2 h, xylene ii) H3O+ 47% O H compare to O O Wieland–Miescher Ketone see also: Danishefsky J. Am. Chem. Soc. 1979, 101, 6996, 7001, 7008, 7013. 239 Modern Organic Chemistry The Scripps Research Institute Companion Strategy: Woodward J. Am. Chem. Soc. 1952, 74, 4223; Bloom J. Org. Chem. 1959, 24, 278. regioselectivity: ortho adduct diastereoselectivity: 2o orbital interaction of endo addition O CH3O (endo) 50% CH3 O O 110 oC 5.5 d CH3 CH3O O H vinylogous ester, not as reactive Al2O3 (epimerization) O O NaBH4 CH3O CH3O H OH O i) MsCl, Et3N, CH2Cl2 ii) Zn/HOAc (reductive elimination) vinylogous ester, so this carbonyl not reduced by NaBH4 OH CH3O See also: H O CH3O H H very useful Robinson J. Am. Chem. Soc. 1961, 83, 249. Orchin, Butz J. Org. Chem. 1943, 8, 509. Kishi Tetrahedron Lett. 1970, 5127. Kakushima Can. J. Chem. 1976, 54, 3304. Can also add nucleophiles (RLi, H–) to the "vinylogous ester" carbonyl: O CH3O i) R'Li (R' = alkyl, H, etc.) H ii) H3O+ H H O R' CH3O H R R H3O+ as above R' O CH3 O CH3O O 240 R H R Key Ring Forming Reactions Dale L. Boger -Aromatic Annulation CH3O + CO2CH3 O CO2CH3 O OR O CO2CH3 any oxygenated aromatic substitution pattern using different electron-rich olefins. OCH3 OCH3 OCH3 OCH3 CH3O CH3O OCH3 OCH3 Boger J. Org. Chem. 1984, 49, 4033, 4045 and 4050. Use of aromatic annulation in total synthesis: OCH3 CH3 CH3O OH N CH3O X HO CH3 Juncusol OR Rufuscine, Imelutine Norrufuscine X = H, OR Heteroatom Substituted Dienes: CO2CH3 O LICA O THF O 90% CO2CH3 Diels–Alder or Michael–Michael Reaction Lee Tetrahedron Lett. 1973, 3333. OLi OR CO2CH3 CO2CH3 60% Kraus Tetrahedron Lett. 1977, 3929. O O O CH3O CH3O PhS PhS HCl [O] H2O –PhSOH 5:1 RS > OR O complement to Danishefsky diene Diels–Alder product. Trost J. Am. Chem. Soc. 1980, 102, 3554. 241 Modern Organic Chemistry The Scripps Research Institute Danishefsky Diene: (see summary list) OCH3 W W OCH3 W HCl O TMSO TMSO CO2CH3 OCH3 O O CO2CH3 1) KOH 2) KI3 O TMSO H O I H Iodolactonization OH O O H O Vernolepin O Danishefsky J. Am. Chem. Soc. 1977, 99, 6066. OSiR3 OR • OR , O Note the dienophile and diene equivalency list O O i. 80–140 °C OMe ii. HCl, aq. THF Cl OSiR3 O OH OH O OH Brassard Tetrahedron Lett. 1979, 4911. Danishefsky Applications Reviews: Danishefsky Chemtracts: Org. Chem. 1989, 2, 273. Danishefsky Acc. Chem. Res. 1981, 14, 400. 242 dienes J. Am. Chem. Soc. 1979, 101, 6996, 7001 and 7008. tatettine J. Am. Chem. Soc. 1980, 102, 2838. coriolin J. Am. Chem. Soc. 1980, 102, 2097. prephenate J. Am. Chem. Soc. 1979, 101, 7013. griseofulvin J. Am. Chem. Soc. 1979, 101, 7018. pentalenolactone J. Am. Chem. Soc. 1979, 101, 7020. vernolepin J. Am. Chem. Soc. 1977, 99, 6066. lasiodiplodin J. Org. Chem. 1979, 44, 4716. papulacandin aglycon Carbohydr. Res. 1987, 171, 317. vineomycinone J. Am. Chem. Soc. 1985, 107, 1285. Key Ring Forming Reactions Dale L. Boger methyllincosaminide J. Am. Chem. Soc. 1985, 107, 1274. KDO and N-acetylneuraminic acid J. Am. Chem. Soc. 1988, 110, 3929. tunicaminyluracil J. Am. Chem. Soc. 1985, 107, 7761. mevinolin J. Am. Chem. Soc. 1989, 111, 2596. Pure App. Chem. 1988, 60, 1555. compactin J. Am. Chem. Soc. 1989, 111, 2599. avermectin A1a J. Am. Chem. Soc. 1987, 109, 8119. J. Am. Chem. Soc. 1987, 109, 8117. J. Am. Chem. Soc. 1989, 111, 2967. octosyl acid J. Am. Chem. Soc. 1988, 110, 7434. methyl-α-peracetylhikosanamide J. Am. Chem. Soc. 1989, 111, 2193. zincophorin J. Am. Chem. Soc. 1988, 110, 4368. 6a-deoxyerythronolide Silicon Chem. 1988, 25 (Ellis Horwood Ltd.) -Unactivated dienes O O CO2CH3 O CO2CH3 CO2CH3 HBr double activation permits reaction even with deactivated dienes Boger J. Org. Chem. 1985, 50, 1904. O O N N OR intramolecular reaction permits use of unactivated diene or dienophile Boger Tetrahedron Lett. 1991, 32, 7643. -Deslongchamps: Tetrahedron Lett. 1990, 31, 3969; Synlett 1990, 516. R1 O CO2CH3 1. Cs2CO3, CH2Cl2 R2 + E R1 R2 2. TsOH O CO2 Bu H t via [4 + 2] Diels–Alder reaction O O E = CO2CH3 R1 R2 OH CO2tBu 243 Modern Organic Chemistry The Scripps Research Institute -Compilation of Representative Functionalized Dienes Review: Petrzilka, Grayson Synthesis 1981, 753. diene reference R = SiMe3 RO R = Et R = Ac R = P(O)(OEt)2 R = CH3, Ac R = Ac R = CH3, 3-Me R = CH3, 4-Me R = Ac, 3-Me OR OMe Danishefsky's diene Me3SiO OR OMe Me3SiO OMe Tetrahedron Lett. 1976, 3869, 3873. J. Am. Chem. Soc. 1977, 99, 8116. Tetrahedron Lett. 1978, 1387. Tetrahedron Lett. 1978, 3869. J. Chem. Soc., Chem. Commun. 1980, 197. Syn. Commun. 1980, 233. J. Org. Chem. 1980, 45, 4825. J. Am. Chem. Soc. 1974, 96, 7807. J. Org. Chem. 1975, 40, 538. J. Am. Chem. Soc. 1977, 99, 5810. J. Am. Chem. Soc. 1979, 101, 6996, 7001. See Danishefsky reference list. see also: J. Chem. Soc., Perkin Trans. 1 1979, 3132. R = Me R = Et R = SiMe3 J. Org. Chem. 1982, 47, 4774. J. Am. Chem. Soc. 1978, 100, 7098. Syn. Commun. 1977, 7, 131. Chem. Lett. 1978, 649. Tetrahedron Lett. 1976, 3169. Chem. Pharm. Bull. 1978, 26, 2442. Synthesis 1981, 30. Tetrahedron Lett. 1979, 159. Tetrahedron Lett. 1980, 21, 3557. R = SiMe3 Tetrahedron Lett. 1979, 4437. Chem. Lett. 1978, 649. J. Chem. Soc., Perkin Trans. 1 1976, 1852. J. Org. Chem. 1978, 43, 379. J. Am. Chem. Soc. 1979, 101, 7001. See Danishefsky reference list. RO OR Tetrahedron Lett. 1976, 2935. J. Chem. Soc., Chem. Commun. 1974, 956. J. Chem. Soc., Chem. Commun. 1966, 1152. J. Am. Chem. Soc. 1980, 102, 3270. J. Am. Chem. Soc. 1976, 98, 1967. Helv. Chim. Acta 1979, 62, 442; Synthesis 1981, 753. R = Me J. Org. Chem. 1977, 42, 1819. Me3SiO SePh 244 Key Ring Forming Reactions Dale L. Boger diene reference OR R = CH3 R = Ac, 2-Me R = SiMe3 OR R = Ac RO R = SiMe3 RO Others OR OMe R = CH3 R = SiMe3 R = CH3, 3-Me OEt J. Am. Chem. Soc. 1978, 100, 7098. J. Org. Chem. 1976, 41, 2625. J. Org. Chem. 1976, 41, 1799. Tetrahedron Lett. 1980, 21, 3413. J. Org. Chem. 1965, 30, 2414. Org. Syn. 1970, 50, 24. Angew. Chem., Int. Ed. Eng. 1979, 18, 304. J. Chem. Soc., Dalton Trans. 1974, 956. Chem. Ber. 1957, 90, 187. J. Org. Chem. 1976, 41, 1655, 2625. J. Org. Chem. 1978, 43, 4559. J. Chem. Soc., Chem. Commun. 1974, 956. J. Org. Chem. 1978, 43, 2726. Chem. Lett. 1977, 1219; 1978, 649. Synthesis 1971, 236. Synthesis 1976, 259. Tetrahedron Lett. 1972, 4593. J. Org. Chem. 1960, 25, 1279. J. Am. Chem. Soc. 1957, 79, 3878. J. Am. Chem. Soc. 1941, 63, 131. J. Chem. Soc., Perkin Trans. 1 1979, 1893. Recl. Trav. Chim. Pays-Bas 1975, 94, 196. Tetrahedron Lett. 1979, 4911. Tetrahedron Lett. 1979, 4912. J. Org. Chem. 1976, 41, 3018. Can. J. Chem. 1974, 52, 80. J. Org. Chem. 1978, 43, 1435. EtO J. Chem. Soc., Perkin Trans. 1 1979, 3132. Me3SiO OEt J. Chem. Soc., Perkin Trans. 1 1979, 3132. Me3SiO OEt OMe OMe R = H, OSiMe3 R J. Chem. Soc., Perkin Trans. 1 1979, 3132. J. Org. Chem. 1978, 43, 1435. OMe 245 Modern Organic Chemistry The Scripps Research Institute diene reference J. Org. Chem. 1976, 41, 3218. J. Org. Chem. 1978, 43, 1208. Angew. Chem., Int. Ed. Eng. 1966, 5, 668. J. Chem. Soc., Chem. Commun. 1978, 657. RS J. Org. Chem. 1976, 41, 3218. J. Am. Chem. Soc. 1972, 94, 2891. (also reports corresponding sulfoxides). J. Org. Chem. 1978, 43, 1208. SR OR R1 R = CH3, R1 = H R = SiMe3, R1 = H, Me J. Chem. Soc. 1964, 2932, 2941. Tetrahedron Lett. 1976, 3169. R = H, R1 = Me R = H, R1 = Ac R = Me, R1 = SiMe3 Tetrahedron Lett. 1970, 4427. J. Am. Chem. Soc. 1968, 90, 113. Tetrahedron Lett. 1977, 611. R = SiMe3 Tetrahedron Lett. 1981, 22, 645. J. Am. Chem. Soc. 1980, 102, 3654 and 5983. J. Chem. Soc. 1964, 2932 and 2941. J. Chem. Soc., Perkin Trans. 1 1973, 3132; 1976, 2057. Tetrahedron Lett. 1970, 3467 and 4427. Tetrahedron 1967, 23, 87. R1 RO R R R R1O OR R = CH3 OR J. Org. Chem. 1978, 43, 4559. J. Am. Chem. Soc. 1977, 99, 8116. SR J. Am. Chem. Soc. 1976, 98, 5017. J. Am. Chem. Soc. 1977, 99, 8116. J. Am. Chem. Soc. 1980, 102, 3548 and 3554. RO RS RO SR J. Org. Chem. 1982, 47, 4005. J. Org. Chem. 1978, 43, 4052. J. Org. Chem. 1976, 41, 3218. Org. Syn. 1979, 59, 202. SR SR J. Org. Chem. 1976, 41, 2934. RO SR R 246 SR J. Org. Chem. 1972, 37, 4474. Key Ring Forming Reactions Dale L. Boger diene R reference OSiR3 Tetrahedron Lett. 1980, 21, 3423. J. Chem. Soc., Chem. Commun. 1981, 211. O R OSiR3 NR2 = NEt2 NR2 = NHCOX J. Org. Chem. 1966, 31, 2885. J. Am. Chem. Soc. 1976, 98, 2352 and 8295. NR2 = NHCOX NR2 = NHCO2R Tetrahedron Lett. 1976, 3089. J. Org. Chem. 1979, 44, 4183. Tetrahedron Lett. 1980, 21, 3323. J. Am. Chem. Soc. 1976, 98, 2352. J. Org. Chem. 1978, 43, 2164. Helv. Chim. Acta 1975, 58, 587. Tetrahedron Lett. 1979, 981. Chem. Ber. 1957, 90, 238. Chem. Ber. 1942, 75, 232. J. Liebigs Ann. Chem. 1969, 728, 64. R2N NR2 NR2 = NEt2 NR2 (comparison) Me3Si • O J. Org. Chem. 1980, 45, 4810. CO2Et J. Org. Chem. 1970, 35, 3851. EtO SiR3 Tetrahedron 1979, 35, 621. J. Chem. Soc., Chem. Commun. 1976, 679, 681. R3Si R3X Tetrahedron Lett. 1980, 21, 355. X = Si, Sn 13. Heterodienes -Typically, heterodienes are electron-deficient and participate in inverse electron demand Diels–Alder reactions Reviews: Boger Tetrahedron 1983, 34, 2869. Comprehensive Org. Syn., Vol. 5, 451. Behforouz Tetrahedron 2000, 56, 5259. 247 Modern Organic Chemistry The Scripps Research Institute -Acyclic azadienes, N-sulfonyl-1-azadienes: OR R SO2Ph SO2Ph N R R OR N * Regiospecific and R Diastereospecific R R R R R R * * * * R N R SO2Ph endo Boat TS R RO R R Secondary orbital interaction (C-2 diene/OR) n–σ* stabilization (T.S. anomeric effect) Solvent independent rate Dienophile geometry conserved * Pressure-induced endo diastereoselectivity * k (trans) > k (cis) * C-3 EWG accelerates reaction (25 °C) * And C-2 or C-4 EWG accelerate reaction * C-3 > C-2 or C-4 (25 °C) Boger J. Am. Chem. Soc. 1991, 113, 1713. O OH O O MeO O MeO OH O H2N O HO N O N H N CH3 OH H2N N H O N O OMe Streptonigrone OMe Boger J. Am. Chem. Soc. 1993, 115, 10733. Fredericamycin A Boger J. Am. Chem. Soc. 1995, 117, 11839. CH3 X = OH, H X=O X (–)-Mappicine Nothapodytine B Boger J. Am. Chem. Soc. 1998, 120, 1218. -Representative heteroaromatic azadiene Diels–Alder reactions taken from the work of Boger N R R N N R = CO2CH3 R = H, Cl R=H R = CO2Et R = SCH3 R R1 N N R = CO2CH3 R = CO2CH3 R = SCH3 R = OMe EDG O R N N R=H R = CO2Et N N N N N R N N R R N R = CO2CH3 O R = SCH3 R2 R1 R N N R = CO2CH3 R = SCH3 O R2 R = SO2CH3 R1 N N O N R2 R Reviews: Boger Tetrahedron 1983, 34, 2869. Prog. Heterocycl. Chem. 1989, 1, 30. Chem. Rev. 1986, 86, 781. Bull. Chim. Soc. Belg. 1990, 99, 599. Chemtracts: Org. Chem. 1996, 9, 149. 248 R N R = OMe, SMe R = SMe, NHCOR R R N R R R R 2 CO2CH3 R N N O NH N R R1 CO2CH3 R Key Ring Forming Reactions Dale L. Boger -Heterocyclic azadiene Diels–Alder reaction total synthesis applications taken from the work of Boger O O MeO H2N N N O H2N CO2H H2N N N O CH3 OH CO2H CH3 HN OMe OMe Streptonigrin J. Am. Chem. Soc. 1985, 107, 5745. Lavendamycin J. Org. Chem. 1985, 50, 5782 and 5790. C5H11 N MeO CH3 HO OH HO HO OH HO OH OH O NH NH O Prodigiosin J. Org. Chem. 1988, 53, 1405. N O O N H O Ningalin A Nigalin B J. Am. Chem. Soc. 1999, 121, 54. OH J. Org. Chem. 2000, 65, 2479. MeO HO MeO N H cis-Trikentrin A J. Am. Chem. Soc. 1991, 113, 4230. O HO MeO2C OH CO2Me N Me N Me O O Isochrysohermidin J. Am. Chem. Soc. 1993, 115, 11418. O OH n OH Bu N NH HN N N MeO OH CO2H O Phomazarin J. Am. Chem. Soc. 1999, 121, 2471. OMP J. Org. Chem. 1984, 49, 4405. H. Fischer received the 1930 Nobel Prize in Chemistry on the structure of haemin and chlorophyll and the subsequent synthesis of haemin. By many, this is regarded as a milestone accomplishment for the field of organic synthesis. Richard M. Willstatter received the 1915 Nobel Prize in Chemistry for his investigations of plant pigments, particularly chlorophyll. His use of chromatography to isolate natural products first popularized the technique introduced in 1906 by M. Tswett and his synthesis of cocaine is considered by many as the launch of modern day natural products total synthesis. 249 Modern Organic Chemistry The Scripps Research Institute H2N O N R OH Me HN N O HO2C OMe N H NH N N O O O N H N O N N H N H2N O O Me CO2H N H N N H N H2N Me O OH O HO OH N H CONH2 HO O O HO O NH HO S H O OH OH OCONH2 OMe OMe OMe OMe MeO N CO2Me H N OMe MeO OH Lamellarin O Lukianol A J. Am. Chem. Soc. 1999, 121, 54. 250 H N N N O O N N H O MeO OH O S Bleomycin A2 J. Am. Chem. Soc. 1994, 116, 5607, 5619, 5631, 5647. (+)-P-3A J. Am. Chem. Soc. 1994, 116, 82. OH O N O H N N H N OH HO H N NH2 NH2 CONH2 Me S Me H N H N R = NH2 R = CH3 J. Am. Chem. Soc. 1987, 109, 2717. H2N O OMe PDE-I PDE-II OH OMe (+)-CC-1065 J. Am. Chem. Soc. 1988, 110, 4796. H2N OH O O OMe Permethyl Storniamide A J. Am. Chem. Soc. 1999, 121, 54. OMe Key Ring Forming Reactions Dale L. Boger O N O OMe N O O Cl HN Anhydrolycorinone J. Org. Chem. 2000, 65, 9120. ent-(−)-Roseophilin J. Am. Chem. Soc. 2001, 123, 8515. 14. Intramolecular Diels–Alder Reactions Review: Ciganek Org. React. 1984, 32, 1. Jung Synlett 1990, 186. Thomas Acc. Chem. Res. 1991, 24, 229. Weinreb Acc. Chem. Res. 1985, 18, 16. Oppolzer Comprehensive Org. Syn., Vol. 5; pp 315. A. General Considerations: -less negative ∆S , which accelerates reaction and results in milder reaction conditions. -naturally affects regioselectivity and diastereoselectivity. -extends Diels–Alder reaction to include systems which are normally unreactive. no activating groups 160 °C H 95% Wilson J. Am. Chem. Soc. 1978, 100, 6289. B. Notable applications in synthesis: -tethered intramolecular Diels–Alder reactions Ph B(OiPr)2 + 1. BHT, PhCH3, 150 °C, 0.5 h OH Ph 2. H2O2, NaOH Me Me B O OiPr Ph OH Me Me Me Me Me 74% (major diastereomer) Me Me OH Batey J. Am. Chem. Soc. 1999, 121, 450. -metal-catalyzed intramolecular Diels–Alder reactions An emerging group of transition-metal mediated [4 + 2] cycloadditions are under development. Ni-catalyzed Ni(COD)2 (0.1 equiv) O TMS O TMS Wender J. Am. Chem. Soc. 1989, 111, 6432. 98% Rh-catalyzed [(C8H14)2RhCl]2 (0.013 equiv) TBSO TBSO Livinghouse J. Am. Chem. Soc. 1990, 112, 4965. 98% 251 Modern Organic Chemistry The Scripps Research Institute -applications in total synthesis CO2Me CO2Me CO2Me 1,2,4-trichlorobenzene H 200 °C, 67% NOMe NOMe H NOMe HN HN HN Oppolzer Helv. Chim. Acta 1981, 64, 478. for lysergic acid t Me O Bu t Me O Bu t Me O Bu H o-dichlorobenzene 180 °C H MeO H H H MeO MeO for estrone Kametani J. Am. Chem. Soc. 1978, 100, 6218. O H O toluene, sealed tube NPiv NPiv N Ac N H Ac 140 °C, 24 h Merour Synlett 1998, 1051. H H NHAlloc O TESO 0.2 mM in dodecane TESO O O H H O CO2tBu H O O H H O OTBS OTBS for pinnatoxin A Kishi J. Am. Chem. Soc. 1998, 120, 7647. OTBS OTBS Me O t O Bu O O O O Me toluene, BHT 70 °C, 20 h O O tBu Me CO2All 40–45% Me3Si Me3Si OMOM Roush J. Am. Chem. Soc. 1998, 120, 7411. 252 NHAlloc O 70 °C O O O O OMOM for chlorothricolide CO2tBu Key Ring Forming Reactions Dale L. Boger 15. Asymmetric Diels–Alder Reaction Catalytic Asymmetric Diels–Alder Reactions: Kagan, H. B.; Riant, O. Chem. Rev. 1992, 92, 1007. Asymmetric Hetero Diels–Alder Reaction: Waldermann, H. Synthesis 1994, 535. A. General considerations -Unsymmetrically substituted dienes or dienophiles have enantiotopic faces. Even with exclusive cis-endo addition and regioselectivity, products occur as a pair of enantiomers. RO2C H Si Re Re Si + CO2R CO2R -There are three possible ways to obtain one of the enantiomers in excess: a) using chiral dienes. b) using chiral dienophiles. c) using chiral Lewis acid catalysts. In addition, double stereoselection can be realized in many situations. -Comparison of chiral substrate vs. chiral catalyst use of a chiral substrate (chiral diene or dienophile): a stoichiometric amount of chiral auxiliary R* is needed and its introduction before and removal after the Diels–Alder reaction are neccessary. R*O2C TiCl4 H Si + + –60 °C CO2R* Re CO2R* use of a chiral catalyst: usually 0.1 equiv. is enough to introduce chirality and the catalyst can be recovered from the reaction mixture and reused. CHO ML*n + + CHO CHO B. Chiral dienophiles Review: Oppolzer Angew. Chem., Int. Ed. Eng. 1984, 23, 876. Ager and East Asymmetric Synthetic Methodology; CRC Press: New York, 1996. -Chiral dienophiles provide the vast majority of the examples of asymmetric Diels–Alder reactions. Type I Type II O O XR* R* X = O, NR* 253 Modern Organic Chemistry The Scripps Research Institute First example: O OR* R*O O TiCl4 COOR* toluene 25 °C COOR* + R* = (–)-menthyl 78% de 80% yield Walborsky Tetrahedron 1963, 19, 2333. COOMe COOMe AlCl4 O + O R R*OOC O CH2Cl2 –30 °C R = CH2Ph, CONHPh 99% de Helmchen Angew. Chem., Int. Ed. Eng. 1981, 20, 205. tBu OH + O tBu O OH conditions endo de yield –20 °C, 24 h 89% 99% 90% ZnCl2, –43 °C, 1 h 94% >99% 95% Masamune J. Org. Chem. 1983, 48, 1137, 4441. O O R Et2AlCl N O + R –100 °C O N O O >86% de O O R Et2AlCl N O R + CH3 –100 °C CH3 Ph O N O Ph O >98% de Evans J. Am. Chem. Soc. 1984, 106, 4261; 1988, 110, 1238. 254 Key Ring Forming Reactions Dale L. Boger other notable chiral dienophiles: O OH N O S O O R N R1 CH3 O Arai J. Org. Chem. 1991, 56, 1983. Boeckman J. Am. Chem. Soc. 1992, 114, 2258. O TolS O R O O N Ph O N SO2 R SO2 Oppolzer Helv. Chim. Acta 1989, 72, 123. Oppolzer Tetrahedron Lett. 1990, 31, 5015. H O O Inverse electron demand Diels–Alder reaction Posner J. Am. Chem. Soc. 1986, 108, 7373. O COOMe O Liu Tetrahedron Lett. 1991, 32, 2005. Boger J. Org. Chem. 1985, 50, 1904. Feringa Tetrahedron: Asymmetry 1991, 2, 1247. O O X R N R' O R* = l-menthyl OR* O O X = O, NAc Roush Tetrahedron Lett. 1989, 30, 7305 and 7309. Kneer Synthesis 1990, 599. CO2Me Meyers Tetrahedron Lett. 1989, 30, 6977. O Me Tol CO2Et S O Koizumi Tetrahedron Lett. 1984, 25, 87. O O R2 Ghosez Tetrahedron Lett. 1989, 30, 5891. OBn H O Et CH3 Danishefsky J. Am. Chem. Soc. 1982, 104, 6457. Danishefsky J. Am. Chem. Soc. 1984, 106, 2455. R1 N O Ph3CO R N O O Koga J. Chem. Soc., Perkin Trans. 1 1990, 426. 255 Modern Organic Chemistry The Scripps Research Institute C. Chiral dienes -These have been much less extensively studied. O (S) O O Ph H OMe BF3•OEt2 Ph H + O CHO H 64% de Trost J. Am. Chem. Soc. 1980, 102, 7595. Ph O MeO O O O O 15 kbar H COR* + 50% de 23 h, 20 °C 62% O O H Dauben Tetrahedron Lett. 1982, 23, 4875. EtO2C O O N + O O 15 kbar EtO2C N H 23 h, 20 °C 62% O H O H O Smith Tetrahedron Lett. 1989, 30, 3295. TMSO Me O TMSO O OAc + N Ph 90% de N Ph Me O OAc O O R*O H O OAc OAc Stoodley J. Chem. Soc., Perkin Trans. 1 1990, 1339. OMOM MOMO O H O Toluene + Me H (S) OTBS Me N Ph H O THF N Ph 25 °C, 0.5 h O PhS McDougal Tetrahedron Lett. 1989, 30, 3897. 256 H O H OTBS MOMO O + H SPh Me N Ph 25 °C, 48 h O OMOM (R) N Ph H O H Me Key Ring Forming Reactions Dale L. Boger R N R NO2 1. Ar NO2 2. HOAc 26−76%, 95−99% ee O Ar OMe Enders Synthesis 1992, 1242; 1994, 66. Barluenga J. Am. Chem. Soc. 1993, 115, 4403; 1998, 120, 2514. TBSO + R N R' R OTBS Ph N Ph OHC R' CHO TBSO N R O R' CHO R R' CHO R = CH2OMe, Ph 86%, 88% ee Rawal J. Am. Chem. Soc. 1999, 121, 9562. D. Chiral Lewis acid catalysts Review: Oh Org. Prep. Proced. Int. 1994, 26, 129. Age and East Asymmetric Synthetic Methodology; CRC Press: New York, 1996. -Pioneer work catalyst toluene CHO CHO + –78 °C R yield ee Cl 56% 57% O Et 57% 35% R iBu 67% 23% catalyst: ClAl Koga J. Chem. Soc., Chem. Commun. 1979, 437. Tetrahedron Lett. 1987, 28, 5687. a. Boron-based Lewis acids O Me H catalyst Me Me + Me CHO endo catalyst: CH3O O COOH O O OCH3 O O BH CHO + Me Me exo 3:97 (endo:exo) 90% yield 91% ee Yamamoto J. Org. Chem. 1989, 54, 1481. 257 Modern Organic Chemistry The Scripps Research Institute O O O H BH3, HOAc Ph O OH O OH OH Ph B O O O OH O H Ph OCH3 OCH3 70–90% yield 98% ee Ph Kelly J. Am. Chem. Soc. 1986, 108, 3510. O O O B(OMe)3 HO NHAr O OH O HO O NHAr B O OH O H H O NHAr OSiR3 ArHN OSiR3 73% yield 92% ee Yamamoto Tetrahedron Lett. 1986, 27, 4895. other boron-based catalysts SO2Ar R N HB O O R = Et R = iPr R = 3-indole O O O BB O O O Yamamoto Synlett 1990, 194. Helmchen Synlett 1990, 197. Mukaiyama Chem. Lett. 1991, 1341. Corey J. Am. Chem. Soc. 1991, 113, 8966. C3-symmetric Kaufmann Angew. Chem., Int. Ed. Eng. 1990, 29, 545. See also: Yamamoto J. Am. Chem. Soc. 1998, 120, 6920. tBuCH 2 BBr2•SMe2 CH3 Br B CH3 Cl2B Hawkins J. Am. Chem. Soc. 1991, 113, 7794. 258 Kaufmann Tetrahedron Lett. 1987, 28, 777. Kaufmann J. Organomet. Chem. 1990, 390, 1. Key Ring Forming Reactions Dale L. Boger b. Aluminum-based Lewis acids BnO O O N catalyst + O O CH2OBn O –78 °C CH2Cl2 N O 94% yield 95% ee catalyst: Ph CF3O2SHN Ph Al NHSO2CF3 CH3 OMe Corey J. Am. Chem. Soc. 1989, 111, 5493. Corey J. Am. Chem. Soc. 1992, 114, 7938. Me O Me H + O 1) (R)-catalyst O 2) CF3COOH TMSO Ph Me Me 95–97% ee catalyst: SiAr3 O Al Me O SiAr3 Yamamoto J. Am. Chem. Soc. 1988, 110, 310. Ar = Ph, 3,5-xylyl other chiral ligands used for chiral aluminum-based Lewis acids: CH3 H Ph Ph CH3O Ph Ph OH OH Ph Ph OH OH OH HO OH Kagan Tetrahedron: Asymmetry 1990, 1, 199. OH OBn OBn BnO OBn OH Wulff, Rheingold J. Am. Chem. Soc. 1993, 115, 3814. CH3 H Ph Ph NH SO2 Chapuis Helv. Chim. Acta 1987, 70, 436. 259 Modern Organic Chemistry The Scripps Research Institute c. Titanium-based Lewis acids O O R* Ti Cl R Cl R N O O O + + O N R N O O endo catalyst: exo Cl Ti R* O Cl R* = Ph endo:exo (90:10) endo 92% ee Ph Ph O OH Me O OH Ph Ph Narasaka J. Am. Chem. Soc. 1989, 111, 5340. Seebach Helv. Chim. Acta 1987, 70, 954. Other Titanium catalysts: O Ph O Ph O O O TiCl2 TiCl2 O O Oh J. Org. Chem. 1992, 57, 396. O CH3 Chapuis Helv. Chim. Acta 1987, 70, 436. X Ph OH O O TiCl2 TiCl2 OH O O OH OH X X = Ph, SiPh3, SitBuPh2, SiiPr3, Si(o-tolyl)3 Ph CH3 Mikami Tetrahedron: Asymmetry 1991, 2, 643. Chapuis Helv. Chim. Acta 1987, 70, 436. Yamamoto J. Org. Chem. 1993, 58, 2938. d. Copper-based Lewis acids R 260 R O O N Cu(OTf)2 O O + bis(oxazoline) O N O R = H, CH3, Ph, CO2Me 90–97% ee 85–92% yield Key Ring Forming Reactions Dale L. Boger bis(oxazoline): O CH3 CH3 O N N R R = Ph iPr tBu R Evans J. Am. Chem. Soc. 1993, 115, 6460. Evans Tetrahedron Lett. 1993, 34, 7027. Review: Evans Acc. Chem. Res. 2000, 33, 325. Me Me Me H+ catalyst + (MeO)2P O O OEt (MeO)2P O O MeO2C OEt CHO 94–99% ee catalyst: CH3 CH3 O O N Cu N 2+ or 2 Me3C CH3 CH3 O O –OTf CMe3 N Cu 2+ 2 –OTf N Ph Ph Evans J. Am. Chem. Soc. 1998, 120, 4895; 1999, 121, 7559 and 7582. e. Iron, Magnesium-based Lewis Acids CH3 CH3 O O N Ph I Fe + CH3 CH3 N I Ph O N Ph Corey J. Am. Chem. Soc. 1991, 113, 728. CH3 CH3 O I Mg CH3 CH3 N I Ph Corey Tetrahedron Lett. 1992, 33, 6807. f. Miscellaneous chiral Lewis acids C3F7 O O Yb(OTf) O O Eu 3 Eu(hfc)3 Kobayashi Tetrahedron Lett. 1993, 34, 4535. Danishefsky J. Am. Chem. Soc. 1986, 108, 7060. 261 Modern Organic Chemistry The Scripps Research Institute E. Biological catalysts COOR Baker's yeast COOR COOR + COOR 100% exo, against the Alder endo rule R = Me, Et Rao Tetrahedron Lett. 1990, 31, 5959. Catalytic antibodies (abzymes): O O abzyme + N N NHAc O HN O NHAc O O O– – O O NH O O Schultz J. Am. Chem. Soc. 1990, 112, 7430. Schultz Science 1998, 279, 1929. Review: Schultz, Lerner Science 1995, 269, 1835. O CONMe2 IgG 4D5 (endo) NHCO2R + CONMe2 IgG 13D5 CONMe2 NHCO2R (exo) R = 4-carboxybenzyl Houk, Janda, Lerner Science 1993, 262, 204. Janda J. Am. Chem. Soc. 1995, 117, 7041. Houk, Janda, Wilson Science 1998, 279, 1934. Cl Cl O SO2 NHCO2R Cl abzyme + N Et Cl Cl Cl Cl O S O Cl N Et O Cl O Cl N O Cl Et Hilvert J. Am. Chem. Soc. 1989, 111, 9261. F. Double asymmetric induction O (S) O O Ph H OMe MeO O OH + t BF3•OEt2 Ph O O OH H Bu t Bu ds > 130:1 O O (R) O Ph MeO H MeO O + OH BF3•OEt2 H O O OH Ph tBu tBu ds 35:1 Masamune J. Org. Chem. 1983, 48, 4441. 262 O Cl O Key Ring Forming Reactions Dale L. Boger S O O catalyst Ph N + H Ph S –20 °C, 36 h O Bn N conversion 72% endo:exo > 97:3 endo1:endo2 97:3 O Bn matched S O O catalyst Ph N + H Ph S –20 °C, 36 h O Bn O Bn catalyst: mismatched 2+ H N Cl N conversion 7% endo:exo 97:3 endo1:endo2 57:43 H N Cl Cu Cl Cl 2 –OTf Evans Tetrahedron Lett. 1993, 34, 7027. G. Intramolecular Diels–Alder reactions CH3 O R (l-bornyloxy)AlCl2 CO2R* CO2R* R R + O (CH3)2Ph : 82 18 64% ee Roush J. Am. Chem. Soc. 1982, 104, 2269. CH3 S O O N catalyst O S H O N H S O O CH3 S 70% yield catalyst: Ph Ph O Me O Ph Ph O TiCl2 O Ph 87% ee Narasaka Chem. Lett. 1989, 1947. 263 Modern Organic Chemistry The Scripps Research Institute 16. Some Classic and Favorite Total Synthesis Applications OH MeO HO N N H OH H MeO CH3 O H OMe O O N OMe OMe OMe Reserpine Woodward Tetrahedron 1958, 2, 1. Wender J. Am. Chem. Soc. 1980, 102, 6157. Pyridoxol Harris J. Org. Chem. 1962, 27, 2705. Doktorova Tetrahedron 1969, 25, 3527. O N O N H H O H Ibogamine Sallay J. Am. Chem. Soc. 1967, 89, 6762. Trost J. Am. Chem. Soc. 1978, 100, 3930. OH OH OH Fraxinellone Fukuyama Tetrahedron Lett. 1972, 3401. OH OH HO HO OH OH O OH OH OH myo-Inositol allo-Inositol Kowarski J. Org. Chem. 1973, 38, 117. α-Damascone Cookson J. Chem. Soc., Chem. Commun. 1973, 161, 742. HO HO O O COOH HO O OH OH O Cantharidin Stork, Burgstahler J. Am. Chem. Soc. 1953, 75, 384. Dauben J. Am. Chem. Soc. 1980, 102, 6893. Grieco J. Am. Chem. Soc. 1990, 112, 4595. Quinic acid Raphael J. Chem. Soc. 1960, 1560. Smissman J. Am. Chem. Soc. 1963, 85, 2184. Wolinsky J. Org. Chem. 1964, 29, 3596. Raphael Tetrahedron Lett. 1968, 1847. Newkome Tetrahedron Lett. 1968, 1851. O– HO O HO HN N OH NH H OH OH Tetrodotoxin Kishi J. Am. Chem. Soc. 1972, 94, 9217. 264 OH Patchouli alcohol Naf, Ohloff Helv. Chim. Acta 1974, 57, 1868. Key Ring Forming Reactions Dale L. Boger COOH MeO O NHAc MeO MeO HO O OH OMe Prostaglandins Corey J. Am. Chem. Soc. 1970, 92, 397. Taub Tetrahedron Lett. 1975, 3667. Colchicine Eschenmoser Helv. Chim. Acta 1961, 44, 540. Boger J. Am. Chem. Soc. 1986, 108, 6713. O Nootkatone Dastur J. Am. Chem. Soc. 1974, 96, 2605. α-Copaene Corey J. Am. Chem. Soc. 1973, 95, 2303. O O O O R N H O H OH O O Steroids Sarett J. Am. Chem. Soc. 1952, 74, 4974. Sarett J. Am. Chem. Soc. 1954, 76, 5026. Chelidonine Oppolzer J. Am. Chem. Soc. 1971, 93, 3836. Me OH Me Me H HO O O N O Lycorine Torssell Tetrahedron Lett. 1974, 623. O N Me Dendrobine Kende J. Am. Chem. Soc. 1974, 96, 4332. Roush J. Am. Chem. Soc. 1980, 102, 1390. N HO H N CH3 Hasubanan Derivative Evans J. Am. Chem. Soc. 1972, 94, 2891. N H CO2CH3 Minovine Spitzner J. Am. Chem. Soc. 1973, 95, 7146. Spitzner J. Am. Chem. Soc. 1970, 92, 3492. 265 Modern Organic Chemistry The Scripps Research Institute COOH HO OH N H OH Shikimic acid Raphael J. Chem. Soc., Chem. Commun. 1960, 1560. Raphael Tetrahedron Lett. 1968, 1847. Newkome Tetrahedron Lett. 1968, 1851. Smissman J. Am. Chem. Soc. 1962, 84, 1040. Smissman J. Am. Chem. Soc. 1959, 81, 2909. Wolinsky, Vasileff J. Org. Chem. 1964, 29, 3596. COOH Me OH H HO HO Pumilotoxin Oppolzer Helv. Chim. Acta 1977, 60, 48, 204. Inubushi Chem. Pharm. Bull. 1978, 26, 2442. Inubushi Tetrahedron Lett. 1976, 3169. Overman Tetrahedron Lett. 1977, 1253. Overman J. Am. Chem. Soc. 1978, 100, 5179. OH O OH Prostaglandins Sakai, Kobori Tetrahedron Lett. 1981, 115. OH HO O OH Fomannosin Illudol Semmelhack J. Am. Chem. Soc. 1980, 102, 7567. Semmelhack J. Am. Chem. Soc. 1981, 103, 2427. Semmelhack J. Am. Chem. Soc. 1982, 104, 747. O H HO OH O OH CONH2 O CH2R2 OH O H H NMe2 OH (−)-Tetracycline Tatsuta Chem. Lett. 2000, 646. O HO H R1 O OH OR3 R3 = CH3 HO NH2 Anthraquinone antibiotics (aglycon) Kelly J. Am. Chem. Soc. 1980, 102, 5983. Cava J. Am. Chem. Soc. 1981, 103, 1992. Vogel Tetrahedron Lett. 1979, 4533. Brassard Tetrahedron Lett. 1979, 4911. Gesson Tetrahedron Lett. 1981, 22, 1337. Rapoport Tetrahedron Lett. 1980, 21, 4777. Gesson Tetrahedron Lett. 1980, 21, 3351. N HO N H Estrone (orthoquinodimethide) CO2CH3 Grieco J. Org. Chem. 1980, 45, 2247. Saegusa J. Am. Chem. Soc. 1981, 103, 476. Vollhardt J. Am. Chem. Soc. 1980, 102, 5245 and 5253. Vinca alkaloids and related analogs Nicolaou J. Org. Chem. 1980, 45, 1463. Kuehne J. Org. Chem. 1980, 45, 3259. 266 O Key Ring Forming Reactions Dale L. Boger CH3 O CH3 N O CH3 O H H Stemoamide Jacobi J. Am. Chem. Soc. 2000, 122, 4295. Seychellene Yoshkoshi J. Chem. Soc., Perkin Trans. 1 1973, 1843. Jung Tetrahedron Lett. 1980, 21, 3127. HOOC O O O O OC HO CH3O OH O CH3 CO2H Gibberellic acid Corey Tetrahedron Lett. 1973, 4477. Corey J. Am. Chem. Soc. 1978, 100, 8031, 8034. Fumagillin Corey J. Am. Chem. Soc. 1972, 94, 2549. O OMe MeO MeO H2N N MeO H N N O H2N CH3 OH OMe OMe OMe Streptonigrone Boger J. Am. Chem. Soc. 1993, 115, 10733. Rufescine Boger J. Org. Chem. 1984, 49, 4050. H2N Me O N N H N H2N Me HO O OH O OH Me S H N O NH2 H N CONH2 HO O N H N O O HO O OH OH OCONH2 OH Bleomycin A2 Boger J. Am. Chem. Soc. 1994, 116, 5607, 5619, 5631, 5647. N O H N N H O O NH H2N NH2 H N S CONH2 N N S H O N H N H2N O O CH3 COOH N H H N N H (+)-P-3A Boger J. Am. Chem. Soc. 1994, 116, 82. 267 Modern Organic Chemistry The Scripps Research Institute MeO2C OH MeO Me N MeO O N H O MeO2C N HO Me cis-Trikentrin A Boger J. Am. Chem. Soc. 1991, 113, 4230. Isochrysohermidin Boger J. Am. Chem. Soc. 1993, 115, 11418. O MeO O H2N N N O H2N HO CO2H Me H2N CO2Me N N O Me HN MeO OMe Streptonigrin Boger J. Am. Chem. Soc. 1985, 107, 5745. Weinreb J. Am. Chem. Soc. 1980, 102, 3962. Lavendamycin methyl ester Boger J. Org. Chem. 1985, 50, 5790. H O O N NH HN H N OH Trichodermol Still J. Am. Chem. Soc. 1980, 102, 3654. H2N Octamethylporphin Boger J. Org. Chem. 1984, 49, 4405. O N OH Me MeO C5H11 NH N Me HN N OMe OMe NH O NH HN O Cl Roseophilin Boger J. Am. Chem. Soc. 2001, 123, 8515. Prodigiosin Boger J. Org. Chem. 1988, 53, 1405. N N O O N H OH OMe (+)-CC-1065/PDE-I and PDE-II Boger J. Am. Chem. Soc. 1987, 109, 2717. Boger J. Am. Chem. Soc. 1988, 110, 4796. CH3 OH MeO HO HO OMe N CH3 Juncusol Boger J. Org. Chem. 1984, 49, 4045. 268 Sendaverine Boger J. Org. Chem. 1984, 49, 4033. Key Ring Forming Reactions Dale L. Boger H H Ph H H COOH n H n = 0: Endiandric acid E n = 1: Endiandric acid F Nicolaou J. Am. Chem. Soc. 1982, 104, 5555, 5557, 5558, 5560. Ph HOOC H n n = 0: Endiandric acid D n = 1: Endiandric acid G Nicolaou J. Am. Chem. Soc. 1982, 104, 5555, 5557, 5558, 5560. OMe O N N H O MeO O CO2Me Catharanthine Trost J. Org. Chem. 1979, 44, 2052. O Quassin and Quassinoids Grieco J. Am. Chem. Soc. 1980, 102, 7586. O HO HO H O N HO H CO2H O Indicine N-oxide Keck J. Am. Chem. Soc. 1980, 102, 3632. Retigeranic acid Corey J. Am. Chem. Soc. 1985, 107, 4339. NH OH O Dodecahedrane Paquette J. Am. Chem. Soc. 1982, 104, 4503. NC Perhydrohistrionicotoxin Keck J. Org. Chem. 1982, 47, 3590. O 9-Isocyanopupukeanone 9-Pupukeanone Yamamoto J. Am. Chem. Soc. 1979, 101, 1609. White J. Org. Chem. 1980, 45, 1864. Sativene Snowden Tetrahedron Lett. 1981, 22, 97, 101. 269 Modern Organic Chemistry The Scripps Research Institute OMe O OMe MeO H O MeO2C MeO O Me N MeO N MeO O OH O O Phyllanthocin Burke Tetrahedron Lett. 1986, 27, 4237. O OH OMe Grandirubrine Imerubrine Boger J. Am. Chem. Soc. 1995, 117, 12452. O MeO O N N O OH HO O O N H Fredericamycin A Boger J. Am. Chem. Soc. 1995, 117, 11839. X = OH, H2 X=O HO OH X (–)-Mappicine and Nothapodytine B Boger J. Am. Chem. Soc. 1998, 120, 1218. HO OH HO HO CH3 OH OH O N O O O N H O O OH OH Ningalin A J. Am. Chem. Soc. 1999, 121, 54. Nigalin B J. Org. Chem. 2000, 65, 2479 O O O N OH N O O OH Rubrolone J. Am. Chem. Soc. 2000, 122, 12169. 270 Anhydrolycorinone J. Org. Chem. 2000, 65, 9120. Key Ring Forming Reactions Dale L. Boger B. Robinson Annulation R. Robinson was awarded the 1947 Nobel Prize in Chemistry for his work on the synthesis of natural products, especially steroids and alkaloids. Notably, he was also the first to address the issue of reaction mechanisms with applications of valence theory to reaction mechanisms, and is credited with the first use of the curved arrow to indicate electron movement. His synthesis of tropinone (1917) is viewed by many to represent the first natural product total synthesis from simple precursors (succindialdehyde, acetone, and methylamine). Reviews M. Jung, Tetrahedron 1976, 32, 3. Org. React. 1959, 10, 179. Org. React. 1968, 16, 3. Synthesis 1976, 777. Synthesis 1969, 49. Robinson J. Chem. Soc. 1917, 762. (tropinone) + O Ph NaNH2 O NH3-Et2O Ph 43% O Robinson J. Chem. Soc. 1935, 1285. Generated a great deal of interest and subsequent work because of relationship to steroid synthesis. 1. Scope - Formally, a [4 + 2] condensation approach O O 1 2 O Michael Reaction + HO O O 3 4 O O H. Wieland received the 1927 Nobel Prize in Chemistry for his work in isolating and deducing the structures of bile acids/steroids including cholic acid. He concluded his Nobel Lecture with the statement that he had a "duty" to synthesize the bile acids even though the task was insurmountable at the time. O Aldol Condensation O O O O Wieland–Miescher ketone OH Wieland and Miescher Helv. Chim. Acta 1950, 33, 2215. - Alternative "[3 + 3] Robinson Annulation" – Both the [4 + 2] and [3 + 3] approaches were first generalized by Robinson J. Chem. Soc. 1937, 53. + O O O - Org. Synth., Coll. Vol. 5, 486. O + O O cat. 0.01 N KOH CH3OH O O O N H benzene reflux O O 60–65% 271 Modern Organic Chemistry The Scripps Research Institute - With stronger base, other reactions are observed: O O– OCH3 CH3O– –O O O O OCH3 irreversible step O O O O - Double addition of methyl vinyl ketone (MVK) sometimes a problem, especially at more acidic sites. O O O O O -Solutions O NaH NaH CH3O2C O CH3O R O O O OCH3 R = CO2CH3 O - For the preparation of the useful starting octalone derivatives, the low yield has been considered acceptable since it is prepared from readily available materials. tBuOK tBuOH O + 35% O At low temperature, MVK polymerization is slow and Michael reaction OK, but, the conditions are not sufficiently vigorous for H2O elimination, so the reaction is conducted in two steps. O Gaspert J. Chem. Soc. 1958, 624. (CO2H)2, H2O MVK, NaOEt EtOH–Et2O –10 °C, 54% O OH But, many variations on the reaction have provided general improvements. steam distill 86% Marshall J. Org. Chem. 1964, 25, 2501. MVK, cat. H2SO4 Acid-catalyzed variant of reaction. O C6H6, reflux, 16 h 49–55% O Reaction simple to set up, but, conversion still modest. Heathcock and McMurry Tetrahedron Lett. 1971, 4995. Lewis acid catalyzed variant of reaction. OTMS O O O NaOMe Bu2Sn(OTf)2 CH2Cl2 MeOH 89% overall based on MVK Nozaki Tetrahedron 1991, 47, 9773. J. Am. Chem. Soc. 1992, 113, 4028. 272 O Superb conversions possible. Key Ring Forming Reactions Dale L. Boger - Alternatives to methyl vinyl ketone: MVK difficult to employ due to tendency to polymerize X O X = NR2 X = N+R3 X = Cl + CH2O + HNR2 Robinson J. Chem. Soc. 1937, 53. Theobald Tetrahedron 1966, 22, 2869. Halsall J. Chem. Soc. 1964, 1029. O - Other equivalents Julia Bull. Soc. Chim., Fr. 1954, 5, 780. Cl Cl OEt Stork J. Am. Chem. Soc. 1956, 78, 501. I R Cl O Stork J. Am. Chem. Soc. 1967, 89, 5461 and 5463. N Stork Tetrahedron Lett. 1972, 2755. Wenkert J. Am. Chem. Soc. 1964, 86, 2038. O CO2CH3 Fried J. Am. Chem. Soc. 1968, 90, 5926. + O Li OCH3 Li O P(OR)2 – O + CO2R O O O P(OR)2 O O – (RO)2P O O SiMe3 Stork J. Am. Chem. Soc. 1974, 96, 3682. I (allylic alkylation reaction is rapid and yield is high) CO2tBu Stotter J. Am. Chem. Soc. 1974, 96, 6524. I TMS O Stork J. Am. Chem. Soc. 1973, 95, 6152. Boeckman J. Am. Chem. Soc. 1973, 95, 6867. 273 Modern Organic Chemistry The Scripps Research Institute Enamine Annulations O + N O O O + N N H Stork J. Am. Chem. Soc. 1956, 78, 5129. J. Am. Chem. Soc. 1963, 85, 207. Henderickson J. Am. Chem. Soc. 1971, 93, 1307. O O O O O + N Bn N O Bn Stevens J. Chem. Soc., Chem. Commun. 1970, 1585. Evans Tetrahedron Lett. 1969, 1573. Evans J. Org. Chem. 1970, 35, 4122. O O O + CHO (Wichterle annulation) CHO Corey J. Am. Chem. Soc. 1963, 85, 3527. - The bridged annulation + O O O O reversible aldol reversible aldol OH O irreversible irreversible O O O OH slow, difficult –H2O: requires vigorous H+conditions 274 usually kinetic aldol product but formed reversibly elimination especially effective under basic conditions Key Ring Forming Reactions Dale L. Boger - Helminthosporal synthesis, Corey J. Am. Chem. Soc. 1963, 85, 3527. O 1. HCO2Et 2. MVK, Et3N O BF3•OEt2 O CH2Cl2 3. K2CO3, EtOH-H2O O O OHC 6 steps CHO H Aromatic Annulation H O S Ph PhOS syn-sulfoxide elimination + O O HO O Boger J. Org. Chem. 1980, 45, 5002. OH t CH3OS BuOK OBn tBuOH OBn + O O 61% HO HO Juncusol Boger J. Org. Chem. 1984, 49, 4045. 2. Diastereoselectivity R When R = H, also subject to equilibration to most stable isomer. O Substituents at these positions subject to thermodynamic equilibration to most stable product. allylic strain R R1 R2 General Observations: R1 H R R O R4 substituents adopt equatorial positions H R2 O− 3 axial attack O 275 Modern Organic Chemistry The Scripps Research Institute 3. Tandem Robinson Annulation (Incorporation of more than four carbons from MVK for more convergent syntheses) - Examples O CH3O2C Karady Tetrahedron Lett. 1976, 2401. Velluz Angew. Chem., Int. Ed. Eng. 1965, 4, 181. O N O via Michael addition to vinyl pyridine Birch reduction to dihydropyridine, and hydrolysis to diketone Danishefsky J. Am. Chem. Soc. 1968, 90, 520. Danishefsky J. Am. Chem. Soc. 1975, 97, 380. Elements of three sequential Robinson annulations (3) O CH3O (2) O (1) O via Birch reduction of aromatic ring, followed by hydrolysis OH MeO Poirier Tetrahedron 1989, 45, 4191. Cl O CO2tBu Danishefsky J. Am. Chem. Soc. 1971, 93, 2356. 276 Key Ring Forming Reactions Dale L. Boger 4. Robinson Annulation: Key Synthetic Transformations of the Robinson Annulation Product R R R Claisen m-CPBA HO R R CrO3 Li/NH3 LiO HO O Rearrangement H(R') reduction Simmons–Smith cyclopropanation CHO NaBH4 (R'Li) R R CuLi BH3, H2O2 oxidation O O 2 HO O Key Intermediate Derived From Robinson Annulation R R CHO R R R NaOH Li/NH3 LiO cyclopropanation O O O hν O R R Li/NH3 DDQ RX O R H O R R KOtBu, LDA, MeI MeI O O R 0.95 equiv Ph3CLi MeI O R R R2AlCN O CN R R NH2NH2 base O R'2CuLi H2O2, NaOH O O O R' R R O Ph2P(O)O [O] H O H R X X = OH, H X=O HO OH cat. O R O3 HO2C Ph2P(O)Cl H BH3, H2O2 O O cat. H+ Li/NH3 R O tBuOH R R'2CuLi H H2, Pd–C H R R Li/NH3 R Ph3P=CH2 O R R OsO4 H+ O HO OH 277 Modern Organic Chemistry The Scripps Research Institute R R NaBH4 or LiAlH4 HO R LisBu3BH THF O H– equatorial axial –OH axial delivery equatorial –OH H– HO delivery - Deconjugation with ketalization or reduction R R ethylene glycol O TsOH, C6H6 O R Ac2O R NaBH4 EtOH O AcO HO Marshall J. Org. Chem. 1972, 37, 982. - Reductive deoxygenation: - without double bond migration R R 1. LiAlH4, Ac2O 2. Li, EtNH2 1. BF3•OEt2 ethanedithiol R 2. Raney–Ni EtOH O - with double bond migration R 1. Li, NH3 ClPO(NMe2)2 2. Li, EtNH2 via enol phosphate R R R NaCNBH3 HCl, DMF TsHNN O via N N H Hydrogenation: McMurry J. Am. Chem. Soc. 1968, 90, 6821; Can. J. Chem. 1972, 50, 336. Birch reduction: For exceptions to generalizations which can exist, see: Boger Tetrahedron Lett. 1978, 17. HO2C Pb(OAc)4 O H HO2C HO2C Pb(OAc)4 H2 Li/NH3 Pd–C Cu+2 O O H cis 5. Asymmetric Robinson Annulation and Related Reactions O H trans Taber J. Org. Chem. 1989, 54, 3831. H3CO O H O CO2R* O O 278 Ar O Cu+2 O H Key Ring Forming Reactions Dale L. Boger Asymmetric Michael Revial Tetrahedron Lett. 1989, 30, 4121. d'Angelo J. Am. Chem. Soc. 1985, 107, 273. Guingant Tetrahedron: Asymmetry 1993, 4, 25. R R R EWG EWG HN N O Ph Ph H O H 90%, 90% ee O Ph 1. H2O, HOAc O N 2. NaOMe N H O Ph Revial Org. Syn. 1992, 70, 35. Review: d'Angelo Tetrahedron: Asymmetry 1992, 3, 456. Asymmetric Aldol O (MeO)2P O O O O HO O 64–80% CO2R* 91–98% de O O D-proline Mandai J. Org. Chem. 1994, 59, 5847. O DMSO 82% O O 69% ee O O O L-proline TsOH, benzene 69% O O 63% ee O O Harada Synthesis 1990, 53. Swaminathan Tetrahedron: Asymm. 1996, 7, 2189. O L-proline 93% O O 88% ee O O Hajos J. Org. Chem. 1974, 39, 1615. O ab 38C2 O O >95% ee Lerner J. Am. Chem. Soc. 1998, 120, 2768. 279 Modern Organic Chemistry The Scripps Research Institute 6. Steroid Synthesis Steroid synthesis: Woodward (Nobel 1965), Robinson (Nobel 1947) Isolation methods: Chromatography Conformational analysis: Barton (Nobel 1969) UV spectroscopy: Woodward, Fieser ORD: Djerassi Biosynthesis theory: Bloch and Lynen (Nobel in Medicine 1964), Cornforth (Nobel 1975) Adolf Windaus received the 1928 Nobel prize in Chemistry for his work in the sterol area contributing to the structure determination of cholesterol, ergosterol, vitamin D, and vitamin B1. 1. Cholesterol Isolation: 1812 Structure, wrong!, Windaus (Nobel 1928) and Wieland (Nobel 1927) 1932, correct planar connectivity (Wieland) 1947, stereochemistry (Hodgkin, X-ray, Nobel 1964) 1952, absolute stereochemistry (Ruzicka, Nobel 1939) HO H H H Leopold Ruzicka received the 1939 Nobel Prize in Chemistry that recognized his contribution in three areas: macrocyclic compounds, higher terpenes, and steroids including the male sex hormones. He was the first to use Wallach's isoprene rule (1887) and defined monoterpenes as naturally occurring compounds composed of two isoprene units, sesquiterpenes (three), and diterpenes (four). His biogenetic isoprene rule and the complete structure elucidation of cholesterol are among his greatest achievements. 2. Sex Hormones OH H H HO H Estradiol OH O Adolf Butenandt, a student of A. Windaus, received the 1939 Nobel Prize in Chemistry for his work on the isolation and structure elucidation of sex hormones. In 1929, he isolated estrone simultaneously with E. Doisy, the hormone that determines sexual development in females in pure crystalline form. Within a few years, he isolated androsterone (1931), a male sex hormone, and progesterone (1934), a hormone involved in pregnancy. The male sex hormone 1931, Butenandt isolated androsterone (metabolite of testosterone) 15,000 L of men's urine: 15 mg 1935, testosterone isolated from 100 kg bull testicles: 10 mg, E. Laquer 1939, planar structure elucidated by Butenandt, Ruzicka (Nobel 1939) H H The hormone responsible for female development and maintenance of reproductive organs and secondary sex characteristics. Pure material isolated 1929, E. Doisy (St. Louis Univ. Medicine Nobel 1943) and A. Butenandt (Gottingen, Nobel 1939) 4 tons of sow ovaries: 25 mg H Testosterone O H H H The pregnancy hormone: maintains proper uterine environment for development of fetus, inhibits further ovulation, nature's contraceptive. 1934, isolation and planar structure, Butenandt 50,000 sows to provide 625 kg ovaries: 20 mg O Progesterone 3. Cortisone OH O H H O 280 H Structure: 1935–38, Kendall, Reichstein, Wintersteiner from adrenal cortex of 1.25 million cattle 1952, 36 step synthesis via degradation of bile acids (Sarett, Merck) O 1949, Hench and Kendall (Mayo Clinic), 1950 Nobel with Reichstein for anti-arthritic OH activity 1951, Djerassi (Syntex), synthesis from Mexican yam steroid 1951, Upjohn microbial process for C11 oxidation of progesterone Tadeus Reichstein received the 1950 Nobel Prize in Medicine for the isolation and structural characterization of pituitary hormones, including cortisone. Key Ring Forming Reactions Dale L. Boger Natural steroid hormones are present in such trace amounts in mammals that it is not a practical source. Synthetic steroids, e.g. 19-nor steroids, became commercially important. Russell E. Marker (Syntex, Penn. State) Degradation of sapogenins and other plant products J. Am. Chem. Soc. 1947, 69, 2167. Diosgenin is obtained from the Mexican diocorea plant (Mexican yams). H O H H O H (1) Ac2O/C7H11CO2H 2 h, 240 °C O H (2) KOH, MeOH reflux, 0.5 h 85–90% H HO H OH (1) Ac2O/pyr 0.5 h, 150 °C (2) CrO3, 90% aq. HOAc 1.5 h, 30 °C, 75% H HO Pseudodiosgenin Diosgenin O O O H H Testosterone Estrone Estradiol O HOAc, 2 h, reflux H H 95% AcO H Progesterone H AcO OAc Diosone 16-Dehydropregnen-3(β)-ol-20-one acetate (> 60% overall) Dehydropregnenolone is easily transformed to progesterone in 3 steps: (1) H2, Pd–C (2) hydrolysis (3) Oppenauer oxidation: cyclohexanone, Al(OiPr)3 Upjohn avoided attempted monopoly by use of stigmasterol obtained from soybeans: CHO H H H H 1. Oppenauer oxidation H benzene, reflux 2. O3 H H HN H O HO Stigmasterol H N H H O H O3 O H H H H O Progesterone 281 Modern Organic Chemistry The Scripps Research Institute O NHAc 1. NH2OH, HCl, pyr 2. SOCl2 H H AcO 16-Dehydropregnenolone acetate (5 steps from diosgenin) O H H O H 1. H2 H 2. Jones 2. NaOH H AcO H H HO Beckmann Rearrangement Dehydroepiandrosterone O H H H O Br 1. CH3I O 2. acetylene KOtAm H HO H Br2, HOAc Br H 1. H3O+ H H O O collidine H H H 530 °C H with mineral oil H O OH H H H H MeO Mestranol (16 steps from diosgenin) Estrone CH3I O O 1. Li, NH3 H H H H 2. HOAc, CrO3 H H selective protection of enone carbonyl EtO H O MeO 2-O-Methyl Estrone O HC(OEt)3 HCl H H H H more stable isomer OH 1. acetylene KOtAm H 2. HCl H H O Norethindrone (20 steps from diosgenin) There are more stories told about Russell Marker (1902−1995) than perhaps any other chemist. Marker achieved the first practical synthesis of progesterone which led to the creation of Syntex S.A. in Mexico. Marker received not only his B.Sc. (1923), but also a M.S. degree in physical chemistry from the Univ. of Maryland (1924) and subsequently completed enough work in 1 year for his doctoral degree with M. Kharasch at Maryland. However, he did not receive his Ph.D. because he refused to complete his physical chemistry coursework, which he considered a waste of time. In 1925, he joined Ethyl Corp. where he invented the gasoline "octane number" rating system. Following a subsequent position at Rockefeller Univ. with P. A. Levene, he joined Penn State College in a position funded by Parke−Davis. After discovering an economical source of a steroid starting material (diosgenin) in a Mexican yam, Marker developed a degradation synthesis of progesterone producing 3 kg at a time it was selling for $80/g. Marker commercialized his process in 1944 at Syntex in Mexico which he cofounded. After a dispute in 1945, Marker left Syntex and took with him the details of the synthesis, the key operations which only he had conducted. He founded another company Botanica-Mex which became Hormonosynth and subsequently Diosynth. Syntex did not fade into the background. After a few months, it was back up a running recruiting C. Djerassi and entrepreneur A. Zaffaroni. Using Syntex progesterone, Djerassi focused on the discovery of a mimic that would not only prevent ovulation like progesterone, but would also be orally active. His group prepared norethindrone, the active ingredient of the first birth control pill. 282 Key Ring Forming Reactions Dale L. Boger The Total Synthesis Of Steroids Representative strategies employing the Robinson and related annulations The Velluz Approach (Roussel–Uclaf, Paris) Compt. rend. 1960, 250, 1084, 1511. Angew. Chem., Int. Ed. Eng. 1965, 4, 181. Cl O Stork isoxazoles, J. Am. Chem. Soc. 1967, 89, 5464. O N O S. Danishefsky vinyl pyridines, J. Am. Chem. Soc. 1975, 97, 380. N J. Tsuji via Wacker oxidation of terminal double bonds, J. Am. Chem. Soc. 1979, 101, 5070. O Comparison of strategies employing the intramolecular Diels–Alder reaction: First applications of this strategy were developed independently in laboratories of T. Kametani and W. Oppolzer. Examples T. Kametani, Tetrahedron Lett. 1978, 2425. J. Am. Chem. Soc. 1976, 98, 3378. J. Am. Chem. Soc. 1977, 99, 3461. J. Am. Chem. Soc. 1978, 100, 6218. O OtBu DMF, 1 h, 40 °C 17 steps 12% CN Na/THF/NH3 I 49% optically pure NC NaH, DMF 10 min, 25 oC O Br OtBu EtOH, 1 h, –78 oC 85% NaNH2/NH3 MeO 3 h, 180 °C (o-Cl2C6H4), N2 84% OtBu 2 h, –33 °C 65% OMe OMe exo transition state MeO HCl, pyr HCl/H2O dioxane 45 min, 240 °C 7 h, reflux, 84% 81% OtBu H H OH H H MeO H H HO (+)-Estradiol Oppolzer Helv. Chim. Acta 1977, 60, 2964. Oppolzer Angew. Chem., Int. Ed. Eng. 1977, 16, 10. Oppolzer Helv. Chim. Acta 1980, 63, 1703. 283 Modern Organic Chemistry The Scripps Research Institute O O 1. NaBH4, MeOH 2. TBSCl CuLi MeO2C OTBS 2 Br I 3. LiAlH4 4. TsCl, pyr 5. NaI, acetone CO2Me 6:1 95% 77% NaH THF, HMPA 82% OTBS SO2 NC 1. I2, AgSO4 H2SO4 1:1 SO2 SO2 2. NaCN, (Ph3P)4Pd toluene Cl NC (–SO2) 213 oC Cl Cl OH H H OTBS 1. MeLi 2. CF3CO3H H 3. HCl, THF, MeOH H H H NC HO (+)-Estradiol 80% retro-cheletropic cycloaddition followed by Diels–Alder reaction T. Saegusa J. Am. Chem. Soc. 1981, 103, 476. O O CsF >86% Me3Si H H MeO NMe3+I– H MeO Estrone K. P. C. Vollhardt and R. Funk J. Am. Chem. Soc. 1977, 99, 5483. MgBr(CuI) O THF, 45 min –60 to –40 oC TMSCl, Et3N (HMPA) 0.5 h, –40 to 25 oC 89% 284 OSiMe3 1. LiNH2, NH3, THF 0.5 h, –33 oC 2. alkylation, THF 25 oC, 64% I O neat TMSC≡CTMS CpCo(CO)2 N2, 35 h, 140 oC Key Ring Forming Reactions Dale L. Boger O O ∇ Me3Si 4πe– electrocyclic ring opening followed by Diels–Alder reaction Me3Si TFA, Et2O, CCl4 20 h, 25 °C H Me3Si H 100% H Me3Si O H H H (±)-Estra-1,3,5(10)-trien-17-one K. Vollhardt J. Am. Chem. Soc. 1979, 101, 215. O TFA, CHCl3, CCl4 –30 °C H Me3Si H H Me3Si Me3Si O O Pb(OAc)4 H H H H H H HO 90%, 9:1 regioselectivity Estrone Total Synthesis of Cortisone R. B. Woodward received the 1965 Nobel Prize in Chemistry for "Contributions to the Art of Organic Synthesis" and the award preceded the total synthesis of vitamin B12 carried out in collaboration with A. Eschenmoser, the principles of orbital symmetry conservation (Hoffmann Nobel Prize in 1981), the Wilkinson structure determination of ferrocene (Nobel 1973) carried out with Woodward, and the collaborative delineation of the steroidal biosynthesis involving stereoselective cation–olefin cyclizations in collaboration with Bloch (Nobel 1964). Woodward changed synthesis from the application of empirical reactions to a mechanistic foundation for predicting reactions and substrate reactivity (rates, stereoselectivity) and designed this rationale into the preplanned synthesis. The results were stunning with unattainable objectives falling one after another: quinine (1944), patulin (1950), cholesterol (1951), cortisone (1951), lanosterol (1954), lysergic acid (1954), strychnine (1954), reserpine (1956), chlorophyll (1960), tetracyclines (1962), colchicine (1963), cephalosporin C (1966), most before the wide spread usage of 1H NMR. Breathtaking natural product structure determinations: penicillin (1945), strychnine (1948), patulin (1949), terramycin (1952), aureomycin (1952), cervine (1954), magnamycin (1956), gliotoxin (1958), oleandomycin (1960), streptonigrin (1963), and tetrodotoxin (1964) also preceded the reliance on 1H NMR. The formal total synthesis of vitamin B12 was completed in 1972 in collaboration with A. Eschenmoser (>100 postdoctoral fellows) and synthetic cobyric acid was converted to vitamin B12 in 1976. R. B. Woodward The chemical publication with the most coauthors (49) is the J. Am. Chem. Soc. 1951, 73, 2403, 3547, 4057. posthumous account of the total synthesis of erythromycin by J. Am. Chem. Soc. 1952, 74, 4223. Woodward (J. Am. Chem. Soc. 1981, 103, 3210). Physics holds the record with 406 coauthors: Phys. Rev. Lett. 1993, 70, 2515. O O 1. benzene 100 °C, 96 h + MeO 2. NaOH; H+MeO O 2. 2 N H2SO4 O H O H NaOMe HCO2Et O 1. Ac2O, pyr 1. LiAlH4 O H HOHC 1. EVK tBuOK tBuOH H OH 1. OsO4 H 2. KOH 2. Zn H 2. acetone, CuSO4 O 285 Modern Organic Chemistry The Scripps Research Institute H2 Pd–SrCO3 O H H O O H O OsO4 H O CH2=CHCN H H O H 2. C6H5NHMe O MeOH H O O 1. NaOMe HCO2Et O CHNMeC6H5 O Ac2O, NaOAc H O Triton B tBuOH HO2C O H H O O O CHO O 1. MeMgBr H O + 2. KOH; H H O 1. HIO4•2H2O H 2. HOAc piperidine benzene H O CO2Me 1. Na2Cr2O7•2H2O 2. CH2N2 3. H2, Pd–SrCO3 1. NaBH4, EtOH H 2. Ac2O, pyr 3. PhCO3H H O CO2Me O H AcO H H Br CO2Me O 1. NaOMe 2. Na2Cr2O7 CrO3–H2O HBr H O HO H O H O Zn–HOAc H H O H oC O H H HO H 1. KMnO4 CH3COCH3 O 2. TsOH CH3COCH3 H H O 1. HBr 2. 2,4-dinitrophenyl hydrazone O OH 3. pyruvic acid 4. hydrolysis H H O Cortisone H O H H CH2OH OH H CH2OAc H H HO H O CH2OAc O H CH2OAc O 4. SOCl2 5. CH2N2; HOAc H 2. POCl3, pyr 286 1. NaBH4, 0 2. Ac2O, pyr 3. KOH H H NC 1. HCN, Et3N H H CO2Me CO2Me O Tadeus Reichstein received the 1950 Nobel Prize in Medicine for the isolation and structural characterization of pituitary hormones, including cortisone. Key Ring Forming Reactions Dale L. Boger C. Birch Reduction H3O+ Li/NH3 MeO MeO O Robinson annulationtype product - See the discussion in the sections on the Birch reduction and the Robinson annulation. - Allows an aromatic ring to be incorporated into a synthesis and converted into a useful, nonaromatic ring system. D. Dieckmann Condensation - An intramolecular Claisen condensation, see enolate section for a more detailed discussion. O CO2Et CO2Et CO2Et E. Intramolecular Nucleophilic Alkylation - Powerful approach to closure of rings Examples: - Kinetic enolate generation (Note: O-alkylation may compete). O O - Gem dimethyl effect facilitates cyclization LDA 55–66% Br House J. Org. Chem. 1978, 43, 700. O O LDA 52–63% Br - Versus thermodynamic enolate generation (Note: O-alkylation may compete). O O O tBu KO O O tBuOH Br ∆ 7–19% 58–72% 5–7% 5% - Closure subject to stereoelectronic control. X 180° / SN2 displacement O - Note Baldwins Rules Preceded by Eschenmoser Helv. Chim. Acta 1970, 53, 2059. O LDA Br Et2O 25 °C X O Not possible 70% Not formed O H 287 Modern Organic Chemistry The Scripps Research Institute - Examples OMs O O O Cl KOtBu O toluene 53% O N R N H OH Gibberelic Acid, Corey J. Am. Chem. Soc. 1979, 101, 1038. O Duocarmycin SA, Boger O OMs O NaH N MeO2C 83% J. Am. Chem. Soc. 1992, 114, 10056. J. Am. Chem. Soc. 1993, 115, 9025. N MeO2C O N H O N H J. Am. Chem. Soc. 1988, 110, 4796. O N H O CC-1065, Boger N NaH Duocarmycin A, Boger J. Am. Chem. Soc. 1996, 118, 2301. J. Am. Chem. Soc. 1997, 119, 311. O OH F. Intramolecular Aldol Condensation - The intramolecular aldol condensation has been used extensively to close or form rings. Representative Examples: - Two aldol closures possible: Robinson Annulation O R BF3•OEt2 O Base or H2SO4 O O R R OR O OR O OR OH NaOCH3 CHO OR RO OR Fredericamycin A Boger J. Org. Chem. 1991, 56, 2115. J. Am. Chem. Soc. 1995, 117, 11839. G. Intramolecular Michael Reaction Michael J. Prakt. Chem. 1887, 36, 113. TMS 1 h, 0 °C toluene 50% O H O Majetich J. Org. Chem. 1985, 50, 3615. Tetrahedron Lett. 1988, 29, 2773. EtAlCl2 O H O 50% O O 288 House J. Org. Chem. 1965, 30, 2513. Key Ring Forming Reactions Dale L. Boger MeO2C MeO2C NaOMe MeOH 100% O Mander J. Am. Chem. Soc. 1979, 101, 3373. MeO2C MeO2C O O O H. Cation–Olefin Cyclization 1. Reviews Johnson van Tamelen Harding Goldsmith Lansbury Speckamp Sutherland Acc. Chem. Res. 1968, 1, 1. Angew. Chem., Int. Ed. Eng. 1976, 15, 9. Bioorg. Chem. 1976, 5, 51. Acc. Chem. Res. 1968, 1, 111. Bioorg. Chem. 1973, 2, 248. Fortschr. Chem. Org. Nat. 1972, 29, 363. Acc. Chem. Res. 1972, 5, 311. Recl. Trav. Chim. Pays-Bas. 1981, 100, 345. Comprehensive Org. Syn. Vol 3, pp 341−377. 2. Representative Cation–Olefin Cyclizations COOH SnCl4 Cl Cl O O Monti J. Org. Chem. 1975, 40, 215. O SnCl4 benzene O O Grieco Tetrahedron Lett. 1974, 527. OAc H+ O BF3 Money J. Chem. Soc., Chem. Commun. 1969, 1196. Goldsmith J. Org. Chem. 1970, 35, 3573. Cl BF3 OAc O Cl Money J. Chem. Soc., Chem. Commun. 1971, 766. HCO2H O Cl Lansbury J. Am. Chem. Soc. 1966, 88, 4290. J. Am. Chem. Soc. 1970, 92, 5649. 289 Modern Organic Chemistry The Scripps Research Institute COCl SnCl4 O Marvell J. Org. Chem. 1970, 35, 391. OTs OCH2CF3 Baldwin Tetrahedron Lett. 1975, 1055. TsO HOAc OAc NaOAc Bartlett J. Am. Chem. Soc. 1965, 87, 1288. Johnson J. Am. Chem. Soc. 1964, 86, 5593. OH OR HCO2H Marshall J. Am. Chem. Soc. 1965, 87, 2773. J. Am. Chem. Soc. 1966, 88, 3408. H SnCl4 MeNO2, –23 °C HO H 3 h, 70% H Progesterone total synthesis Johnson J. Am. Chem. Soc. 1968, 90, 2994. O O H O H O HO CF3CO2H 70% H Johnson J. Am. Chem. Soc. 1970, 92, 4461. J. Am. Chem. Soc. 1980, 102, 7800. 290 H Progesterone total synthesis Key Ring Forming Reactions Dale L. Boger O O H CF3CO2H 70% MeO MeO Shionone total synthesis Ireland J. Am. Chem. Soc. 1974, 96, 3333. J. Org. Chem. 1975, 40, 973. J. Am. Chem. Soc. 1970, 92, 2568. OH HCO2H Cedrene OH Corey J. Am. Chem. Soc. 1969, 91, 1557. Tetrahedron Lett. 1973, 3153. Stork J. Am. Chem. Soc. 1955, 77, 1072. J. Am. Chem. Soc. 1961, 83, 3114. OH O Cl H Lansbury J. Am. Chem. Soc. 1966, 88, 4290. J. Chem. Soc., Chem. Commun. 1971, 1107. Tetrahedron Lett. 1973, 5017. O N2 O BF3•OEt2 CH2Cl2 MeO MeO Mander J. Chem. Soc., Chem. Commun. 1971, 773. Erman J. Am. Chem. Soc. 1971, 93, 2821. O O Nazarov cyclization Hiyama J. Am. Chem. Soc. 1974, 96, 3713. OH CHO SnCl4 MeNO2, 0 °C 10 min, 30–40% Ireland J. Am. Chem. Soc. 1974, 96, 3333. J. Org. Chem. 1975, 40, 973. J. Am. Chem. Soc. 1970, 92, 2568. 291 Modern Organic Chemistry The Scripps Research Institute H H CHO OH H PCC H CHO O Naves Helv. Chim. Acta 1964, 47, 51. Corey J. Org. Chem. 1976, 41, 380. OH O PCC OH O PCC Corey, Boger Tetrahedron Lett. 1978, 2461. H+ O O and aldehyde OMe Johnson J. Am. Chem. Soc. 1967, 89, 170. J. Am. Chem. Soc. 1973, 95, 2656. SnCl4 CH2Cl2 1.5 min, 90% OHC β-Vetivone and Vetispirene total syntheses HO McCurry, Jr. Tetrahedron Lett. 1973, 3325. CO2Me CO2Me OPO(OEt)2 Hg(OCOCF3)2 O NaCl ClHg TBDMSO Aphidicolin total syntheses H TBDMSO Corey, Tius J. Am. Chem. Soc. 1980, 102, 1742. (Aphidicolin) J. Am. Chem. Soc. 1980, 102, 7612. (Stemodinone) J. Am. Chem. Soc. 1982, 104, 5551. (K-76) OR Tf2O H HO H Corey J. Am. Chem. Soc. 1987, 109, 6187. (Atractyligenin) J. Am. Chem. Soc. 1987, 109, 4717. (Cafestol) 292 OR Key Ring Forming Reactions Dale L. Boger 3. Background Squalene cyclization first suggested as a biosynthetic precursor to cholesterol J. L. Goldstein and M. S. Brown received the 1985 Nobel Prize in Medicine for their discoveries concerning the regulation of cholesterol metabolism. Heilbron, Kamm, and Owens J. Chem. Soc. 1926, 1630. Robinson Chem. Ind. 1934, 53, 1062. - Robinson's proposal Cholesterol HO - Correct cyclization scheme Lanosterol HO H - Lanosterol was proposed in 1953 by Woodward and Bloch. - Experimental verification that cholesterol is biosynthesized from squalene was developed independently by J. Biol. Chem. 1953, 200, 129. Bloch Cornforth Biochem. J. 1954, 58, 403. Biochem. J. 1957, 65, 94. K. Bloch received the 1964 Nobel Prize in Medicine for his discoveries concerning the mechanism and regulation of the cholesterol and fatty acid metabolism. J. W. Cornforth received the 1975 Nobel Prize in Chemistry jointly with V. Prelog for outstanding intellectual achievement on the stereochemistry of reactions catalyzed by enzymes. - Stork–Eschenmoser hypothesis: the trans-anti-trans stereochemistry of the steroids and many terpenoids is a consequence of a concerted polyene cyclization. Cyclization about a trans olefin Y Y OH R H Cyclization about a cis olefin H OH R H R R OH Y H H H OH Y - Anti addition of a carbocation and nucleophilic olefin on opposite faces of a π-bond analogous to trans electrophilic addition to alkenes. Therefore, cyclization of a trans olefin leads to a trans ring fusion and cyclization of a cis olefin leads to a cis ring fusion. 293 Modern Organic Chemistry The Scripps Research Institute O Squalene Squalene monooxygenase H HO Squalene-2,3-oxide O H+ 2,3-Oxidosqualene lanosterol cyclase –H+ H H H HO HO Dammaradienol 8 chiral centers with 256 possible stereoisomers H H - Two methyl migrations and two hydride transfers –H+ HO Lanosterol H Twenty enzymatic reactions Cholesterol 294 Key Ring Forming Reactions Dale L. Boger 4. Key Publications - Initial experimental demonstrations of multiple cascade cyclizations and the Stork-Eschenmosher steroid-type cyclizations: Stork and Burgstahler J. Am. Chem. Soc. 1955, 77, 5068. Eschenmoser, Ruzicka, Jeger, and Arigoni Helv. Chim. Acta 1955, 38, 1890. First disclosed in lectures and proposals as early as 1950, but experimental verification was difficult. - A clear verification of Stork–Eschenmoser hypothesis: Johnson J. Am. Chem. Soc. 1964, 86, 1959. J. Am. Chem. Soc. 1964, 86, 2085. trans only OH HCO2H 12% Only bicyclic products isolated or generated H ONs cis only OH HCO2H 16% ONs 5. Three Stages of Reaction - Initiation - Cyclization and Propagation - Termination - Mechanistically all three may take place simultaneously or stepwise paths may be involved. - Depends on the nature of the substrate and the reaction medium. - Without careful control, the formation of many products will result in a complex mixture. - For example: Johnson verification of Stork–Eschenmoser hypothesis. ONs HCO2H NaOH HCO2Na H2O 75 °C, 1 h H2O to hydrolyze the formates OH 51.2% HO 13.5% OH H 6.7% OH 3.3% 5.4% H 2.9% OH H OH 2.2% 1.6% total trans = 12% total cis = 0% - Much effort expended to control the reaction through mild, selective and efficient initiation and termination. 295 Modern Organic Chemistry The Scripps Research Institute A. Initiation - Alkenes O O 75% H2SO4 OH 25 °C, 25 min 66% β-Ionone Vitamin A Isler Helv. Chim. Acta 1949, 32, 489. used in perfumes - Alcohols and Derivatives HO OCHO HCO2H 25 °C, 5 min Johnson J. Am. Chem. Soc. 1964, 86, 1972. tertiary allylic alcohols have been extensively used - Epoxides OAc OAc 85:15 β:α BF3•OEt2 C6H6 HO H O van Tamelen J. Am. Chem. Soc. 1963, 85, 3295. - Aldehydes and Ketones OH MeAlCl2 CHO CH2Cl2 0 °C, 24 h 76% Snider J. Am. Chem. Soc. 1980, 102, 7951. - Aldehyde or Ketone Derivatives SnCl4 O O O C6H6 25 °C, 5 min O H N HCO2H OEt O N 25 °C, 18 h 100% OCHO OH Johnson J. Am. Chem. Soc. 1968, 90, 5277; 1974, 96, 3979. TsOH MeO Speckamp Tetrahedron Lett. 1975, 4047. MeO 25 °C, CH3CN MeS SMe Me SMe Trost J. Am. Chem. Soc. 1979, 101, 257. - Carboxylic Acids and Derivatives AlCl3 COCl O Cl 74% Kemp J. Chem. Soc., Chem. Commun. 1973, 84. 296 O O SR SeR also extensively studied Key Ring Forming Reactions Dale L. Boger - Ketene Acetals and Thioacetals CF3 O CH3SO3H S S S heptane CF3CH2OH 0 °C, 15 min H S Andersen, Yamamoto Tetrahedron Lett. 1975, 4547. - α,β-Unsaturated Ketones, Esters,...... OAc HClO4 HOAc−Ac2O 25 °C, 1.5 h O OAc 50% Harding Tetrahedron Lett. 1977, 3321. B. Cyclization and Propagation a. Alkenes 5-exo 6-endo 6-exo 7-endo 4-exo 5-endo In the absence of olefin substituent directing effects: • 5-endo >> 4-exo, the latter violates Baldwin's rules • 6-endo > 5-exo • 6-exo > 7-endo b. Alkynes R 5-exo 6-endo R = alkyl R = H, R3Si R but can further rearrange to 6-endo product 6-exo R R 7-endo R = alkyl R=H R 297 Modern Organic Chemistry The Scripps Research Institute c. Allenes R 5-exo 6-endo R = alkyl R=H R C. Termination - Alkenes and Arenes Elimination of H+ reintroduces double bond or aromatic system. Can result in complex mixture of products. SnCl4 O C6H6 25 °C O O + H O OH 84% + H OH O 6% OH Allylsilanes can be enlisted to direct the termination. X− SiMe3 E+ E SiMe3 E SiMe3 MeO OMe OMe Fleming J. Chem. Soc., Chem. Commun. 1976, 182. SiMe3 SnCl4 O O pentane 0−15 °C, 34% H O H H OH Johnson J. Am. Chem. Soc. 1983, 105, 6653. Substitution on alkene can also alter regioselectivity (5-exo vs 6-endo) - Substituted Alkenes X X Allows regiocontrol, but need to select substituents that avoid complications with initiation. 298 H 4% Key Ring Forming Reactions Dale L. Boger Vinyl chlorides and fluorides OH HCO2H Cl 40% CO2H Cl Landsbury Acc. Chem. Res. 1972, 5, 311. OBs CH3CN Et3N, ∆ O OMe Felkin J. Chem. Soc., Chem. Commun. 1968, 60. - Acetylenes R Cl R = Me TiCl4 CH2Cl2 94% OH O R=H TiCl4 O Cl CH2Cl2 60% O O OH Sutherland J. Chem. Soc., Chem. Commun. 1978, 526. - Allenes see: Harding J. Am. Chem. Soc. 1978, 100, 993. - Organostannanes O SnBu3 TiCl4 TiCl4 CH2Cl2, 25 °C 72% OH O 82% SnBu3 Macdonald J. Am. Chem. Soc. 1980, 102, 2113; 1981, 103, 6767. 6. Synthesis of Estrone SnCl4 H OH H MeO 1. TsNCl2 H2O−DME MeO O O BF3•OEt2 H H MeO 2. Me4NOH H H H H H MeO Bartlett and Johnson J. Am. Chem. Soc. 1973, 95, 7501. 299 Modern Organic Chemistry The Scripps Research Institute 7. Synthesis of Progesterone Johnson J. Am. Chem. Soc. 1971, 93, 4332. J. Am. Chem. Soc. 1978, 100, 4274. O O CF3CO2H O 0 °C, 2 h O O O HO - Tertiary allylic alcohol for initiation - Substituted alkyne for termination - 5-exo-dig vs. 6-endo-dig H H Efficient trap of vinyl cation 10% aq. K2CO3 CH3OH, 70% CF3CO2H, pentane, ClCH2CH2Cl 1 h, 0 °C, 78% O OCOCF3 H Ring expansion via diketone and aldol 13% cis-α Me epimer H H H 1 1. O3, CH3OH–CH2Cl2, 2 min, –70 °C 2. Zn–HOAc, 1 h, 25 °C 3. KOH, CH3OH, 20 h, 25 °C 1. O3, CH3OH–CH2Cl2, 0.5 h, –70 °C 2. Zn–HOAc, 1 h, 25 °C, 84% (2 steps) 3. KOH, CH3OH, 20 h, 25 °C, 70% O O 49% overall H H H O (± )-4-Androstene-3,17-dione H O ( ± )-Progesterone O F O but also gave H 10% Johnson J. Am. Chem. Soc. 1980, 102, 7800. gave 78% 1 and only 3.5% cis-α Me epimer - More recent efforts have reduced this to the synthesis of optically active agents. - How would you imagine doing this? - Remember chair-like transition states for the cyclization. 300 H Key Ring Forming Reactions Dale L. Boger 8. Enantioselective Synthesis of 11-Hydroxyprogesterone enantioselective ketone reduction O H HO O HO TFA 50% HO H HO 13 H H H H + 20% 13α isomer Johnson J. Am. Chem. Soc. 1977, 99, 8341. H O I. Free Radical Cyclizations 1. Reviews Acyloin Condensation: Bloomfield, J. J.; Owsley, D. C.; Nelke, J. M. Org. React. 1976, 23, 259. McMurry Coupling: McMurry, J. E. Acc. Chem. Res. 1983, 16, 405. Julia Free Radical Cyclization: Julia, M. Acc. Chem. Res. 1971, 4, 386. Pure App. Chem. 1967, 15, 167. - General Reviews Beckwith, A. L. J.; Ingold, K. U. Rearrangements in Ground State and Excited States, Vol. 1; de Mayo, P., Ed.; Academic: NY, 1980, pp 182–220. Beckwith, A. L. J. Tetrahedron 1981, 37, 3073. (Regioselectivity of ring cyclization) Giese, B. Radicals in Organic Synthesis: Formation of Carbon–Carbon Bonds, Pergamon: Oxford, 1986. Symposium-in-print: Tetrahedron 1985, 41, no. 19. Curran, D. P. Synthesis 1988, 417 and 489. Hart, D. J. Science 1984, 223, 883. Ramaiah, M. Tetrahedron 1987, 43, 3541. Comprehensive Org. Syn., Vol. 4, Chapter 4.1 and 4.2, pp 715–831. Laird, E. R.; Jorgensen, W. L. J. Org. Chem. 1990, 55, 9. Giese, B. Org. React. 1996, 48, pp 301–856. 2. Reductive Coupling of Carbonyl Compounds a. Acyloin Condensation CO2CH3 CO2CH3 toluene 57% OH Sheehan J. Am. Chem. Soc. 1950, 72, 3376. - Mechanism O 2e O Na • • O OCH3 O radical coupling O 2e O O OCH3 - Alternative O e OCH3 • CO2CH3 • e OCH3 O • OCH3 • • OCH3 O O OCH3 O OCH3 O O O O O O 2e O O First report: Freund Justus Liebigs Ann. Chem. 1861, 118, 33. Macrocyclization: Finley Chem. Rev. 1964, 64, 573. Review: Comprehensive Org. Syn. Vol. 3, 613. 301 Modern Organic Chemistry The Scripps Research Institute b. Rühlmann Modification with Me3SiCl CO2CH3 OSi(CH3)3 Na–K Et2O, Me3SiCl OSi(CH3)3 CO2CH3 Bloomfield Tetrahedron Lett. 1968, 591. Ruhlmann Synthesis 1971, 236. 3. Reductive Coupling of Ketones and Aldehydes (Pinacol Coupling and McMurry Reaction) - Low valent Ti reagents used to generate ketyl radicals and chosen to permit generation of either the pinacol or olefin product. n OH Ti CHO CHO n CHO CHO n OH Mg–Hg OH TiCl4 THF 32% OH Corey, Danheiser J. Org. Chem. 1976, 41, 260. Mg–Hg O OH TiCl4 THF 43% OH O Zn–Cu O TiCl3 DME 79% O McMurry J. Org. Chem. 1977, 42, 2655. LiAlH4 O CO2Et TiCl3 DME 80% OEt McMurry J. Am. Chem. Soc. 1983, 105, 1660. CHO O O H CH3O O Zn–Ag TiCl3 DME H CH3O Estrone Synthesis: Ziegler J. Org. Chem. 1982, 47, 5229. 302 Key Ring Forming Reactions Dale L. Boger - Other Functional Groups: Corey Tetrahedron Lett. 1983, 24, 2821. O Zn OH (CH3)SiCl 77% CO2CH3 CO2CH3 OH O O CN CO2CH3 83% CO2CH3 OH NHOCH3 O NOCH3 84% CO2CH3 CO2CH3 4. SmI2 Promoted Reductive Coupling Reactions (Radical Mechanisms) - Lanthanide chemistry reviews Molander Chem. Rev. 1992, 92, 29. Molander in Chemistry of the Carbon Metal Bond, Hartley, F. R.; Patai, S., Eds.; Wiley: NY, 1989, Vol. 5. Molander in Comprehensive Org. Syn., Vol. 1, 262. Kagan New. J. Chem. 1990, 14, 453. Kagan Tetrahedron 1986, 42, 6573. Soderquist Aldrichim. Acta 1991, 24, 15. a. Ketyl–Olefin Coupling Reactions - Intermolecular (Only effective for activated olefins) 2 SmI2 Ph CHO CO2CH3 Ph O O THF–HMPA 1.5 equiv iPrOH 78% e–, H+ –OCH3 SmI2 O Ph (III)Sm Sm(III) • H O • CO2CH3 Ph CO2CH3 Inanaga Tetrahedron Lett. 1986, 27, 5763. Tetrahedron Lett. 1989, 30, 2837. O Ph 2 SmI2 Si(CH3)3 THF–HMPA tBuOH 93% OH Ph Si(CH3)3 303 Modern Organic Chemistry The Scripps Research Institute - Intramolecular O O HO R 2 SmI2 R Y R' COY R' THF–MeOH 60–80% Molander Tetrahedron Lett. 1987, 28, 4367. CO2Et J. Am. Chem. Soc. 1989, 111, 8236. R' J. Org. Chem. 1991, 56, 1439. Y = OR", NR2" O HO R O 2 SmI2 R R' EtO2C OEt THF–MeOH 90% J. Org. Chem. 1993, 58, 7216. CO2Et OH O O HO 2 SmI2 O J. Org. Chem. 1994, 59, 3186. O THF–acetone 85% Sm(III) 2 e– O O O (III)Sm H+ O O OH 1. 2 SmI2 THF–HMPA O O 2. (PhSe)2 81% O 1. 4 SmI2 THF–HMPA O I SePh OEt HO + 2. H 61% H+ 2 e– 2 e– O O I2Sm OEt OH CHO 2 SmI2 TBSO CO2CH3 O O TBSO CO2CH3 73% O Enholm J. Am. Chem. Soc. 1989, 111, 6463. 304 O Key Ring Forming Reactions Dale L. Boger CHO O OH H SmI2 ( ± )-Coriolin O THF–HMPA O H 91% O Curran J. Am. Chem. Soc. 1988, 110, 5064. O 8-endo 2 SmI2 OH THF–HMPA 81% OAc Molander J. Org. Chem. 1994, 59, 3186. - Imminium ion generated in situ 2 SmI2 CH3CN ClO4– N N H Ph Martin Tetrahedron Lett. 1988, 29, 6685. Ph - Hydrazone (5-exo hydrazone >> 5-exo alkene; 6-exo hydrazone > 5-exo alkene) Ph2N H N O Ph2N SmI2 THF–HMPA n e– Ph2N N H O n n NH OH N NPh2 H OH n = 1: 72% : 0% n = 2: 4.2 : 1 Sm(III) • Fallis J. Am. Chem. Soc. 1994, 116, 7447. J. Org. Chem. 1994, 59, 6514. - Fragmentation–cyclization O O SmI2 THF–HMPA MeOH TMS 79% TMS e– O 5-exo-dig Sm(III) (III)Sm TMS O • • TMS Motherwall Tetrahedron Lett. 1991, 32, 6649. 305 Modern Organic Chemistry The Scripps Research Institute b. Alkyl/Aryl Radical Cyclizations Br OAc 2 SmI2 CH3CN HMPA–tBuOH 61% Inanaga Tetrahedron Lett. 1991, 32, 1737. O O Br O O SmI2 THF HMPA–tBuOH 31% Br SmI2 THF HMPA–tBuOH 88% N Ac N Ac OH 2 SmI2 O O I THF–HMPA 57% O Molander J. Org. Chem. 1990, 55, 6171. I O HO O 2 SmI2 THF–HMPA 81% O Curran Synlett 1990, 773. c. Pinacol-type Coupling Reactions - Intermolecular O 1. 2 SmI2 2 R R' aldehydes or ketones 2. H3O+ 80–95% HO R' R R' R OH Kagan Tetrahedron Lett. 1983, 24, 765. - Intramolecular O iPr OHC O 2 SmI2 OEt THF–tBuOH 73% HO iPr HO Molander J. Org. Chem. 1988, 53, 2132. 306 CO2CH3 >200 : 1 Key Ring Forming Reactions Dale L. Boger O O O O 2 SmI2 N O THF–tBuOH 52% CHO O N O Molander J. Org. Chem. 1988, 53, 2132. O O HO 2 SmI2 OEt THF–tBuOH O 45% NC Molander J. Org. Chem. 1988, 53, 2132. CO2CH3 COCH3 OH OH CO2Et >200 : 1 CO2CH3 2 SmI2 81% 92% de TBDPSO OH CHO OH Hanessian Tetrahedron Lett. 1991, 32, 1125. OTBDPS OTBDPS OH O O CHO 2 SmI2 CHO THF–tBuOH O O OH 86% OTBDPS OTBDPS 92 : 8 Chiara Tetrahedron Lett. 1994, 35, 2969. TBDPSO OTBDPS OH O O OH OTBDPS - A recent total synthesis of (–)-Grayanotoxin III incorporated two ketyl–olefin cyclization reactions and a pinacol coupling reaction (SmI2-promoted). - Shirahama J. Org. Chem. 1994, 59, 5532. H OH HO HO OH OH OH (–)-Grayanotoxin III CHO 2 SmI2 O O OH SPh O THF–HMPA 86% OMOM OH O OH TBSO MOMO 2 SmI2 THF–HMPA, 78% O H OMOM H HO TBSO O OHC OMOM OMOM HO MOMO MOMO SmI2 THF–HMPA, 54% H OMOM OH H HO HO OMOM HO OH MOMO OH HO OH OH 307 Modern Organic Chemistry The Scripps Research Institute 5. Radical–Olefin Cyclizations a. Representative Examples - Concurrent with Johnson's investigation of cation–olefin cyclizations, Julia initiated radical–olefin cyclization studies. CH3O2C NC CH3O2C BzOOBz NC cyclohexane ∆ 57% Julia Compt. rend. 1960, 251, 1030. CH3O2C Reversible, thermodynamically controlled reactions. CH3O2C NC 6-endo-trig NC 88% b. Reactivity and Regioselectivity PO(OEt)2 : typical electron-deficient olefin. - Relative rates of addition to CH3• krel = CH3CH2• 1 CH3OCH2• 1 (CH3)2CH• 2.7 (CH3)3C• 4.8 24 - Alkyl radicals are regarded as nucleophilic. Steric Effects on Addition Regioselectivity olefin krel % addition to: Ca Cb >95 <5 1.16 >95 <5 18.4 >95 <5 2 × 136 50 50 2 × 0.50 50 50 2 × 0.63 >95 5 15 <5 >95 13.9 a b a b a b a b a b a b a b CO2CH3 C6H11• R krel R=H R = tBu CO2CH3 tBu 308 H 1 0.24 5 × 10–5 β-substitution strongly decelerates intermolecular addition with activated acceptors Key Ring Forming Reactions Dale L. Boger I CN Nucleophilic radical • 1.0 95% Electrophilic acceptor alkene Bu krel CN Bu3SnH Cl Ph 8.4 CO2CH3 84 CHO 3000 8500 Note the substantial effect of two geminal vs vicinal electron-withdrawing groups • CO2CH3 CO2CH3 CO2CH3 krel CO2CH3 CH3O2C 150 (450000) 1.0 (3000) CO2CH3 5 (15000) 0.01 (30) ( ), relative to Bu Note the substantial deceleration of the reaction rate by β-substitution (100×) EtO2C Cl OtBu EtO2C Electrophilic radical EtO2C OtBu EtO2C Bu3SnH 60% CO2Et Nucleophilic acceptor alkene Ph Ph Ph • N EtO2C CO2CH3 O krel 23 3.5 1 309 Modern Organic Chemistry The Scripps Research Institute c. Cyclization Rates, Regioselectivity, and Diastereoselectivity 1° • < 2° Stability • • but 5-exo > 6-endo 98% 2% Beckwith J. Chem. Soc., Chem. Commun. 1974, 472. Beckwith J. Chem. Soc., Chem. Commun. 1980, 484. • • • 6-exo > 7-endo 90% 10% - Chair-like transition state subject to stereoelectronic and kinetic control rather than thermodynamic control. • 5-exo Stereochemical features of substitution can be rationalized and predicted based on these models. • 6-exo • • krel exo • • • • • krel endo Product ratio 1.0 0.02 (98 : 2) 1.4 0.02 (99 : 1) 2.4 <0.01 (>200:1) 0.022 0.04 (36 : 64) endo predominates 0.16 <0.002 exo >> endo (>80:1) - Linker chain effects kexo/kendo • X X = CH2 X=O R 310 endo > exo exo >> endo krel • R 0.55 38.6 R=H R = CH3 1 10 gem dimethyl effect Key Ring Forming Reactions Dale L. Boger k ring size • n=1 n=2 n=3 n krel ~105 5 6 7 s-1 1 0.1 0.001 ~104 s-1 ~102 s-1 exo >> endo 7-membered ring closure so slow that reduction competes. - Stabilized radicals participate in reversible cyclizations and the thermodynamic product is observed. CO2Et • CO2Et CO2Et • CO2Et CO2Et • CO2Et 3:2 • only NC • CO2Et CO2Et NC - Alkynyl radicals give 5-exo closure (stereoelectronic) even with stabilized radicals. R R CN • • CN CO2Et CO2Et - Note effect of additional sp2 centers in the linking chain: 5-exo closure takes precedence over the overall 1° vs 3° stability of the resulting free radical. • • • not O O O • • O O more stable 1° vs stabilized 2° not • O more stable - Closure onto carbonyls possible OH CHO Ph 6-exo HCO > 5-exo C=C • Ph - Macrocyclizations are very facile O O O O n n • - Requires unsubstituted and activated acceptor alkene to compete with reduction. Porter J. Am. Chem. Soc. 1987, 109, 4976. 311 Modern Organic Chemistry The Scripps Research Institute d. Initiator Groups S R OH R O R X X = SR, OR, SeR Bu3Sn• R X SnBu3 S Bu3Sn• R• O • X Barton deoxygenation reaction R• Bu3SnX X = Br, I Bu3Sn• R SePh Bu3SnSePh R• Bu3Sn• R N O OSnBu3 R• • R NO2 Bu3Sn• R SO2R R• Hg(OAc)2 HgOAc NHCBZ NaBH(OR)3 N CBZ N CBZ • - Different Initiators M–H Bond strength (kcal/mol) 74 nBu Sn 3 weakest 79 (Me3Si)3Si H H Special reagent that increases reactivity of Si–H so it may be used effectively in synthesis. 84 90 n < Sn-H H Bu3Ge Et3Si < Ge-H More competitive reduction by H• abstraction from reagent Giese Tetrahedron Lett. 1989, 30, 681. Ingold Int. J. Chem. Kinet. 1969, 7, 315. - Initiation Conditions In situ generation of Bu3SnH (catalytic amount of Sn) (Bu3Sn)2O + Me Si O n H Bu3SnH PMSH (polymethylsiloxane), readily avaible Green J. Org. Chem. 1967, 32, 882. e. Rearrangements are possible • • • • O O• R • • O 312 Ph R=H R = Ph Si-H H Key Ring Forming Reactions Dale L. Boger f. Functionalized Free Radicals Stork, vinyl radicals • Br SPh • N Me N Me Hart J. Am. Chem. Soc. 1997, 119, 6226. O O O O O SePh O • O O N SePh N • Keck Synlett 1999, 1657. review: Chatgilialoglu, Crich, Ryu Chem. Rev. 1999, 99, 1991. Boger, acyl radicals J. Org. Chem. 1988, 53, 3377. Intramolecular J. Org. Chem. 1989, 54, 1777. Intermolecular J. Am. Chem. Soc. 1990, 112, 4003. Tandem cyclization O O J. Am. Chem. Soc. 1990, 112, 4008. Macrocyclization J. Org. Chem. 1990, 55, 5442. Ring expansion J. Org. Chem. 1992, 57, 1429. Full description Israel J. Chem. 1997, 37, 119. Review - Examples Bu3SnH COX X = SePh, 84% X = SPh, 0% X = Cl, 59% COSePh O 86% O COSePh 69% O H COSePh 82% O O COSePh X n X=H X = CO2CH3 X n n=0 81% ring size 5 n=1 76% 6 n=2 74% 7 n=0 88% 5 n=1 84% 6 n=2 92% 7 313 Modern Organic Chemistry The Scripps Research Institute COSePh CO2CH3 O n n n=0 83% ring size 6 n=1 71% 7 CO2CH3 O COSePh 58% Note: Alkyl and vinyl radicals are subject to faster reduction. Cyclizations such as the above example or those for the formation of 7-membered rings are not very successful, but acyl radicals are much more stable and not subject to competitive reduction. O R H Strong CH bond R Weak CH bond H - Tandem Cyclizations Ph PhSe X O O O3 X = CHPh X=O O3 X = CHPh X=O O3 X = CHPh X=O 77% H > 98% cis Ph X O 72% H O > 97% cis PhSe X Ph O 82% H O 6 : 4 cis : trans PhSe - Cyclization–Addition Reactions Bu3SnH O SePh CO2CH3 O 63% CO2CH3 314 Key Ring Forming Reactions Dale L. Boger - Addition–Cyclization Reactions CO2CH3 O CO2CH3 SePh CO2CH3 2.4 : 1 diastereomers 61% Ph O CO2CH3 SePh O O Bu3SnH CO2CH3 Ph 71% Ph CO2CH3 - Macrocyclization Reactions O O n SePh O O activated, unsubstituted acceptor alkene - decarbonylation very slow - reduction very slow - macrocyclization proceeds exceptionally well O n ring size n = 15 20 O 57% n = 11 16 68% n=9 14 55% n=7 12 46% n=6 11 47% - Macrocyclization onto activated acceptor is faster than 6-exo, 7-exo or 6-endo closure. - Competitive with 5-exo closure. O O O O R = H, 30% R R = CH3, 74% R O O SePh - Rearrangement/Ring Enlargement Cyclization O Br Bu3SnH O O H H O3 Ph O Ph 5-exo-dig cyclization O O• • O H • Ph More stable 3° radical 315 Modern Organic Chemistry The Scripps Research Institute - Applications N N SEM N COSePh SEM OMe O O HN Hong, Boger J. Am. Chem. Soc. 2001, 123, 8515. Cl ent-(−)-Roseophilin Remarkabley, ent-(−)-roseophilin was found to be 10-fold more potent than the natural enantiomer in cytotoxic assays. To our knowledge, this is the first example of an unnatural enantiomer of a naturally occurring antitumor agent diaplaying more potent activity although In vitro cytotoxic activity Table. several instances of comparable activity have been disclosed. IC50 (µM) (+)- and ent-(−)-CC-1065: compound Kelly J. Am. Chem. Soc. 1987, 109, 6837. L1210 CCRF-CEM Boger and Coleman J. Am. Chem. Soc. 1988, 110, 4796. ent-(−)-roseophilin 0.02 0.1 Natural and ent-fredericamycin A nat-(+)-roseophilin 0.2 1.5 Boger J. Am. Chem. Soc. 1995, 117, 11839. Natural and ent-mitomycin C Fukuyama and Tomasz J. Am. Chem. Soc. 1995, 117, 9388. g. A case study comparison of cyclization approaches H Br N N H SO2Ph 77% 5-exo-dig OBn N Bu3SnH N H SO2Ph BH3•THF H2O2 OBn OH N N N N H OBn N SO2Ph N H O O N H O OH N H OBn (+)-CC-1065 Boger and Coleman J. Am. Chem. Soc. 1988, 110, 1321. J. Am. Chem. Soc. 1988, 110, 4796. - A useful comparison series employed in the preparation of analogs of CC-1065 and the duocarmycins (Boger) 316 O OH OBn NH2 Key Ring Forming Reactions Dale L. Boger OH H 5-exo-dig Br NBOC NBOC 1. Bu3SnH 2. BH3•THF OBn 60% overall OBn J. Am. Chem. Soc. 1989, 111, 6461. J. Org. Chem. 1989, 54, 1238. 1. NaIO4, OsO4 J. Am. Chem. Soc. 1990, 112, 5230. 2. NaBH4 SPh Br NBOC NBOC Bu3SnH, 75% self terminating 5-exo-trig cyclization OBn OBn J. Org. Chem. 1990, 55, 5823. OTHP OTHP Br NBOC NBOC Bu3SnH 97% OBn OBn J. Org. Chem. 1992, 57, 2873. O N I NBOC NBOC Bu3SnH TEMPO 97% OBn OBn J. Org. Chem. 1995, 60, 1271. THPO THPO BnO OBn Br NBOC NBOC Bu3SnH 5-exo-trig cyclization OBn OBn J. Am. Chem. Soc. 1992, 114, 9318. Cl Cl I NBOC NBOC Bu3SnH 90% OBn OBn Tetrahedron Lett. 1998, 39, 2227. 317 Modern Organic Chemistry The Scripps Research Institute h. Further Notable Examples CO2CH3 O HgClOAc CO2CH3 O HgCl C5H11 OOH C5H11 O Bu3SnH CO2CH3 O H O2 Biomimetic approach to PGG2 and PGH2 HOO C5H11 Corey Tetrahedron Lett. 1984, 25, 5013. For a more successful alternative see Corey Tetrahedron Lett. 1994, 35, 539. CO2CH3 CO2CH3 H CO2CH3 ∆ • N • N H diyl Hirsutene synthesis Little J. Am. Chem. Soc. 1981, 103, 2744. i. Selected Notable Free Radical Reactions Barton Nitrite Photolysis O HO OAc HON HO 1) NOCl H H H O H H 2) hν H H H 21% O O OAc O O ONO H H H HO H H O • NO H H H OAc HO O N H H H H H H Barton J. Am. Chem. Soc. 1960, 82, 2640. This process was used to produce 60 g of aldosterone at a time the world supply was in mg quantities. The aldosterone synthesis ("a good problem") was achieved in 1961 by J. M. Beaton ("a good experimentalist") through a nitrite photolysis ("a good idea"), quotes from D. H. R. Barton, 1991 ACS autobiography. Barton J. Chem. Soc., Chem. Commun. 1983, 939. Barton Decarboxylation S NaON CH3(CH2)14COCl 318 S O CH3(CH2)14CO N S S PhSSPh CH3(CH2)14SPh 74% ∆ Barton Tetrahedron Lett. 1984, 25, 5777. Key Ring Forming Reactions Dale L. Boger S COCl O N OH S O N Br BrCCl3 75% AIBN 130 °C Barton Tetrahedron Lett. 1985, 26, 5939. Barton−McCombie Deoxygenation O O O O S NaH, CS2 OH O O O MeI O O Bu3SnH SMe O Br2 Br• −Br• O Br −CO2 O R CO2H HgO O Hunsdiecker, H.; Hunsdiecker, C. Ber. 1942, 75, 291. R• O• Br Br2 HO2C O R Br O R ∆ Barton, McCombie J. Chem. Soc., Perkin 1 1975, 1574. Hunsdiecker Reaction R CO2Ag O tBuLi Wiberg Acc. Chem. Res. 1984, 17, 379. Br Kochi Reaction Pb(OAc)4 RCO2H Kochi J. Org. Chem. 1965, 30, 3265. Org. React. 1972, 19, 279. RCl LiCl Bergman Cyclization H-atom abstraction enediyne Bergman J. Am. Chem. Soc. 1972, 94, 660. Acc. Chem. Res. 1973, 6, 25. Calicheamicin and esperamicin derive their biological properties through DNA binding and trisulfide cleavage which initiates a reaction cascade which culminates in a Bergman cyclization which results in DNA H-atom abstraction and DNA cleavage. Ellestad J. Am. Chem. Soc. 1987, 109, 3466. Nicolaou Angew. Chem., Int. Ed. Eng. 1991, 30, 1387. R HO MeSSS O OMe calicheamicin R = OH esperamicin R = MeO NHCO2Me H OSugar O O HO Me NH MeO O O 319 Modern Organic Chemistry The Scripps Research Institute R R O HO O HO NHCO2Me MeSS S NHCO2Me Bergman cyclization S Nu− OSugar OSugar R O NHCO2Me HO R DNA HO DNA cleavage S O NHCO2Me S OSugar OSugar Myers Cyclization H-atom abstraction Myers J. Am. Chem. Soc. 1988, 110, 7212; 1992, 114, 9369. Neocarzinostatin is activated for DNA cleavage by thiol addition generating the reactive enyne allene. O O O O HO O O Me O MeO MeHN O Me HO OH neocarzinostatin chromophore R' R' + OH MeO2CCH2SH RO Myers cyclization RO O O MeHN O Me O MeHN HO OH RO R' OH MeO2CH2CS DNA O MeHN Me HO OH R' OH MeO2CH2CS RO O O Me HO OH 320 OH MeO2CH2CS DNA cleavage MeHN O Me HO OH Key Ring Forming Reactions Dale L. Boger J. Anionic Cyclizations Li Li stable at –78 °C t1/2 = 5.5 min at 25 °C Bailey J. Am. Chem. Soc. 1992, 114, 8053. J. Am. Chem. Soc. 1991, 113, 5720. J. Am. Chem. Soc. 1987, 109, 2442. Intramolecular carbometalation, review: Comprehensive Org. Syn., Vol. 4, 871. 1. tBuLi I 2. E+ E 63–91% tandem I cyclizations E 65–90% H tandem E cyclizations I H 65–87% Stereochemistry and comparison with radical cyclizations: Cooke J. Org. Chem. 1992, 57, 1495. Br N R 1) 2.2 equiv tBuLi 2) (−)-sparteine 3) E+ (H+) 60−90% ee E N R R = CH2CH=CH2 R = CH3 R = Bn Bailey J. Am. Chem. Soc. 2000, 122, 6787. Groth J. Am. Chem. Soc. 2000, 122, 6789. Funk J. Am. Chem. Soc. 1993, 115, 7023. OR 120° 5-endo-dig cyclization SO2Ph line of attack OEt OEt SO2Ph R SO2Ph OEt Li SO2Ph OEt OEt Li RX SO2Ph SO2Ph Li Synthetic aspects of magnesium (Grignard) carbometalation have been studied in detail. For a review see: Oppolzer Angew. Chem., Int. Ed. Eng. 1989, 28, 38. 321 Modern Organic Chemistry The Scripps Research Institute 1) Mg powder 2) 60 °C, 23 h Li 1) OH Cl 3) O 2) SOCl2, 25 °C O H 57% 76% SOCl2 Et2O H 1) Mg powder 2) 25 °C, 20 h * H H H ∆9(12)Capnellene 72% OH 3) O2 * H Cl 70% (3 : 2) Oppolzer Tetrahedron Lett. 1982, 23, 4669. K. 1,3-Dipolar Cycloadditions Review: 1,3-Dipolar Cycloaddition Chemistry, Padwa, A., Ed., Wiley: New York, 1984. - 2πs + 4πs Cycloaddition - Subject to FMO control: can predict regioselectivity and reactivity. - FMO Control: (a) Reactivity: ∆E (HOMO/LUMO) and the reactivity of the system is related to the magnitude of the smallest energy gap of the pair of HOMO–LUMO combinations. (b) Regioselectivity: depends on the magnitude of the orbital coefficients and is determined by the orbital coefficients on the predominant HOMO–LUMO interaction. The largest coefficient on the 1,3-dipole binds to the largest coefficient on the dipolarophile. (c) Diastereoselectivity: influenced by stabilizing secondary orbital interactions and subject to an endo effect. (d) Olefin geometry is maintained in the course of the cycloaddition reaction, they are concerted reactions. (e) No solvent effect on the reaction rate: concerted reactions. (f) No rearrangement products from postulated zwitterion or biradical. (g) Trans-1,2-disubstituted olefins react faster than cis-1,2-disubstituted olefins. Cis olefins are generally more reactive than trans olefins in ionic or radical addition reactions. 1. Azomethine Ylides Ar N + R R Ar N R' R R' R ∆ H RO2C Ar N + 322 R H N R' R R R H R' R''O2C R' ∆ Ar CO2R'' R''O2C R' H H + RO2C N Ar H 1,3-dipole Ar N R' R' CO2R'' Key Ring Forming Reactions Dale L. Boger 2. Azomethine Imines R' N R'' + N R H 3. Nitrones R' R N + N R + O Oxidation of hydroxylamine OH R'CHO R' HgO RNHOH - Symmetrical precursor or a precusor with one adjacent oxidizable center. X X R' R' R' N O R N R + O X + N O R X = Ph, CO2R, OEt X = NO2 - The regioselectivity depends on X and the substitution pattern of the nitrone. - Review: Confalone Org. React. 1988, 36, 1. 4. Diazoalkanes R' R R R N2 R=H R ∆ or hν N R N R' R − N2 R R' R N N + R R N N + 5. Azides Ph N N N CO2Me PhN3 25 °C 5 days, 77% Ph N N N PhN3 N R SEt O N3 OMe H H Ph OTMS Me N R N R = Ph, 49% Ph MeO − N2 N N N R R = Ph (160 °C) R = COPh (40 °C) BnO Ph N N N ∆ N CO2Me Ph OTMS OBn O 110 °C toluene MeO SEt O O Me N OMe N N OTMS OBn − N2 SEt O MeO O Me Fukuyama J. Am. Chem. Soc. 1989, 111, 8303. N OMe Mitomycins 323 Modern Organic Chemistry The Scripps Research Institute 6. Nitrile Oxides R R X N ∆ − HX N N O OH O N O X=H X = Cl, Br, I O RCH2NO2 N R O R N C O H R R CO2R N N O CO2R O 7. O3 / Carbonyl Oxides O O O 1,3-dipolar + O cycloaddition O primary ozonide O O O 1,3-dipolar cycloreversion 1,3-dipolar final ozonide O O O H + cycloaddition O O O O O 8. Nitrile Ylides Ar N Ar' Ar C N Ar' Ar N Et3N Ar' Ar N CN Ar' N Ar Ar' (–HCl) Cl CN ∆ or hν N Ar N Ar H H R' O –CO2 N O R' N R R R R 9. Carbonyl Ylides R R O R' O CO2R O C R' - problem: collapse of the carbonyl ylide to the epoxide 324 R R' CO2R Key Ring Forming Reactions Dale L. Boger 10. Methylene Cyclopropanone Ketals CN ∆ O O O O O O CN 4π three carbon 1,3-dipole Nakamura J. Am. Chem. Soc. 1989, 111, 7285. J. Am. Chem. Soc. 1991, 113, 3183. Key: reversible ring opening generation of the 4π component 11. Cyclopropenone Ketal (CPK) Diels–Alder/Dipolar Cycloadditions CO2CH3 H OR H OR OR OR H R OR O H OCH3 CO2CH3 OR O O O R OCH3 O OCH3 O OCH3 75 °C 75 °C O CH3O O CO2CH3 O CO2CH3 OCH3 RO2C Boger, Brotherton–Pleiss: Advances in Cycloaddition Chemistry, Vol. 2, JAI: Greenwich, 1990, 147. Boger: J. Am. Chem. Soc. 1995, 117, 12452. J. Org. Chem. 1994, 59, 3453. J. Org. Chem. 1988, 53, 3408. Org. Syn. 1987, 65, 98. J. Org. Chem. 1985, 50, 3425. J. Am. Chem. Soc. 1986, 108, 6695 and 6713. J. Am. Chem. Soc. 1984, 106, 805. Tetrahedron 1986, 42, 2777. Tetrahedron Lett. 1984, 25, 5611 and 5615. O OR H CO2CH3 OR CH3O2C R R H O CO2R O CO RO OR OR RO2C R CO2R OR OR R H O OR OR OR 325 Modern Organic Chemistry The Scripps Research Institute L. 1,3-Sigmatropic Rearrangement 1. Vinylcyclobutane rearrangement ∆ 350–600 °C Overberger J. Am. Chem. Soc 1960, 82, 1007. CH3 H3C KH, THF, ∆ NCH3 H 91% NCH3 H CH3 Bauld J. Am. Chem. Soc. 1988, 110, 8111. H3C O N nBu O 20 °C N 66% OH CO2Et OH 4NF, OH CO2Et O Sano Chem. Pharm. Bull. 1992, 40, 873. 2. Vinylcyclopropane rearrangement First report: Neureiter J. Org. Chem. 1959, 24, 2044. Review: Hudlicky Chem. Rev. 1989, 89, 165. 500–600 °C Org. React. 1985 33, 247. Mechanism: diradical concerted TMS 570 °C TMS 80% Paquette Tetrahedron Lett. 1982, 23, 263. R CO2Me R CO2Me Et2AlCl, CH2Cl2 RO 85−95% RO Davies Tetrahedron Lett. 1992, 33, 453. SPh toluene, 250 °C 94% MeO 326 hydrolysis SPh MeO Trost J. Am. Chem. Soc. 1976, 98, 248. 73% O MeO Key Ring Forming Reactions Dale L. Boger MeO AlMe3, Et2O, ∆ MeO2C MeO2C MeO2C OMe (–MeOH) 48% nPr Prn Prn Harvey Tetrahedron Lett. 1991, 32, 2871. O O O hν, benzene + H Wood, Smith J. Am. Chem. Soc. 1992, 114, 10075. 3. Carbonyl/Imine cyclopropane rearrangement OMe OMe OMe OMe aldimine hydrobromide 76% NMe NMe Stevens J. Am. Chem. Soc. 1968, 90, 5580. O O hν 100% N BOC N BOC Boger, Garbaccio J. Org. Chem. 1997, 62, 8875. Note: The di-π-methane rearrangement produces substrates that may be used in the vinylcyclopropane rearrangement. R R R R hν R R R R Zimmerman, Grunewald J. Am. Chem. Soc. 1966, 88, 183. Zimmerman Chem. Rev. 1973, 73, 531; 1996, 96, 3065. 327 Modern Organic Chemistry The Scripps Research Institute M. Electrocyclic Reactions Comprehensive Org. Syn., Vol. 5, 699. C8H17 Calciferol (Vitamin D) C8H17 C8H17 HO ∆, <100 °C 1,7 H-shift HO H C8H17 Lumisterol hν HO Ergosterol hν HO Precalciferol (Previtamin D) C8H17 C8H17 heat 100-200 °C H disrotatory ring closure HO 6π e– Havinga Tetrahedron 1960, 11, 276. Tetrahedron 1961, 12, 146. HO Isopyrocalciferol Pyrocalciferol Provided the impetus for the Woodward–Hoffmann rules Ph H Total Synthesis of Endiandric Acids H H CO2R CO2R H Ph 8π e– conrotatory closure 2πs + 4πs Diels–Alder reaction 6π e– disrotatory Ph CO2R closure H H CO2R Ph H Nicolaou J. Am. Chem. Soc. 1982, 104, 5555, 5557, 5558 and 5560. N. Nazarov Cyclization 4π e– Conrotatory electrocyclic ring closure Review: Santelli–Rouvier, C.; Santelli, M. Synthesis 1983, 4295. Nazarov Usp. Khim. 1949, 18, 377.; Usp. Khim. 1951, 20, 71. Denmark Org. React. 1994, 45, 1–158. Denmark Comprehensive Org. Syn., Vol. 5, pp 751–784. 328 Key Ring Forming Reactions Dale L. Boger OH+ O OH R1 R1 R2 R2 conrotatory R2 electrocyclic ring closure R1 R1 Woodward, Hoffmann Angew. Chem. 1969, 81, 797. R1 R2 –H+ O Nazarov Bull. Acad. Sci., USSR 1946, 633. J. Gen. Chim., USSR 1950, 20, 2009, 2079, 2091. O OH 4π e– H+ OH R2 R1 O R2 O HCO2H 70% H3PO4 90 °C, 7 h Nazarov Chem. Abstr. 1948, 42, 7731a, 7731h, 7732g, 7733e, 7734a, 7734. O O H3PO4 Me Braude J. Chem. Soc. 1953, 2202. Me - Silicon-directed Nazarov cyclization. OH O O FeCl3 95% CH2Cl2 via: TMS TMS Cl– Denmark J. Am. Chem. Soc. 1982, 104, 2642. O under usual Nazarov conditions: isomerization to CN O Li O O 1. Br2 + PPA 100 °C 62% 2. LiBr, Li2CO3 Eaton J. Org. Chem. 1976, 41, 2238. - Extensions to annulation procedures. O OLi OH O OH H2SO4 Li 70% 88% Raphael J. Chem. Soc. 1953, 2247. J. Chem. Soc., Perkin Trans. 1 1976, 410. 329 Modern Organic Chemistry The Scripps Research Institute - Stereochemical course of the reaction: via Nazarov cyclization. OH O OH O O + conrotatory 4π e– electrocyclization 67% 10% Hiyama J. Am. Chem. Soc. 1979, 101, 1599. Bull. Chem. Soc. Jpn. 1981, 54, 2747. - Lewis acid-catalyzed reactions. O O MeO2C O MeO2C MeO2C GaCl3 + MeO2C MeO2C Also: FeCl3 BF3•Et2O MeO2C H 49% 40% Tsuge Bull. Chem. Soc. Jpn. 1987, 60, 325. - Tin-directed Nazarov cyclization. O O Bu3Sn R BF3•Et2O R' 44–93% R R' Johnson Tetrahedron Lett. 1986, 27, 5947. O. Divinylcyclopropane Rearrangement Comprehensive Org. Syn., Vol. 5, 971. Org. React. 1992, 41, 1. (2σs + 2πs + 2πs) - Mechanism: H H H H H H boat-like transition state H ∆ H H - Synthesis of functionalized 7-membered rings: H silyl enol ether O O H MeO H O TMSCl, Et3N Et2O 100% OTMS MeO H O H 210 °C MeO benzene 96% Marino J. Org. Chem. 1981, 46, 1912. 330 O OTMS KF MeOH MeO O Key Ring Forming Reactions Dale L. Boger - Fused ring systems: α,β-unsaturated enone O Li OEt O 1. H n O 170–180 °C n 2. HCl, H2O benzene H n=1 n=2 Wender J. Org. Chem. 1976, 41, 3490. n=1 n=2 n n = 1, 72% n = 2, 74% P. Carbene Cycloaddition to Alkenes 1. Halocabenes Parman, Schweizer Org. React. 1963, 13, 55. Moss Acc. Chem. Res. 1989, 22, 15. Acc. Chem. Res. 1980, 13, 58. Kostikov, Molchanov, Khlebnikov Russ. Chem. Rev. 1989, 58, 654. 2πs + 2ωa CH2 cycloaddition Addition of a singlet carbene proceeds by a concerted process in a syn fashion. X X X X Triplet carbene behaves as a diradical. - Methods for generating halocarbenes: For a comprehensive list see: Kirmse Carbene Chemistry, 1971, 313. CHCl3 + KOtBu CCl2 BrCCl3 + nBuLi CCl2 CH2Cl2 + RLi CHCl N2CHBr CHBr Cl3CO2R + RO– PhHgCCl2Br CCl2 ∆ CCl2 - Reaction with alkenes: Br CBr2 H H H H reactivity of carbenes CH2 > CHCl > CCl2 > CBr2 > CF2 H H CBr2 H H Br Stereospecific Br Br Doering J. Am. Chem. Soc. 1956, 78, 5447. - Reaction with aromatic C=C bonds (cyclopropanation followed by rearrangement): Cl OMe CCl2 Cl OMe Cl O Parman, Schweizer J. Am. Chem. Soc. 1961, 83, 603. 331 Modern Organic Chemistry The Scripps Research Institute Cl H MeLi CH2Cl2 N H N Li Closs, Schwartz J. Org. Chem. 1961, 26, 2609. N 2. Simmons–Smith Reaction Simmons Org. React. 1973, 20, 1. Simmons, Smith J. Am. Chem. Soc. 1958, 80, 5323; 1959, 81, 4256. + CH2I2 + Zn(Cu) + ZnI2 + Cu - Mechanism: ZnI C I C ZnI C H2C C C H2 C CH2 + ZnI2 I C 1) concerted mechanism likely (above) 2) reaction is stereospecifically syn 3) alkenes with higher alkyl substitution react faster 4) electron donating substituents accelerate reaction i.e., enol ethers, enamines... - Addition can be directed by a hydroxyl group or ether functionality: OH CH2I2 Zn(Cu) OH H 60%, 100% cis H OMe CH2I2 Zn(Cu) OMe H 70%, 100% cis H Rickborn J. Am. Chem. Soc. 1968, 90, 6406. J. Org. Chem. 1972, 37, 738. - Examples: enone CO2Et MeO CH2I2 Zn(Cu) CO2Et MeO N N H H Shen Chem. Abstr. 1967, 67, 108559m. HO HO OMe HO OMe enol ether 91% Wenkert, Berges J. Am. Chem. Soc. 1967, 89, 2507. 332 O Key Ring Forming Reactions Dale L. Boger 3. Diazocarbene Addition and Rearrangement Review: Burke and Grieco Org. React. 1979, 26, 361. O O O N2 CH2N2 Cl Re Cu HCO2H Re ∆ Re Rz O H2O Rz z e R R OH Rz Li/NH3 OLi regioselective enolate generation Rz Re O O O Cu 1. NaH CO(OMe)2 O C6H6 O O O HCl H THF 2. NaBH4 N2 OH2+ MeO2C O HO2C O Deslongchamps Can. J. Chem. 1970, 48, 3273. Can. J. Chem. 1980, 58, 2460. Agarospirol HO OLi dianion alkylation O CO2Et Li O CO2Et + Et3N Cu N2 C5H11 Br C5H11 H OH PhS sulfoxide [2,3]-sigmatropic rearrangement used to install Nu– CO2R CO2R O CO2Et CO2H Nu– CO2R Toluene C5H11 O O PGA2 CO2Et TsN3 PhSH CO2Et C5H11 t C5H11 KO Bu H Taber J. Am. Chem. Soc. 1977, 99, 3513. homoconjugate addition vs. conjugate addition CO2R 333 Modern Organic Chemistry The Scripps Research Institute 4. Metal Carbene Cycloaddition Reactions Comprehensive Org. Syn., Vol. 5, 1065. E. O. Fischer received the 1973 Nobel Prize in Chemistry for his work in organometallic chemistry with transition metal complexes including metallocenes and his stabilized carbene complexes. - Three-membered ring [2 + 1] Bookhart, Studabaker Chem. Rev. 1987, 87, 411. Doyle Chem. Rev. 1986, 86, 919. Reaction works well for electron-rich, electron-poor and unactivated C=C bonds. (CO)5Cr (CO)5Cr OEt neat, 50 °C enol ether 100 atm CO 61% OMe + Ph Ph OMe Ph OMe + OEt (76 : 24) Ph OMe OMe + Ph CO2Me neat, 90 °C Ph OMe + CO2Me (29 : 71) 60% enone OEt CO2Me Fischer, Dötz Chem. Ber. 1972, 105, 3966. Chem. Ber. 1972, 105, 1356. - Four-membered rings [2 + 1 + 1] (CO)5Cr OMe + hν R1 R2 O R1 = H, R2 = OEt, 85% R1 = R2 = Me, 61% R1 = H, R2 = Ph, 30% OMe CH3CN R1 R2 hν (CO)5Cr OMe Hegedus J. Am. Chem. Soc. 1989, 111, 2335. O - Fischer carbene addition to alkynes typically leads to 6-membered ring , 4- and 5-membered rings form only under special circumstances. tBu (CO)5Cr OMe + Ph Cr leads to 6membered ring (CO)5W OMe + 65 °C O Ph OMe 4-membered ring formation is a result of the large tbutyl group. THF tBu CO2Et 93% Yamashita Tetrahedron Lett. 1986, 27, 3471. CO2Et Ph Ph Ph 100 °C Ph Ph toluene 90% OMe Foly J. Am. Chem. Soc. 1983, 105, 3064. O N required for 5-membered ring N (CO)5Cr Et Et 100 °C + Et DMF 96% Et N O Yamashita Tetrahedron Lett. 1986, 27, 5915. 334 Ph OMe Key Ring Forming Reactions Dale L. Boger - Six-membered rings [3 + 2 + 1] (Fischer carbene addition to alkynes) Dötz, Fischer Transition Metal Carbene Complexes, VCH: Deerfield Beach, FL, 1983. Dötz Angew. Chem., Int. Ed. Eng. 1984, 23, 587. Casey in Transition Metal Organometallics in Organic Synthesis, Academic Press: New York, 1976, Vol. 1. Dötz Pure Appl. Chem. 1983, 55, 1689. Casey in Reactive Intermediates, Wiley Interscience: New York, 1982, Vol. 2, and 1985, Vol. 3. Hegedus Principles and Applications of Organotransition Metal Chemistry, University Science Books: Mill Valley, CA, 1987, 783. Brown Prog. Inorg. Chem. 1980, 27, 1. Wulff in Advances in Metal-Organic Chemistry, JAI Press: Greenwich, CT, 1989, Vol. 1. - General scheme R2 R3 R1 OH RL L + M(CO)4 RS XR R2 or R3 = H R2 RL R2 R1 RS R1 OMe R3 O C RL RS XR - Most widely studied after cyclopropanation of Fischer carbenes. Extensively applied in natural product synthesis. Examples: OH OH H iPr 1) THF, 45 °C OMe + + (CO)4Cr 2) FeCl3–DMF iPr THF, 25 °C iPr OMe 99.6 : 0.4 OMe 55% Wulff in Advances in Metal-Organic Chemistry, JAI Press: Greenwich, CT, 1989, Vol. 1. OMe O (CO)4Cr O 1. PhH, 75 °C 2. air, 10 min O O + 11-Deoxydaunomycinone O MeO 3. (CF3CO)2O NaOAc CO2tBu 4. TFA 5. aq. NaOH OMe O OH Wulff Tetrahedron 1985, 41, 5797. OH OMe (CO)4Cr CO2Me 85 °C + THF O and O Angelicin OMe CO2Me Sphondin Wulff J. Am. Chem. Soc. 1988, 110, 7419. MOMO MeO Ac2O OTBS MOMO MeO OMe Cr(CO)5 + OMe OTBS Fredericamycin A heptane TBSO MOMO OH OTBS MOMO EtO N EtO N Boger J. Am. Chem. Soc. 1995, 117, 11839. J. Org. Chem. 1991, 56, 2115. J. Org. Chem. 1990, 55, 1919. 335 Modern Organic Chemistry The Scripps Research Institute Q. [2 + 3] Cycloadditions for 5-Membered Ring Formation Review: Comprehensive Org. Syn., Vol. 5, 239. 1. (2π + 2π) - Noyori reaction: J. Am. Chem. Soc. 1972, 94, 1772. J. Am. Chem. Soc. 1973, 95, 2722. J. Am. Chem. Soc. 1977, 99, 5196. J. Am. Chem. Soc. 1978, 100, 1793. R R Br + Fe2(CO)4 O O Br D benzene ∆ R via O–Fe2+ D R stepwise process OFe D Br O Ph Ph Br O Ph n 70% Ph O N n O n = 5, 75% n = 6, 100% O N 70% O Cuparenone Noyori Tetrahedron Lett. 1978, 493. - Intramolecular version: Yamamoto J. Am. Chem. Soc. 1979, 101, 220. Br + O Br - Reviews: Acc. Chem. Res. 1979, 12, 61. Org. React. 1983, 29, 163. 336 O 2:1 58% O Key Ring Forming Reactions Dale L. Boger Cl Cl ZnCl2 + 21% Cl Cl Miller Tetrahedron Lett. 1980, 577. Cl Cl 50% Ph + Ph Cl Cl ZnCl2, HCl + 70% CH2Cl2 OEt OEt + Cl 81% Mayr Angew. Chem., Int. Ed. Eng. 1981, 20, 1027. 2. (2π + 4π) + Ph LDA, THF Ph 41% Ph Ph Ph Ph Kauffman Angew. Chem., Int. Ed. Eng. 1972, 11, 292. CN CN Ph Ph + Ph 25 °C, 2 h Ph Ph 65% Martens Angew. Chem., Int. Ed. Eng. 1972, 11, 724. Ph 337 Modern Organic Chemistry The Scripps Research Institute - Trost trimethylenemethane equivalent: J. Am. Chem. Soc. 1979, 101, 6429. J. Am. Chem. Soc. 1983, 105, 2315. OAc EWG Pd(PPh3)4 + EWG L Pd L via: TMS Stepwise mechanism: CO2Me MeO2C MeO2C CO2Me MeO2C MeO2C CO2Me MeO2C 60% cis : trans 1 : 1.3 32% Related equivalents: Cl O O TiCl4 + Cl O KOtBu TMS 1,4-addition of allylsilane: Knapp Tetrahedron Lett. 1980, 4557. I SO2Ph KH SO2Ph TMS + TMS O Et2O SO2Ph Bu4NF THF O OH Trost J. Am. Chem. Soc. 1980, 102, 5680. O O CO2Me MeO2C O + O O O Nakamura J. Am. Chem. Soc. 1989, 111, 7285. J. Am. Chem. Soc. 1991, 113, 3183. 338 Key Ring Forming Reactions Dale L. Boger R. Cyclopropenone Ketal Cycloadditions Review: Boger Adv. Cycloaddition Chem., JAI Press: Greenwich, CT, Vol. 2, 1990, pp 147–219. 1. [2 + 1] Cycloaddition O CO2Me CO2Me O H 80 °C [1 + 2] H O CO2Me H O H O cis : trans 20 : 1 O OH endo diastereoselectivity Boger J. Am. Chem. Soc. 1986, 108, 6695. - Carbene addition: 2πs + 2ωa suprafacial H H H H OMe OMe O H antarafacial H O OMe H H H R OMe H R endo stabilization H H H O OMe OMe R H H H R OMe H H H OMe H O - Carbene angle of attack: Jorgensen J. Am. Chem. Soc. 1989, 111, 1919. O O O O 117 o O O 75 oC O 75 oC MeO O O O OMe OMe OMe 339 Modern Organic Chemistry The Scripps Research Institute 2. [3 + 2] Cycloaddition - Substrates that contain two geminal electron-withdrawing groups. EWG EWG O 70–80 °C + EWG EWG O R [4 + 2] Tetrahedron 1986, 42, 2777. [1 + 2] Tetrahedron Lett. 1984, 25, 5611. [3 + 4] J. Org. Chem. 1985, 50, 3425. J. Am. Chem. Soc. 1986, 108, 6713. O (total synthesis of Colchicine) O O R J. Am. Chem. Soc. 1984, 106, 805. J. Am. Chem. Soc. 1986, 108, 6695. J. Org. Chem. 1988, 53, 3408. Advances in Cycloaddition Chemistry Vol. 2, JAI: Greenwich, CT, 1990, pp 147–219. O single e– transfer EWG EWG O O EWG EWG + R radical anion O O R radical cation MeO2C CO2Me 95% 1. Solvent independent rate. MeO 2. No addition–elimination or addition–rearrangement products. Note: For substrates that may react via this pathway (e– transfer), [3 + 2] > [1 + 2], [4 + 2], or [3 + 4] cycloadditions MeO2C MeO2C Unusual polarity that uniquely stabilized radical anion. 3. No inhibition by free radical traps. NC 4. Putative carbene addition product (a cyclopropane ketene acetal) does not undergo vinylcyclopropane rearrangement to the product. 5. Little or no loss of olefin stereochemistry and this diastereospecific nature of the reaction increases, not decreases, in polar solvents. CN 89% O MeO NC NC O NC CO2Me 58% NC MeO2C CO2R H H R MeO MeO H H – 340 O Cycloaddition faster than cyclopropylcarbinyl radical rearrangement. - (2πs + 2πa) Cycloaddition MeO MeO O H CO2R' 3π e– bond, little loss of stereochemistry due to bond rotation O O Key Ring Forming Reactions Dale L. Boger Tear Gas, CS Cl NC Used as an antiriot agent, the tear gas CS, named after its two developers B. Corson and R. Stoughton who introduced it in 1928, causes pain and burning in the eyes and skin within seconds. It acts as a sulfhydryl alkylating agent resulting in a copious flow of tears, coughing, sneezing, chest tightening, and dizziness which subside within 30 min. No carcinogenic activity was found in mice exposed to CS for up to 2 years. CN 3. [4 + 3] Cycloaddition O O O O O O + O O O + O − − + O O O H O H MP2/6-31++G(d)//6-31++G(d) O + − O O H O O O H O O + O + - H O O O + syn H H − O O + O H singlet 0.00 kcal H O O O H + H H π-delocalized singlet vinylcarbene O H O – H anti O H H – 1.40 kcal O H H O O H H H - H H H triplet 9.22 kcal 8.73 kcal Singlet carbene stabilized by two alkoxy electron-donating substituents - 2πs + 4πs Cycloaddition or Diels–Alder reaction but via a 2π three carbon dienophile. MeO 80 °C 73% MeO O CO MeO MeO MeO O NHCOMe MeO O MeO MeO O MeO O O O O MeO OMe Colchicine 88% 25 °C 6.2 kbar Boger J. Am. Chem. Soc. 1986, 108, 6713. MeO MeO O CO H O H O 341 Modern Organic Chemistry The Scripps Research Institute 4. [4 + 2] Cycloaddition (standard Diels–Alder reaction) O O O R R 25 °C [4 + 2] O O R O R O O R 25 °C 6–13 kbar [4 + 2] O R O O R O R O O O O R = CO2CH3, 56–65% R = H, 69% R = OCH3, 56–72% + Participates in normal, neutral, or inverse electron demand Diels–Alder reactions, high lying HOMO and low lying LUMO. O O VS O O Exclusive exo addition Note: cyclopropene itself is endo selective. CO2CH3 CO2CH3 O O O OCH3 O 25 °C 80% CO2CH3 KOtBu, 25 °C O –CH3OH O CH3O2C 25 °C X OCH3 6πe– disrotatory electrocyclic ring opening referred to as a norcaradiene rearrangement O X= O X=O OMe OMe MeO O N MeO O MeO MeO N O O O Boger J. Am. Chem. Soc. 1995, 117, 12452. 342 Grandirubrine Imerubrine Granditropone Key Ring Forming Reactions Dale L. Boger S. [2 + 2] Cycloadditions 1. Ketene [2 + 2] cycloadditions Org. React. 1995, 45, 159. H 2πs + 2πa Cycloaddition O O O Et3N hexanes O COCl Baldwin J. Chem. Soc., Chem. Commun. 1972, 1337. 2. Photochemical [2 + 2] cycloaddition Comprehensive Org. Syn., Vol. 5, 123. Org. React. 1993, 44, 297. Ronald Norrish received the 1967 Nobel Prize in Chemistry for his work on photochemistry and flash photolysis. The latter was developed with George Porter with whom he shared the 1967 Nobel Prize and is used for the production and spectroscopic determination of short-lived reaction intermediates. O O Norrish Type I Fragmentation Reaction O O hν + R' R R' R hν H 92% Hermann Staudinger, noted for his pioneering studies of ketenes, received the 1953 Nobel Prize in Chemistry for his pioneering work in macromolecular chemistry. OH Norrish Type II Reaction Cargill Tetrahedron Lett. 1978, 4465. O H hν O H OH + Norrish Trans. Faraday Soc. 1937, 33, 1521. O OEt O 1. LDA, MeI O 1. Ph3P=CH2 hν 2. TsOH 2. MgBr Isocomene Pirrung J. Am. Chem. Soc. 1979, 101, 7130. J. Am. Chem. Soc. 1981, 103, 82. O MgBr 1. CuI 2. CH2O O O OH O 1. TsCl hν 2. base 67% Panasinene C. R. Johnson J. Am. Chem. Soc. 1981, 103, 7667. 343 Modern Organic Chemistry The Scripps Research Institute CHO O EtO I O 1. LDA O O O hν O3 2. LiAlH4 O O O Smith J. Am. Chem. Soc. 1982, 104, 5568. Hibiscone C O O MeO2C hν CO2Me Ph3P=CH2 CO2Me H H + Note: regioselectivity of cycloaddition in excited state. 210 °C, 2 h - Mechanism: CO2Me H CO2Me CO2Me ene reaction retro [2 + 2] H H CHO OH - Ene reaction: CHO H Warburganal H H Wender Tetrahedron Lett. 1982, 23, 1871. - Note regioselectivity: O O hν + MeO OMe OMe OMe O excited state reversed polarity O VS. Corey J. Am. Chem. Soc. 1964, 86, 5570. 344 Key Ring Forming Reactions Dale L. Boger 3. Paterno–Buchi Reaction Comprehensive Org. Syn., Vol. 5, 151. Dermuth Synthesis 1989, 152. First studied in detail by Buchi J. Am. Chem. Soc. 1954, 76, 4327. R5 O R6 R6 hν R1 R2 R3 R5 R4 O + R1 R4 R2 R3 hν * R5 O R1 R6 R5 R6 R4 R3 O R2 R3 R1 R4 R2 a diradical intermediate has been observed -Addition to enol ether occurs with only moderate selectivity ... OEt O Ph hν + O + Ph OEt Ph O Ph OEt Ph Ph (75 : 25) Schroeten J. Org. Chem. 1969, 34, 1181. ... while addition of the carbonyl to a furan occurs with high selectivity. O Ph hν + Ph + Ph O O O O O Ph Ph (1 : 99) Ph Schenk Chem. Ber. 1963, 96, 498. - Intramolecular variant: hν O cat. Na2CO3 benzene O Thromboxane A2 O O Carless J. Chem. Soc., Chem. Commun. 1984, 667. - Diastereoselectivity: R R R fast R CHO hν O H O H O O not formed H R slow O O H H R hν H O O O H O H O O O H R H Aoyoma J. Org. Chem. 1984, 49, 396. Pattenden J. Chem. Soc., Chem Commun. 1980, 1195. J. Chem. Soc., Chem Commun. 1979, 235. 345 Modern Organic Chemistry The Scripps Research Institute T. Arene–Olefin Photoadditions - Discovery in 1966: Wilzbach J. Am. Chem. Soc. 1966, 88, 2066. Bryce–Smith J. Chem. Soc., Chem. Commun. 1966, 512. Comprehensive Org. Syn., Vol. 5, 645. LiO OMe H O + Li/NH3 H Li OMe MeO hν 65% OMe H KOH, N2H4 H O α-Cedrene OMe 1. Br2, CH2Cl2 H diethylene glycol 200 °C H + 2. Bu3SnH (1 : 1) Wender J. Am. Chem. Soc. 1981, 103, 688. 244 °C hν + 72% toluene 50–60% (1 : 1) Isocomene Wender Tetrahedron 1981, 37, 4445. OAc hν 21% 1. KOH, MeOH H OAc 2. BaMnO4 KOtBu, MeI THF 68% 82% 1. Li, Et2NH THF, 0 °C Modhephene OPO(NMe2)2 2. H2, PtO2 93% Wender J. Am. Chem. Soc. 1982, 104, 5805. 346 O O 1. Me2CuLi THF, –78 °C 2. then Cl2PO(NMe2) 3. Et2NH 76% Key Ring Forming Reactions Dale L. Boger U. Intramolecular Ene Reaction Review: H. M. R. Hoffmann Angew. Chem., Int. Ed. Eng. 1969, 8, 556. Comprehensive Org. Syn., Vol. 5, 9. H H ene concerted thermal [4 + 2] cycloaddition eneophile - First systematic study by Alder: O O + O ∆ H O Ph Ph O Alder Chem. Ber. 1943, 76, 27. - First intramolecular versions: O review: Oppolzer Angew. Chem., Int. Ed. Eng. 1978, 17, 476. ∆ O OH H Treibs, Schmidt Chem. Ber. 1927, 60, 2335. 300 °C CO2Me CO2Me 14 h 65% cis AlCl3, 0 °C H BnO 69% Me O BnO OR Smith J. Am. Chem. Soc. 1991, 113, 2071. R N H R CH3 AlCl3, 25 °C N 91% H O OH CH3 Overman Tetrahedron Lett. 1985, 35, 4167. Note the Sharpless mechanism for SeO2 oxidation of olefins: allylic oxidation involves an ene reaction. H Se O O ene reaction Se O OH [2,3]-sigmatropic rearrangement O Se OH or Nu– OH Sharpless J. Am. Chem. Soc. 1972, 94, 7154. J. Am. Chem. Soc. 1973, 95, 7917. 347 Modern Organic Chemistry The Scripps Research Institute Chugaev (Tschugaeff) Reaction RCH2CH2OH syn elimination R 1) NaOH, CS2 2) CH3I H R O 100−250 °C S SMe Tschugaeff Ber. 1899, 32, 3332. Review: Nace Org. React. 1962, 12, 57. DePuy Chem. Rev. 1960, 60, 431. Me2 N – + O Amine Oxide Elimination (Cope Elimination) Org. React. 1960, 11, 361. Org. Syn. 1963, 4. 612. Cope J. Am. Chem. Soc. 1954, 81, 2799. Zutter J. Am. Chem. Soc. 1986, 108, 1039. H Cope J. Am. Chem. Soc. 1949, 71, 3929. ∆ O N + syn elimination Sulfoxide Elimination Trost Chem. Rev. 1978, 78, 363. Acc. Chem. Res. 1977, 11, 453. J. Am. Chem. Soc. 1973, 95, 6840. J. Am. Chem. Soc. 1976, 98, 4887. H O R S O H 110 °C S Me syn elimination O N OH Ziegler J. Am. Chem. Soc. 1984, 106, 721. Schreiber J. Am. Chem. Soc. 1984, 106, 4038. Agosta J. Am. Chem. Soc. 1986, 108, 3385. ∆ + syn elimination O 90% H 220 °C S Ph syn elimination O O RSOH H 80 °C S Ph syn elimination O O O R R O O O R HO O O O PhS O O O SPh 25 °C O O O Boger, Mullican J. Org. Chem. 1980, 45, 5002. J. Org. Chem. 1984, 49, 4045. 348 O SPh HO SPh Key Ring Forming Reactions Dale L. Boger - Selenoxide Elimination Clive Tetrahedron 1978, 34, 1049. Reich Acc. Chem. Res. 1979, 12, 22. H O Se Ph R Br R 25 °C NaSePh O SeAr R Selenoxide elimination occurs at lower temperature. syn elimination O [ox.] R O SeAr ∆ R Bu3P OH NO2 Se CN V. Oxy–Ene Reaction: Conia Reaction Comprehensive Org. Syn., Vol. 5, 20. Review: J. M. Conia Synthesis 1975, 1. O O H O Conia Tetrahedron Lett. 1965, 3305, 3319. O 350–370 °C O 30 min O 85% Epimerized to more stable trans isomer. 350–370 °C O cis 30 min Conia Bull. Chim. Soc., Fr. 1969, 818. O O 335 °C 60 h 50% tandem Conia reactions: Conia Tetrahedron Lett. 1974, 2931. 349 Modern Organic Chemistry The Scripps Research Institute W. Cyclopentenone Annulation Methodology Br 1. O O 1 OLi 2. O2, PdCl2, CuCl2 3. NaOH, EtOH 2 Wacker oxidation, review:Tsuji Synthesis 1984, 369. Wayner J. Org. Chem. 1990, 55, 2924. Br 1. 1 2 2. NaIO4, OsO4 3. NaOH, EtOH McMurry J. Am. Chem. Soc. 1979, 101, 1330. Br Br 1. 1 2 2. H2SO4 3. NaOH, EtOH 1. TMSCl 1 2. SnCl4, CH2=C(Me)NO2 3. NaOH, EtOH 2 1. Br TMS 2. KOH, MeOH (–TMS) 1 2 3. Hg(OAc)2, H+ 4. NaOH, EtOH OMe 1. Br CO2Me O OLi O OEt Br PO(OMe)2 Piers Tetrahedron Lett. 1979, 3279. 350 2. H2SO4, H2O 3. NaOH, EtOH Br PPh3 CO2Me Used in Quadrone total synthesis: Helquist J. Am. Chem. Soc. 1981, 103, 4647. Altenbach Angew. Chem., Int. Ed. Eng. 1979, 18, 940. Key Ring Forming Reactions Dale L. Boger - Flemming–Greene Annulation: 1. Cl3CCOCl Zn–Cu O Cl 2πs + 2πa cycloaddition O O 62% 2. CH2N2 Cl 3. Zn, HOAc Zn, HOAc O CH2N2 O O Cl 59% Cl olefin–ketene cycloaddition Cl Cl Loganin: Flemming J. Chem. Soc., Chem. Commun. 1977, 81. Hirsutene: Greene Tetrahedron Lett. 1980, 3059. Hirsutic Acid: Greene J. Am. Chem. Soc. 1983,105, 2435. R O O SiR3 TiCl4 + Cl3Ti O R SiR3 R OTiCl3 R SiR3 OTiCl3 R SiR3 SiR3 Danheiser J. Am. Chem. Soc. 1981, 103, 1604. Tetrahedron 1983, 39, 935. - Cyclopropylphosphonium salts: CO2Me + O PPh3 NaH CO2Et THF 90% CO2Me CO2Et Fuchs J. Am. Chem. Soc. 1974, 96, 1607. PPh3 Marino Tetrahedron Lett. 1975, 4531. SPh 351 Modern Organic Chemistry The Scripps Research Institute - β-Vetivone synthesis: O O CHO PPh3 + CO2Et EtO NaH CO2Et HMPA EtO 38% Dauben J. Am. Chem. Soc. 1975, 97, 1622. H PPh3 O + O PPh3 Burgstahler, Boger Tetrahedron 1976, 32, 309. - Benzothiazoles as carbonyl equivalents: N Li OEt E N S S E+ O 1. (MeO)2SO2 E 2. NaBH4 3. H+, Ag(I) E CHO O O Corey, Boger Tetrahedron Lett. 1978, 5, 9, 13 and 4597. I Br i) LDA, Me2NN ii) CuCl2, H2O H I BuLi O O OH Piers Tetrahedron Lett. 1993, 35, 8573. - Additional reviews: Denmark Org. React. 1994, 45, 1. Hudlicky Chem. Rev. 1989, 89, 1467. Sehore Chem. Rev. 1988, 88, 1085. Ramarah Synthesis 1984, 529. 352 H PCC Key Ring Forming Reactions Dale L. Boger X. Pauson–Khand Reaction [2 + 2 + 1] Comprehensive Org. Syn., Vol. 5, pp 1037–1064. Org. React. 1991, 40, 1. Pauson Tetrahedron 1978, 41, 5855. Schore Chem. Rev. 1988, 88, 1081. Brummond Tetrahedron 2000, 56, 3263. First detailed study: Khand J. Chem. Soc., Perkin Trans. 1 1973, 977. Co2(CO)6 O CO - Mechanism: OMe large H Me MeO + (CO)3Co Co(CO)3 – CO H Me MeO CO Co Co(CO)3 (CO)2 H H H Co (CO)3 Co(CO)3 less hindered exo face MeO H MeO H H H H H O CO Co(CO)3 MeO Co(CO)3 H reductive elimination – Co2(CO)6 H small Me O CO inserted 60% only isomer large Me H O Co(CO)3 Co (CO)3 1. Regio- and stereochemistry are controlled by steric factors. 2. Complexation of alkene and insertion into Co–C bond occurs from less hindered face. 3. Insertion of the alkene carbon bearing the largest allylic substituent to form the first C–C bond occurs at the alkyne carbon bearing the smallest substituent. 4. Subsequent CO insertion occurs next to the largest alkyne substituent. 5. Reductive elimination followed by decomplexation gives the final product. - Intermolecular: HO HC CH HO H H 6 steps Co2(CO)6 OMe DME, 65 °C 4 days MeO H O 65% Schore J. Org. Chem. 1987, 52, 3595. - Intramolecular RO RO H OTBDPS O entry into guaianolide and pseudoguaianolide natural products RO H H Co2(CO)8 O TMS The dimethyl and alkyne substituents accelerate the reaction. heptane 80–90 °C + TMS R = H, 18% R = MOM, 69% O TMS R = H, 7% R = MOM, 0% Magnus J. Am. Chem. Soc. 1983, 105, 2477. 353 Modern Organic Chemistry The Scripps Research Institute H Co2(CO)8 H + O heptane 110 °C, 20 h O 45% 6% Schore J. Am. Chem. Soc. 1988, 110, 5224. TMS TMS OTBDMS OTBDMS Co2(CO)8 O OTBDMS isooctane 160 °C H H Epimerization occurs via the Co-stabilized propargyl cation. H OTBDMS 76% Serratosa Tetrahedron Lett. 1985, 26, 2475. Tetrahedron 1986, 42, 1831. OH Mo(CO)6 HO OTBS H DMSO−toluene 110 °C, 10 min HO 69% O HO OTBS O hyrdoxymethylacylfulvene Brummond J. Am. Chem. Soc. 2000, 122, 4915. -Heterosubstituted systems: O H benzene O 60 °C, 4 h H CO2(CO)6 O 85% Schreiber J. Am. Chem. Soc. 1986, 108, 3128. O O Co2(CO)8 O hexane 60 °C, 4 h O 45% Smith Tetrahedron Lett. 1986, 27, 1241. 354 O Key Ring Forming Reactions Dale L. Boger Y. Carbonylation Cyclizations Comprehensive Org. Syn., Vol. 4, 1015. Alper Acc. Chem. Res. 1995, 28, 414. - Pd mediated carbonylation O R1 CO2Me PdCl2(PPh3)2 R1 Et3N, CO MeOH (catalytic) R2 I R1 (not catalytic) R2 R2 O CO2Me PdCl2(PPh3)2 Et3N, CO I O Pd(PPh3)4 CO 65% O CO2Me PdCl2(PPh3)2 Et3N, CO I 66% Negishi J. Am. Chem. Soc. 1985, 107, 8289. - Formation of lactones PdCl2, PPh3 SnCl2, CO OH O O 93% Norton J. Am. Chem. Soc. 1981, 103, 7520. - Formation of amides Heck J. Org. Chem. 1975, 40, 2667. Pd(OAc)2 PPh3, CO NHBn NBn 63% Br O Mori J. Org. Chem. 1978, 43, 1684. BnO Boc N Pd2(dba)3 PPh3, CO Boc N Boc Pd O N BnO 51% Nakanishi Synlett 1991, 91. OBn - Alternative carbonylation method: Hydroboration/Carbonylation BH2 H B 1. CO, H2O 1000 psi 2. NaOAc, H2O2 H 60% Brown, Negishi J. Chem. Soc., Chem. Commun. 1967, 594. J. Am. Chem. Soc. 1967, 89, 5477. H O H 355 Modern Organic Chemistry The Scripps Research Institute Z. Olefin Ring Closing Metathesis K. Ziegler and G. Natta shared the 1963 Nobel Prize in Chemistry for their discovery and development of transition metal catalyzed preparation of polyethylene and stereoregular polymers including polypropylene. Grubbs Comprehensive Org. Syn., Vol. 5, 1115. Acc. Chem. Res. 1995, 28, 446. Tetrahedron 1998, 54, 4413. Schrock J. Am. Chem. Soc. 1990, 112, 3875 and 8378. J. Am. Chem. Soc. 1991, 113, 6899. -General concept: Ring Opening n Metathesis Ring Closing X Metathesis X Acyclic Cross + R1 R2 Metathesis - Mechanism: R2 R1 R1 R1 M M R2 R1 The mechanism appears to be the same regardless of transition metal used. R1 M R1 R2 M R2 Grubbs Comprehensive Organometallic Chem., Vol. 8, 1982, 499. Sehrer J. Sci. Ind. Res. 1983, 42, 250. - Defined Catalysts 1. Early catalysts were poorly defined and incompatible with basic functionality. 2. Development of well-defined catalysts lead to high catalytic activity and compatibility with a wide variety of funtionalities. 3. Catalysts are based on variety of transition metals including: Mo, Ru, W, Re, Ti and Ta. 4. The mechanism appears the same for all transition metals. 5. The most widely used catalysts are: iPr iPr (CF3)2MeCO N Mo Ph PCy3 PCy3 Cl Ru Cl PCy3 Ph Cl Ru Cl Ph Ph PCy3 (CF3)2MeCO 1 Schrock 356 2 Grubbs 3 Grubbs Key Ring Forming Reactions Dale L. Boger - Applications to organic synthesis Review: Phillips, Abell Aldrichim. Acta 1999, 32, 75. Ring closing metathesis is rapidly becoming one of the more powerful methods for preparing medium and large rings. Modern use of ring closing metathesis traced back to: M=CHR X n X n X = O, NR, CHR n = 1, 2, 3 Grubbs, R. H.; Fu, G. C. J. Am. Chem. Soc. 1992, 114, 5426, 7324. J. Am. Chem. Soc. 1993, 115, 3800. Recent examples: OH O O HO N O O O N 3 (1 mol%) CH2Cl2 30 min Ph HO O HO Ph 97% carbocyclic nucleosides Crimmins J. Org. Chem. 1996, 61, 4192. Jacobsen J. Org. Chem. 1996, 61, 7963. H O H O PMP O H C5H12, 25 °C n H R2 O H R1 1 (13 mol%) O R1 O C6H6, 60 °C n n H H R1 1 (25 mol%) R1 O R1 = H, n = 1, 2 >90% R1 = Et, n = 1, 2 42-73% R2 R1R2 1 2 2 2 O PMP O H n R1 R2 conc (M) Yield n H H Et H Et Et H H 0.008 0.003 0.003 0.003 97% 86% 14% 58% note dependence on conformation between two diastereomers. Clark, Kettle Tetrahedron Lett. 1997, 38, 123 and 127. OAc OAc O NHCOCF3 OAc OAc O NHCOCF3 O O 1 (20 mol%) O O HN C6H6, 60 °C 90% Sch 38516 HN Hoveyda J. Am. Chem. Soc. 1995, 117, 2943. J. Am. Chem. Soc. 1996, 118, 10926. 357 Modern Organic Chemistry The Scripps Research Institute - Danishefsky, Nicolaou and Schinzer have all prepared Epothilone A using ring closing metathesis as the key cyclization step. S S N H N O O X H O O ring closing metathesis X Epothilone A Y OR Y OR Danishefsky J. Am. Chem. Soc. 1997, 119, 2733. Nicolaou Angew. Chem., Int. Ed. Eng. 1997, 36, 166. Schinzer Angew. Chem., Int. Ed. Eng. 1997, 36, 523. - Application to ring closing metathesis of enynes: R R H N O H H O N O H O N O H (–)-Stemoamide R = Me: 2 (5 mol%), C6H6, 50 °C, 73% R = CO2Me: 3 (4 mol%), CH2Cl2, 25 °C, 87% Kinoshita, Mori J. Org. Chem. 1996, 61, 8356. - Application to the synthesis of fused nitrogen heterocycles: O O x R N n = 0, R = Me n = 1, R = H n = 2, R = H n = 3, R = H x 1, benzene N n 25 or 50 °C n a) x = 1 b) x = 2 H a) x = 1 b) x = 2 CO2Me O O N H 1 H BnN benzene 50 °C 64% CO2Me H BnN O N Manzamine A O H Martin Tetrahedron 1996, 52, 7251. 358 a (68%) a (92%); b (91%) a (81%); b (84%) a (47%); b (50%) Olefin Synthesis Dale L. Boger XI. Olefin Synthesis A. Wittig Reaction G. Wittig received the 1979 Nobel Prize in Chemistry for "many significant contributions to Organic Chemistry" which included not only the Wittig reaction, but also PhLi prepared by metal–halogen exchange, benzyne, and the Wittig rearrangement. Reviews: Comprehensive Org. Syn., Vol. 1, 755. Org. React. 1965, 14, 270. Angew. Chem., Int. Ed. Eng. 1964, 3, 250. Top. Stereochem. 1970, 5, 1. Pure. Appl. Chem. 1979, 51, 515. Chem. Rev. 1989, 89, 863. 1. Formation of Ylides Ph3P + X CH2R ether + Ph3P CH2R X PhLi, nBuLi, LDA + Ph3P CHR or MeS(O)CH2Na strong electron-withdrawing group pKa ~ 18–20 (R = alkyl, H) Ph3P CHR ylide - Unstabilized ylides are sensitive to H2O, O2 2. Reaction of Ylides with Ketones O + + Ph3P CHR Ylide O + PPh3 CH-R Betaine Ph Ph P Ph O R R + Ph3P O Oxaphosphetane Strong bond formation is part of the driving force for the collapse of the oxaphosphetane. Wittig and Schöllkopf Chem. Ber. 1954, 87, 1318. 359 Modern Organic Chemistry The Scripps Research Institute 3. Mechanism and Stereoselectivity of the Wittig Reaction RCHO Ph3P CHCH3 CH3 R cis olefin from nonstabilized ylides - Stereoselectivity increases as the size of the R group increases. - Accepted mechanism today: irreversible and concerted [2 + 2] cycloaddition. P Ph3 slow (–Ph3P=O) CH3 R cis Ph3P O H H CH3 R H R O π2a + π2s cycloaddition suprafacial CH3 H antarafacial Orientation such that the R groups on the aldehyde and on the ylide are as far apart as possible. - The three alternative [2 + 2] cycloaddition transition states suffer destabilizing steric interactions: Ph Ph Ph P R H O CH3 Ph Ph Ph P R H O H H trans Ph Ph Ph P H R O CH3 H cis CH3 trans Not bad, probably gives rise to trans product - So, the mechanism involves fast, irreversible [2 + 2] cycloaddition (at –78 °C) followed by slow decomposition of oxaphosphetane (frequently requires warming to 0–25 °C). - Nonpolar solvents facilitate the initial addition. - Polar solvents facilitate the final elimination reaction. 4. Representative Examples + PPh3 1) NaN(SiMe3)2 2) OHC(CH2)8CO2CH3 –78 °C, THF CO2CH3 80%, >98% cis Besterman Chem. Ber. 1976, 109, 1694. H O 6.5 equiv CH3PPh3Br 5 equiv nBuLi Et2O, 25 °C, 1 h reflux, 3 h, 56% OH Inhoffen Chem. Ber. 1958, 91, 2309. 360 H vitamin D3 OH Olefin Synthesis Dale L. Boger O OTs HO H H Ph3P CH2 Al2O3 79% H H H Büchi J. Am. Chem. Soc. 1966, 88, 4113. DMSO O – O S+ NaH 70 °C Ph3PCH3Br Na DMSO 25 °C Ph3P CH2 50–55 °C 73% Corey J. Org. Chem. 1963, 28, 1128. H H S 1) SOCl2 O OH N O 2) Ph3P, iPr2NEt 51% RO2C H S N O O PPh3 S 90 °C 48 h, PhMe 89% N O RO2C CO2R Woodward J. Am. Chem. Soc. 1979, 101, 6301. - α-oxygenated substrates PPh3 1) addition O + O OMe 2) H3O+ OH - trisubstituted Z-alkene 85%, >99% Z Still J. Org. Chem. 1980, 45, 4260. - Schlösser modification: allows the preparation of trans vs. cis olefins. + Ph3P CH2R H R1 O– PPh3 PhLi, Et2O Ph3P CHR 25 °C, 10 min + O– PPh3 H R R1 H 1 equiv HCl R R R1 CH3 C5H11 C3H7 CH3 C2H5 C5H11 CH3 C3H7 Ph Ph % yield 70 60 72 69 72 R1CHO –70 °C, 5 min O PPh3 H R1 R KOtBu/tBuOH R1 Et2O, 25 °C 2h H PhLi, –30 °C 5 min R trans:cis 99:1 96:4 98:2 99:1 97:3 Schlösser Angew. Chem., Int. Ed. Eng. 1966, 5, 126. 361 Modern Organic Chemistry The Scripps Research Institute - β-Oxido Phosphonium Ylide Reaction: adaptation of the Schlösser modification for the stereoselective preparation of trisubstituted allylic alcohols. THF Ph3P R + R'CHO H –78 °C O PPh3 H R' OLi sBuLi R PPh3 R' –78 °C R CH2O, 0 °C H R R' H O PPh3 R R' OH O –O H R' – + PPh3 R O – Only 2° alkoxide forms oxaphosphetane that eliminates to form the olefin. Corey, Katzenellenbogen and Posner J. Am. Chem. Soc. 1967, 89, 4245. Corey and Yamamoto J. Am. Chem. Soc. 1970, 92, 226. Corey and Yamamoto J. Am. Chem. Soc. 1970, 92, 6636. Corey and Yamamoto J. Am. Chem. Soc. 1970, 92, 6637. I + Ph3P Ar2CHO Ar1 + 18-crown-6 Ar1 KOH (I– > Cl– > Br–) Ar2 (Z)-alkene C. J. Pedersen (DuPont) received the 1987 Nobel Prize in Chemistry for his discovery and development of crown ethers. (E)-alkene Jean-Marie Lehn received the 1987 Nobel Prize in Chemistry along with D. J. Cram and C. J. Pedersen for their development and use of molecules with structure-specific interactions of high selectivity. > 98:2 Z :E Ar2 Br Cl + Ph2P Ar2CHO Ar1 + 18-crown-6 Ar1 KOH > 96:4 E : Z Chiappe Tetrahedron Lett. 1996, 37, 4225. 5. Stabilized Ylides PPh3 O Br OR ether or benzene + Ph3P Na2CO3 O OR Has two electron-withdrawing groups so the pKa is very low. H2O + Ph3P O OR Ph3P CHCOOR - Stabilized ylides are solid; stable to storage, not particularly sensitive to moisture, and can even be purified by chromatography. - Because they are stabilized, they are much less reactive than alkyl ylides. They react well with aldehydes, but only slowly with ketones. - The first step, involving the addition to the aldehyde, is slow and reversible with stabilized ylides. 362 Olefin Synthesis Dale L. Boger R'CHO Ph3P O H R' ROOC H Ph3PCHCOOR H ROOC + minor kinetic product rotation available before elimination + Ph3P Ph3P O H H ROOC R' O H R' major kinetic product faster slower R' + ROOC + Ph3P ROOC H ROOC R' thermodynamically more stable, and is predominant or exclusive product of the reaction. O H R' - It is also possible that elimination occurs in a stepwise manner via stabilized zwitterionic intermediate that may simply afford the more stable product. - α-Oxygenated substrates - The exception to the generation of E-alkenes with stabilized ylides is their reaction with α-alkoxy aldehydes. O O MeO2C O (EtO)2P O CO2Me NaH, DME –78 to 25 °C CO2Me OHC O O MeO O O MeO2C CO2Me CH3OH –78 to 25 °C CHO cis (Z)-olefin! trans (E)-olefin Krief Tetrahedron Lett. 1988, 29, 1083. - And, this departure is solvent dependent OHC O Ph3P CHCO2Me CO2Et O O Ph3P CHCO2Et O O MeO DMF CHCl3 MeOH 14 : 86 60 : 40 92 : 9 Z:E Z:E trans Z:E cis Tronchet, Gentile Helv. Chim. Acta 1979, 62, 2091. - Reaction with esters, lactones, and activated lactams Ph3P N BOC CN C7H15CO2Me CN CN O CN Ph3P N BOC 79−92% CN O Ph3P O 100 °C 83% C7H15 OMe CN O 25 °C 93% Tsunoda Tetrahedron Lett. 2000, 41, 235. 363 Modern Organic Chemistry The Scripps Research Institute 6. Annulation Applications of the Wittig Reaction OH b) + PPh3 O O O a) NaH a) NaH b) SH O + PPh3 PPh3 O 2 carbon unit O O + PPh3 O 75% [O] PPh3 S O2 S S (–SO2) chelotropic extrusion ∆ 2 carbon unit 4 carbon unit O + NaH + PPh3 COOEt CO2Et - Homoconjugate addition: O OH + 3 carbon unit NaH + PPh3 O - Modest yields because one electron-withdrawing group is not sufficient to activate the cyclopropane ring to nucleophilic ring opening. So: + PPh3 SPh 1) O O N SPh + PPh3 COOEt 1) ClCOOEt PPh3 2) NaBF4 2) NaBF4 Dauben J. Am. Chem. Soc. 1975, 97, 1622. - Applications: EtOOC O COOEt NaH + PPh3 COOEt 90% PhS NaH + PPh3 SPh 82% 364 COOEt H+ (Hg2+) COOEt O H COOEt Olefin Synthesis Dale L. Boger B. Wadsworth–Horner–Emmons Reaction Horner Chem. Ber. 1958, 91, 61; 1959, 92, 2499. Wadsworth, Emmons J. Am. Chem. Soc. 1961, 83, 1733. Org. React. 1977, 25, 73–253. Comprehensive Org. Syn., Vol. 1, 761. Reviews: 1. Arbuzov (Michaelis−Arbuzov) Reaction: Preparation of Phosphonate Esters Arbuzov J. Russ. Phys. Chem. Soc. 1906, 38, 687. Michaelis Ber. 1898, 31, 1048. O O (EtO)3P: Cl + OEt P OEt O CH2CH3 EtO OEt Arbuzov Pure Appl. Chem. 1964, 9, 307. O –EtCl EtO O P(OEt)2 Cl - The same approach to the preparation of β-ketophosphonates is not successful: O (RO)2P (RO)3P O Cl R' Perkow reaction O O R' O P(OR)2 R' - But can use variation on Claisen conditions: OEt EtI P(OEt)3 EtO P+ CH2CH3 O CH3CH2 O (EtO)2P CH3 –78 °C CH3 Li Unstable at higher temperatures or under prolonged reaction times. I Can also use: O (EtO)2P LDA or nBuLi, O (EtO)2P O Cu + Cl O (EtO)2P R O EtO R' CH3 Savignac Tetrahedron Lett. 1976, 2829. R' 2. Mechanism and Stereoselectivity O EtO O P(OEt)2 O NaH EtO THF O P(OEt)2 O (EtO)2P H EtOOC RCHO Na+ OH EtO P O EtO H R EtOOC H ONa H R O (EtO)2P O H R + EtOOC E-selective (trans) H + O (EtO)2P H EtOOC O ONa R H O (EtO)2P O H R EtOOC H Note possibility of C–C bond rotation (may or may not be discrete intermediate) Water soluble (easily removed through aqueous workup) Good reactions for: EtO EtO P O W W = CN, COOR, C(O)R, CHO, SO2Ph, Ph But not W = alkyl, H 365 Modern Organic Chemistry The Scripps Research Institute 3. Modifications and Scope - LiCl/tertiary amines (DBU, iPr2NEt, Et3N) Masamune, Roush Tetrahedron Lett. 1984, 25, 2183. Can substitute for conventional conditions and is especially good for base sensitive substrates (epimerization, elimination). O CH3 O P(OEt)2 O O OMTM LiCl, iPr2NEt O CH3CN 80% CH3 O + H subject to β-elimination OMTM Keck J. Org. Chem. 1989, 54, 896. (thioester was also stable to these conditions) -Hindered phosphonates and hindered aldehydes increase E-selectivity (trans). CH3 CH3 BnO BnO CHO CO2R Ph3P=CHCO2Et, CH2Cl2, 0 °C (iPrO)2POCH2CO2Et, KOtBu, (MeO)2POCH2CO2Me, THF, –78 °C KOtBu, THF, –78 °C 7:1 E:Z 95 : 5 E:Z 1:3 E:Z Kishi Tetrahedron 1981, 37, 3873. - The use of a nonhindered phosphonate, low temperatures, and a strongly dissociating base (KOtBu) can give increased or high Z-selectivity (cis). - Coordinating countercations slow the rate of elimination relative to equilibration. CH3 CO2R + CH3 Ph3P=C(Me)CO2Et, CH2Cl2, 25 °C 95 : 5 Ph3P=C(Me)CO2Et, MeOH, 25 °C 85 : 15 5 : 95 10 : 90 Ph Ph CHO CH3 Stabilized Wittig reagent (MeO)2POCH(Me)CO2Me, KOtBu, THF, –78 °C Wadsworth–Horner– Emmons reagent (MeO)2POCH(Me)CO2Et, KOtBu, KOtBu, THF, –78 °C Ph CH3 CH3 CO2R THF, –78 °C 40 : 60 (iPrO)2POCH(Me)CO2Et, KOtBu, THF, –78 °C 90 : 10 (iPrO)2POCH(Me)CO2iPr, 95 : 5 (EtO)2POCH(Me)CO2Et, KOtBu, THF, –78 °C - Still–Gennari modification selective for Z-alkenes (cis): R'CHO + O (CF3CH2O)2P CO2Me R R = H, Me KHMDS 18-c-6 THF R' R CO2Me Z selective Z : E > 10 : 1 Still Tetrahedron Lett. 1983, 24, 4405. R = Br, Kogen Org. Lett. 2000, 2, 1975. (Trisubstituted olefins via Suzuki or Stille coupling) 366 Olefin Synthesis Dale L. Boger CH3 CO2Me (CF3CH2O)2POCH2CO2Me KH, THF BnO (EtO)2POCH2CO2Et CH3 BnO CHO NaH, THF 84% 11 : 1 Z : E CH3 83% 12 : 1 E : Z Cinquini Tetrahedron 1987, 43, 2369. OH I I CO2Me BnO O (CF3CH2O)2POCH2CO2Me KHMDS, 18-c-6 –78 °C, 30 min 97%, >25:1 Z : E CHO O MeO2C O Combretastatin D-2 Boger J. Org. Chem. 1991, 56, 4204. - Additional Z-selective stabilized phosphonates. RCHO (PhO)2P(O)CH2CO2Et R CO2Et (PhO)2P(O)CH(R')CO2Et Ando J. Org. Chem. 1997, 62, 1934. Ando J. Org. Chem. 2000, 65, 4745. (NaI/DBU vs NaH) RCHO R CO2Et R' Selected diarylphosphonates provide high Z-selectivity Ando J. Org. Chem. 1998, 63, 8411. - Other useful reactions of functionalized phosphonates. H O (MeO)2P CHO - Direct production of alkynes. H Provide a mechanism for this transformation N2 OMe OTIPS tBuOK, THF –78 °C 95% OMe OTIPS Schreiber J. Am. Chem. Soc. 1990, 112, 5583. O O (MeO)2P H OR R = Me, 58% R = tBu, 56% N2 - Synthesis of enol ethers and enamines. t BuOK, ROH or i Pr2NH NiPr2 59% Gilbert Tetrahedron Lett. 1980, 21, 2041, 5003; 1984, 25, 2303. J. Org. Chem. 1983, 48, 448. C. Peterson Olefination Peterson J. Org. Chem. 1968, 33, 780. J. Org. Chem. 1967, 32, 1717. J. Am. Chem. Soc. 1975, 97, 1464. Reviews: Org. React. 1990, 38, 1. 367 Modern Organic Chemistry The Scripps Research Institute 1. Nonstabilized Peterson Reagents - Me3SiCH2Met, Met = Li, Mg, offer an alternative to Wittig or Tebbe procedures. They are more reactive and sterically less demanding than a Wittig reagent and the volatile byproduct (Me3SiOH/ Me3SiOSiMe3) is simpler to remove than Ph3PO. It does, however, require a second step to promote elimination of the β-hydroxysilane. - Example Et3SiO MeO OMe N CH3 O O NMe 1) LiCH2SiMe3 MeO 2) DDQ, THF CH3 OMe Danishefsky J. Org. Chem. 1988, 53, 3391. OMe N NMe O - TMS eliminates in preference to Ph3P or P(O)(OR)2: Ph Ph + O Ph3P SiMe3 Ph Ph Peterson. J. Org. Chem. 1968, 33, 780. + PPh3 Note: this is the origin of its discovery - Modifications include: Me3SiCH2MgBr/ TiCl4 (direct production of olefin), and Me3SiCH2Li/ CeCl3 (enolizable ketones and aldehydes, while esters and acid chlorides give allylsilanes via addition 2x). - The elimination is stereospecific: acid-promoted being anti and base-promoted being syn. Pr Pr Base (syn) Acid (anti) Me3Si Pr OH Me3Si Pr Pr OH Pr Acid (anti) Base (syn) Pr Pr Hudrlik, Peterson J. Am. Chem. Soc. 1975, 97, 1464. - Unstabilized Peterson reagents add to ketones and aldehydes irreversibly with little diastereoselectivity. Therefore, mixtures of cis and trans olefins are obtained and the reactions are not yet as useful as the Wittig reaction. 2. Stabilized Peterson Reagents - The stabilized Peterson reagents give predominantly the most stable trans olefins (E) although this has been studied far less than the Wittig or Wadsworth–Horner–Emmons reactions. The origin of this diastereoselection has not been extensively explored with regard to enolate geometry, reversible/ irreversible addition, or mechanism of elimination. In this case, the elimination takes place under the reaction conditions. 368 Olefin Synthesis Dale L. Boger O OtBu a) LDA, –78 °C OtBu CH3 O b) Me3SiCl OSiMe3 SiMe3 OtBu LDA OtBu R RCHO LiO CO2tBu SiMe3 trans predominates Rathke Tetrahedron Lett. 1974, 1403. Yamamota J. Am. Chem. Soc. 1974, 96, 1620. - via: Me3Si BuO2C H Me3Si 2C OLi H R t O tBuO t H H BuO2C R R major + Me3Si BuO2C H OLi R H t t Me3Si BuO2C Me3Si H O t R H tBuO O 2C R H BuO2C major R H t BuO2C Can be trapped R minor - Both single step and two-step elimination via an equilibration have been proposed. - Additional examples: Cl CH3O CH3 NCOCF3 OHC NtBu CH3 H Li OMEM CH3 OMe S S Cl CH3O CH3 SiMe3 82% OHC CH3 NCOCF3 CH3 CH3 OMEM OMe CH3 S S maytansine Corey, Weigel, Chamberlin, Lipshutz J. Am. Chem. Soc. 1980, 102, 1439. Corey, Enders, Bock Tetrahedron Lett. 1976, 3 and 7. N SiMe3 + S Li N O 92% S Corey and Boger Tetrahedron Lett. 1978, 5. 369 Modern Organic Chemistry The Scripps Research Institute D. The Tebbe Reaction and Related Titanium-stabilized Methylenations reviews: Org. React. 1993, 43, 1. Comprehensive Org. Syn., Vol. 1, 743. - The Wittig, Wadsworth–Horner–Emmons, and Peterson olefination do not convert esters or amides to the corresponding olefin, but rather fail to react or result in the cleavage of the ester or amide bond. - Schrock discovered that Ta and Nb tert-butyl alkylidene complexes behave analogous to phosphorous ylides and, notably, react with esters and amides to provide the corresponding tbutylalkenes. Schrock J. Am. Chem. Soc. 1976, 98, 5399. - The Tebbe reagent was introduced in 1978 and was shown to react with aldehydes, ketones, esters, and lactones to produce the methylene derivatives. O Cp2Ti X X AlMe2 Cl X = H, R, OR, NR2 Tebbe reagent O 65% Tebbe J. Am. Chem. Soc. 1978, 100, 3611. - Tolerates ketal and alkene derivatives. Scope defined by Evans and Grubbs J. Am. Chem. Soc. 1980, 102, 3270. Extended to tertiary amides by Pine J. Org. Chem. 1985, 50, 1212. 81% O Ph Ph OCH3 90% O OCH3 Ph Ph OEt OEt O O O Ph 87% O O O OEt O Ph O 96% OEt 80% N Ph N For an analogous use of Cp2TiMe2: Petasis J. Am. Chem. Soc. 1990, 112, 6392. 370 Ph O Olefin Synthesis Dale L. Boger E. Representative Other Methods for Terminal Methylene Formation References Cainelli Tetrahedron Lett. 1967, 5153. Reagents R2CO, CH2CI2, Mg R2CO, LiCH2PO(NMe2)2 Corey J. Am. Chem. Soc. 1966, 88, 5653. Coates J. Am. Chem. Soc. 1972, 94, 4758. Kuwajima Tetrahedron Lett. 1972, 737. Kuwajima Tetrahedron Lett. 1972, 649. R2CO, LiCH2SPh; CH3SO2Cl; Li/NH3 R2CO, LiCH2SPh; (RO)2PCl; heat R2CO, LiCH2S(O)Ph - Julia Olefination Review: Comprehensive Org. Syn., Vol. 1, 792. OR'' 1) R'CHO R SO2Ar Na–Hg R R' SO2Ar R'' = Ms, Ts, Ac, COPh R R' 2) PhCOCl exclusively or predominantly the more stable trans isomer - Example: CHO 1) addition + 2) BzCl Li H Ts TBSO Na–Hg H Ts BzO H MeOH–THF 2 h, –20 °C 80% OTBS TBSO TBSO OTBS Julia Tetrahedron Lett. 1973, 4833. OTBS Julia developed a more recent, single-step variant that avoids the reductive elimination S Li N ArCHO S OLi SO2 N O SO2 Ar N Li SO2 S S Ar 54% 98:2 E:Z N OLi Ar Julia Bull. Soc. Chim., Fr. 1993, 130, 336. R2CO, LiCH2S(O)tBu; SOCl2–CH2Cl2 –CH(OH)CH2CO2H, HC(OMe)2NMe2, heat RC CH, RCu R2C=CH2 RCO2CH3, Ph3P=CH2 R(CH3)C=CH2 R2CO, PhS(O)(NCH3)CH2Li RCH2SO2CH2Cl, HO– - Ramberg–Backlund reaction R R S O2 Durst J. Am. Chem. Soc. 1973, 95, 3420. Hara Tetrahedron Lett. 1975, 1545. Normant Tetrahedron Lett. 1971, 2583. van der Gen Tetrahedron Lett. 1975, 1439. Johnson J. Am. Chem. Soc. 1973, 95, 6462. Doomes and Corfield J. Am. Chem. Soc. 1970, 92, 2581. R Cl R S O2 R R Org. React. 1977, 25, 1. 371 Modern Organic Chemistry The Scripps Research Institute Reagents References RC CH, H2/ Lindlar catalyst R2CHCH2OAc, ∆ (pyrolysis) Also: xanthates R2CHCH2NMe2, H2O2, ∆ Org. Syn. 1969, 46, 89. Org. React. 1961, 12, 57. Chem Rev. 1960, 60, 431. Org. React. 1960, 11, 317. - Cope Elimination + - it is related to the Hofmann elimination reaction (–NMe3) - Both the acetate pyrolysis and the Cope elimination have been superceeded by the related syn elimination reactions of sulfoxides and selenoxides. J. Chem. Soc., Chem. Commun. 1968, 305. R2C(Hal)CH3, tBuOK F. Olefin Inversion Reactions Ph Vedejs J. Am. Chem. Soc. 1971, 93, 4070. H OLi O Ph Ph Ph2PLi Ph Ph Ph2P H m-CPBA Ph OLi H Ph Li Ph2PCl Ph –Ph2MeP O Ph THF H H MeI OLi Ph Ph H Ph Ph2P O CH3 99% yield >98% cis CH3 Ph H + PPh2 -Other examples: Ph Ph m-CPBA 1) Ph2PLi 2) MeI Ph Ph 95%; > 99% trans m-CPBA 1) Ph2PLi 2) MeI OTHP OTHP 85%; >98% Z m-CPBA 1) Ph2PLi 2) MeI 90%; >99% trans 372 Ph H PPh2 Olefin Synthesis Dale L. Boger -Deoxygenation of epoxides (with retention of geometry) O R R R' R' van Tamelen J. Am. Chem. Soc. 1951, 73, 3444. –SCN Ph3P S , H+ Chan J. Am. Chem. Soc. 1972, 94, 2880. S S Stojnac Can. J. Chem. 1975, 621. N Johnstone J. Chem. Soc., Perkin Trans. 1 1975, 1216. –SeCN Clive J. Chem. Soc., Chem. Commun. 1973, 253. Ph3P Se S Se Chan Tetrahedron Lett. 1974, 2091. N Calo Synthesis 1976, 200. -Deoxygenation of epoxides (with inversion of geometry) O R R R' Me3SiK Dervan J. Am. Chem. Soc. 1976, 98, 1265. PhMe2SiLi -Diol R' Reetz Synthesis 1976, 199. Alkene HO OH R R R' Review: R' Org. React. 1984, 30, 457. S HO OH H H R R' (RO)3P O O H R cis elimination H R' Corey–Winter Olefin Synthesis R' Corey J. Am. Chem. Soc. 1963, 85, 2677. Corey J. Am. Chem. Soc. 1965, 87, 934. OEt HO OH H H R R' R O H+, EtOH O H R H R' (–CO2) cis elimination R R' Eastwood Aust. J. Chem. 1964, 17, 1392. Eastwood Tetrahedron Lett. 1970, 5223. OH OH RR HC(OEt)3 O O RR H H+ R OEt R Burgstahler, Boger Tetrahedron 1976, 32, 309. 373 Modern Organic Chemistry The Scripps Research Institute G. [3,3]-Sigmatropic Rearrangements 1. Claisen and Cope Rearrangement Org. React. 1975, 22, 1. Synthesis 1977, 589. Acc. Chem. Res. 1977, 10, 227. Comprehensive Org. Syn., Vol. 5, 785. D D Cope Rearrangement HO HO Oxy-Cope Rearrangement Claisen Rearrangement O O Introduction of C=O is the driving force of the reaction - Originally conducted on aryl allyl ethers. - Most useful variant established when extended to nonaromatic substrates. - First example of an acyclic Claisen rearrangement: CH3 CH3 cat. Hg(OAc)2 HO CH3 200 °C OEt 12 h 85% O CHO Burgstahler J. Am. Chem. Soc. 1961, 83, 198. 2. Amino-Claisen Rearrangement Me2SO4 N + N ∆ + N H2O O - This reaction occurs best when nitrogen is converted to the ammonium salt. Gilbert Tetrahedron Lett. 1984, 25, 2303. Stille J. Org. Chem. 1991, 56, 5578. 3. Thio-Claisen Rearrangement ∆ H3O+ S S O - This reaction is often run with a reagent that will convert sulfur to oxygen following the reaction. - An advantage of the thio-Claisen rearrangement is that the precursor can be deprotonated and alkylated. 1) nBuLi S 2) RX R ∆ S R R S trans C=C bond Corey J. Am. Chem. Soc. 1970, 92, 5522. Yamamoto J. Am. Chem. Soc. 1973, 95, 2693 and 4446. 374 O Olefin Synthesis Dale L. Boger - Also can be conducted with the corresponding sulfoxide. O S Block J. Am. Chem. Soc. 1985, 107, 6731. 4. The Carroll Reaction R R R ∆ esterification OH HO O R' O R' O O R Carroll J. Chem. Soc. 1940, 704, 1266. Hartung J. Chem. Soc. 1941, 507. Cope J. Am. Chem. Soc. 1943, 65, 1992. Tanabe J. Am. Chem. Soc. 1980, 102, 862. O Base O R' O R H3O+ R' O O –CO2 O R' O 5. Eschenmoser–Claisen Rearrangement MeO OMe 1 CO2Me CO2Me NMe2 O CO2Me O Me2N OMe OH xylene, 140 °C 14 h, 70% O NMe2 NMe2 + MeOH Eschenmoser Helv. Chim. Acta 1964, 47, 2425; 1969, 52, 1030. O 1 NMe2 Me2N xylene H Me O H H 17 h - Chair-like transition state, substituents in equatorial positions lead to trans double bond with transfer of chirality. OH H Hill J. Org. Chem. 1972, 37, 3737. 6. Ireland Ester Enolate Claisen Rearrangement - The most useful of all Claisen rearrangements. The enolate may be trapped with TMSCl or the enolate may be used directly. - The reaction works well with the free enolate and actually allows for a faster rearrangement that will occur at 25 °C (anion accelerated). OSiMe3 R' O R' R OH O R OSiMe3 R O OSiMe3 R' R' R O R O Ireland J. Am. Chem. Soc. 1972, 94, 5897. Larock Comprehensive Org. Trans., 935. OSiMe3 R' O R 375 Modern Organic Chemistry The Scripps Research Institute 7. Oxy-Cope Rearrangement HO HO O H relatively slow 250 °C + KO + KO H3O+ 1010–1017fold rate acceleration, occurs at 25 °C H 250 °C OH H OH O (slow) H H KH H 25 °C OK H H3O+ O OK H H Evans J. Am. Chem. Soc. 1975, 97, 4765. R Li N PhS –40 °C toluene R H Li N PhS –60 °C R NBn K THF Macdonald Tetrahedron Lett. 1993, 34, 247. - For a review of anion accelerated sigmatropic rearrangements: Org. React. 1993, 43, 93. 376 R H K NBn Olefin Synthesis Dale L. Boger 8. Representative [3,3]-Sigmatropic Rearrangement Routes to Olefins X OH O R R ∆ RHC • CHCH2COX Lumbroso–Bader Tetrahedron Lett. 1968, 4139; 1966, 3203. O R OH NaNH2 R O R Br NH2 Katzenellenbogen Tetrahedron Lett. 1975, 3275. O R O Zn OH R O R Br OH Baldwin J. Chem. Soc., Chem. Commun. 1973, 117. O OH R2NLi, Me3SiCl O O 60 °C SPh OH SPh Lythgoe Tetrahedron Lett. 1975, 2593. CHO ∆ O CHO Carnduff J. Chem. Soc., Chem. Commun. 1967, 606. Me3SiO O O ∆ O CH3 O OSiMe3 O O Me3SiO CH3 OSiMe3 CH3 H3C Coates J. Am. Chem. Soc. 1975, 97, 1619. ∆ O S OPh O S OPh Faulkner J. Am. Chem. Soc. 1973, 95, 553. 377 Modern Organic Chemistry The Scripps Research Institute H. [2,3]-Sigmatropic Rearrangements Review: Comprehensive Org. Syn., Vol. 6, pp 834, 873–908. Org. React. 1994, 46, 105–209. - Analogous to [3,3]-sigmatropic rearrangement except it enlists a localized charge (anion) in place of a double bond. - Often times the reaction is referred to as a Wittig [2,3]-rearrangement in honor of Wittig's discovery of the related 1,2-alkyl shift of oxycarbanions (Wittig Rearrangement). The reacton is simply a [2,3]-sigmatropic version of the Wittig rearrangement. - Examples: R R R R R CN R O Julia Tetrahedron Lett. 1974, 2077. R O more stable anion S S S R R CN O - reaction facilitated by loss of positive charge on sulfur S + ylide zwitterion Lythgoe J. Chem. Soc., Chem. Commun. 1972, 757. O R S S :PR3 O R S O Cl O Bu3SnCH2I R SnBu3 :PR3 O S R O nBuLi R base O R Cl Evans Acc. Chem. Res. 1974, 7, 147. - Still's use of the [2,3]-sigmatropic rearrangement: OH OH R [2,3] O H R CH3 Still J. Am. Chem. Soc. 1978, 100, 1927. no 1,3-diaxial interactions A 1,2-strain CH3 R H O CH3 R H O R R H vs. O CH3 H Z-transition state Li O H H H E-transition state one isomer, Z - R prefers the axial versus equatorial position: - Selectivity is lost when A 1,2-strain is removed H OH R R + O H Li 378 H 40:60 R CH3 OH Olefin Synthesis Dale L. Boger R O + O S Ph R S Ph Ph3P O S R OH Ph R trans olefin H H H H R Ph via the transition state: S H OH (EtO)2PCl R2 R1 vs. O H H Ph S R O H R1 O (EtO)2P R2 Bodalski Synthesis 1990, 799. - Ring expansion: Br + S + S B– S 65% S Vedejs J. Am. Chem. Soc. 1975, 97, 6878. Vedejs J. Org. Chem. 1978, 43, 1185. Vedejs Tetrahedron Lett. 1978, 523, 519. Ph + N N 90% RO2C N+ CO2R Ph 83% N Jones J. Org. Chem. 1962, 27, 3572. - Diastereoselectivity: tBu Cl tBu + S Ph Cl H2O 53% + S Ph 59% CO2Et tBu SPh 97:3 SPh 91:9 O tBu CO2Et Evans Tetrahedron Lett. 1972, 5121. 379 Modern Organic Chemistry The Scripps Research Institute S S N Br Ts(H)N SMe SMe Evans Tetrahedron Lett. 1973, 4691. NC + N R Br NMe2 Base R R CHO H3O+ R ∆ NC Mander J. Org. Chem. 1973, 38, 2915. Büchi J. Am. Chem. Soc. 1974, 92, 7573. CH3 CH3 R2NLi S R SH R Kreiser Tetrahedron Lett. 1975, 1669. Stork J. Am. Chem. Soc. 1974, 96, 6774. o-formylation of anilines: Prostaglandin synthesis; sulfenate/sulfoxide rearrangement. note olefin inversion. H N NH2 NH2 + S SMe X RS + N SR OMe O CH3 OH OMe MeO MeO MeO CH3 CH3 CH3 OMe R2N MeO X CH3 CH3 CH3 Juncusol Boger J. Org. Chem. 1984, 49, 4045. H Me3SiOTf CH3 N CO2CH3 + Et3N CH2Cl2, 25 °C HN CO2Me CH3 81:19 Nakai Chem. Lett. 1990, 2069. CH3 H N+ O CH3 TMS H H H See Also: OCH3 Sato J. Am. Chem. Soc. 1990, 112, 1999. CH3 N+ NaNH2 N NH3 di- and trisubstituted olefins 380 CH3 CH3 HN CO2Me CH3 Olefin Synthesis Dale L. Boger I. Olefin Synthesis Exemplified with Juvenile Hormone 1. Trost Synthesis: J. Am. Chem. Soc. 1967, 89, 5292. Wadsworth–Horner–Emmons Reaction O 2. Syntex Synthesis: J. Am. Chem. Soc. 1968, 90, 6224. Me Robinson Annulation Alkylation Diastereoselectivity Fragmentation Reaction Directed Epoxidation Reaction 3. Corey Synthesis: Me CO2Me H J. Am. Chem. Soc. 1968, 90, 5618. Dissolving Metal Reductions: Cyclic Precursors to Trisubstituted Olefins Oxidative Cleavage of Enol Ethers LiAlH4 Reduction of Propargyl Alcohols Cuprate Coupling Reactions Allylic Alcohol Oxidation 4. Johnson Synthesis: J. Am. Chem. Soc. 1968, 90, 6225. Julia Olefin Synthesis Cornforth Nucleophilic Addition 5. Corey Synthesis: J. Am. Chem. Soc. 1970, 92, 6635, 6636, 6637. Lindlar Catalyst Alkyne Reduction 1,5-Hydrogen Migration β-Oxido Ylide Reaction Diimide Reduction 6. Johnson Synthesis: J. Am. Chem. Soc. 1970, 92, 4463. [3,3]-Sigmatropic Rearrangements Claisen Reaction Cope Reaction Oxy-Cope Reaction 7. Stotter–Kondo Synthesis: J. Am. Chem. Soc. 1973, 95, 4444. J. Chem. Soc., Chem. Commun. 1972, 1311. Dihydrothiopyran Strategy: Cyclic Precursors to Trisubstituted Olefins Stabilized Allylic Anions, Desulfurization (Benkeser Dissolving Metal Reduction) Sulfur Ylides Cyclopropane Synthesis Epoxide Synthesis Tetrahedron Lett. 1979, 593. 8. Still Synthesis: [2,3]-Sigmatropic Rearrangement 9. Other Syntheses: Beltsville Synthesis: Mori Synthesis: MacKay Synthesis: Schering Synthesis: Zoecon Synthesis: van Tamelen Synthesis: J. Econ. Entomol. 1968, 61, 866. Tetrahedron 1969, 25, 1667. J. Chem. Soc., Chem. Commun. 1969, 733. Angew. Chem., Int. Ed. Eng. 1969, 8, 271. (Farnesol -> C-18 JH) J. Am. Chem. Soc. 1970, 92, 735. J. Am. Chem. Soc. 1970, 92, 737. 381 Modern Organic Chemistry The Scripps Research Institute 1. Trost Synthesis: O (MeO)2P O J. Am. Chem. Soc. 1967, 89, 5292. CO2Me Wadsworth–Horner–Emmons Reaction 1. LiAlH4, 86% + spinning-band distillation alkylation + 2. PBr3, 45% CO2Me Br CO2Me Wadsworth–Horner– Emmons reaction 37% O (MeO)2P NaOH; O CO2Et H+, –CO2 73% 17% CO2Me + CO2Me O Wadsworth–Horner– Emmons reaction O (MeO)2P Me 39% CO2Me 30% 1. LiAlH4 2. PBr3 3. CH3COCH2CO2Me 4. NaOH 5. H+, –CO2 CO2Me Me Me + CO2Me O Wadsworth–Horner– Emmons reaction m-CPBA 18% Me O CO2Me CO2Me 30% 40% C-18 JH 10% internal epoxide 10% diepoxide Relative Activity nat. C-18 JH syn. C-18 JH t-t-t (epoxide) c-t-t (triene) t-t-t (triene) c-t-t (epoxide) ethyl ester Me 1 1 0.4 0.1 0.04 8 H H H O HH Me CO2Me 382 Synthesis was relatively non-stereoselective - structural assignment - structure–activity studies - prevents adult development from pupa - more potent analog found Stereoselectivity - not much difference between Me and H (second atom steric effect) - both isomers obtained from the Wadsworth– Horner–Emmons reaction (Modern improvements now available) Retrosynthetic Analysis - repeating subunits recognized - repeating reactions utilized Olefin Synthesis Dale L. Boger J. Am. Chem. Soc. 1968, 90, 6224. 2. Syntex Synthesis: O Et O 2. TsOH, C6H6 67% O Et OTHP 2. DHP, H+ O Et Et OH LiAlH(OtBu)3 74% O Et OH LiAlH4 HO O Et Me Directed epoxidation Et2O gives exclusively the isomeric epoxide dioxane 65% Reduction regioselectivity Et OH TsCl, pyr –5 °C 89% OH Et Me TsO Fragmentation reaction 100% stereospecific TsCl, pyr Et OH NaH THF, 25 °C 50% OH Et Me Selective equatorial OTs formation Et OTs 25 °C 95% HO Me 2° vs. 3° TsCl selectivity Et O Et OH 5 °C O O Et Et H+ DHP ROH O THP O OR Et OH O 1. DHP, H+ 2. MeLi 3. H+, H2O 57% Stereochemistry of Nu– addition NaH THF, 25 °C 80% Fragmentation reaction NaBH4 O Et OH m-CPBA CH2Cl2 50% HO Et Me Reduction diastereoselectivity HO Me Thermodynamic enolate: alkylation diastereoselectivty Selective reduction THP protecting group Et OH 2. H+, H2O 54% (4 steps )(95% d.e.) O Et Robinson annulation Et Me 1. KOtBu, MeI 1. NaBH4, 5 °C 1. KOH, MeOH + O Et HO Robinson Annulation Alkylation Diastereoselectivity Fragmentation Reaction Directed Epoxidation Reaction O C-18 JH Selective Reduction - saturated vs. α,β-unsaturated carbonyl - ring strain associated with 5-membered ring carbonyl released on reduction - attack from least hindered face THP Protecting Group - if R group contains chiral centers, diastereomers result - removed by mild acid 383 Modern Organic Chemistry The Scripps Research Institute Thermodynamic Enolate - severe 1,3-diaxial interaction in chair-like T.S. axial alkylation - no steric incumberance to axial alkylation on least hindered face of twist boat T.S. OTHP OTHP – O vs. – O H LiAlH(OtBu)3 Reduction - large reagent, usually equatorial H– delivery - 1,2-interaction (torsional strain) relatively invariant to Nu– size - 1,3-steric interaction highly dependent on Nu– size - due to absence of axial C(3)–H, large reagent now gives axial delivery Dunitz angle OTHP O H O 109° H– H– m-CPBA HO HO Et Me Et OH Et OH Et OH Solvent CH2Cl2 Et2O Epoxidation - in Et2O, coordination of peracid to solvent gives delivery from the least hindered α-face - in CH2Cl2, H-bonding of OH to peracid provides delivery to the less accessible β-face - Teranishi J. Am. Chem. Soc. 1979, 101, 159. + HO O Et Me 50% 0% O Et Me 0% 100% 1st Fragmentation - utilized to control C=C bond stereochemistry - trans periplanar orientation of breaking bonds - dictates Z olefin geometry in product OH OH O H TsO NaH O 2nd Fragmentation - utilized to control C=C bond stereochemistry - trans periplanar orientation of breaking bonds - dictates E olefin geometry in product OTs O H H R H NaH R O H Fragmentation Reactions Grob Angew. Chem., Int. Ed. Eng. 1969, 8, 535. Angew. Chem., Int. Ed. Eng. 1967, 6, 1. Interannular LG LG P P - Trans periplanar arrangement of participating bond orbital and departing bond orbital LG P P Extraannular P 384 LG Intraannular LG LG P O Olefin Synthesis Dale L. Boger - Wharton J. Org. Chem. 1965, 30, 3254. - Fuchs J. Am. Chem. Soc. 1979, 101, 3567. - Case A H OTs H KOtBu + OH OH H H KOtBu H OH E2 elimination, no fragmentation OTs O - Case B H OTs KOtBu trans olefin only 90% OH H O OTs H KOtBu H O H H O - Case C H OTs KOtBu trans olefin only 90% O OH H H OTs O OTs OH H KOtBu O H H most stable conformation H less stable conformation and not set up for fragmentation - Case D H OTs KOtBu cis olefin only 95% OH H TsO H OH O H O KOtBu H 385 Modern Organic Chemistry The Scripps Research Institute - Other groups at "promoter" site can be used OTs O O KOtBu O O 95% H CO2CH3 CO2CH3 Me CO2CH3 OTs O O H Me CO2CH3 O KOtBu O H H H H - Many other types of fragmentation reactions CH3 O N OH O O CH3O CO CH 2 3 OCH3 1 O2 HO2C CO2CH3 N CH3 [4 + 2] Cycloaddition CH3O CH3O2C < 5 °C oxidative decarboxylation HO N CH3 O Boger J. Org. Chem. 1991, 96, 6942. J. Am. Chem. Soc. 1993, 115, 11418. CO2CH3 CH3O N CH3 CH3O CH3O2C N CH3 CH3O 1O 2 HO CO2CH3 N CH3 CH3O CH3O2C CO2H CO2H O O N HO CH3 Isochrysohermidin What is mechanism? CH3O CH3O2C OCH3 N N CH3O2C CO2CH3 CH3O CH3O + N N CH3O OCH3 N N CO2CH3 CO2CH3 CH3O2C N N CO2CH3 CH3O N CH3 CH3O CH3O2C 386 N CH3 CO2CH3 CO2CH3 CO2CH3 1. LiOH 2. TFAA 3. CH2N2 4. H2O CH3O N CH3 CH3O CH3O2C Intramolecular cyclic anhydride formation utilized to differentiate internal acids of tetraacid. N CH3 CO2H CO2H 1. Zn–HOAc 2. CH3I, NaH Olefin Synthesis Dale L. Boger 3. Corey Synthesis: Dissolving Metal Reductions Cyclic Precursors to Trisubstituted Olefins Oxidative Cleavage of Enol Ethers LiAlH4 Reduction of Propargyl Alcohols Cuprate Coupling Reactions Allylic Alcohol Oxidation J. Am. Chem. Soc. 1968, 90, 5618. Cyclic precursor to stereochemically defined trisubstituted olefin MeO MeO Li, THF/tAmOH NH3, –33 °C I OH 1. LiAlH4, NaOMe THF, ∆ 2. I2, –60 °C 65% Directed hydroalumination of alkyne Cuprate substitution 1. LiAlH4, NaOMe THF, ∆ Me2CuLi, 0 °C 1. PBr3, 0 °C 2. I 53% for 3 steps OH 2. I2, –60 °C Li TMS 80% 3. AgNO3, KCN 4. nBuLi, (CH2O)n OH OH Et2CuLi, Et2O –30 °C EtI, 0 °C 78% Li 3. TsOH, MeOH 30% OH 2. LiAlH4, Et2O 65% HO Mechanism 1. TsCl, pyr THPO 2. 1. TsCl, pyr 2. NaBH4, –78 °C 53% Birch reduction note regioselectivity OH CO2Me 1. O3 , –78 °C Me2S/MeOH OH 1. MnO2, hexane 1. NBS, DME/H2O 2. MnO2, NaCN 2. NaOiPr, iPrOH HOAc, MeOH, 70% O CO2Me CO2Me MnO2 oxidation MeO O O Ozonolysis - reacts preferentially with more electron-rich C=C - ring (cleavage) enlisted to control olefin stereochemistry - addition of MeOH gives methyl ester O Me2S: Stereospecific Synthesis of Trisubstituted Olefins - propargylic alcohols can be reduced with LiAlH4 to give an allylic alcohol R R OH LiAlH4 (1.0) NaOMe (2.0) OH R R LiAlH4 AlCl3 (cat.) H 60:1 ratio R H R I2 Al R'2CuLi OH I OH R' O R I R OAl R' R'2CuLi I2 H OH H OH 387 Modern Organic Chemistry The Scripps Research Institute - Cuprate Mechanism I I I Et2CuLi O– OH H O– H + Et2CuLi H O– + Et2CuLi + I– H Et Et CuIII O– + I– + Li+ + EtCu reductive elimination H - Posner Org. React. 1975, 22, 253. Org. React. 1972, 19, 1. Et O– + H CuI Et–Et + Cu O O– H origin for requirement for use of EtI H EtI competitive reductive elimination product Et O– H MnO2 hexane O MnO2 NaCN MeOH NC MnO2 Oxidation - mild oxidation of allylic alcohols - direct, mild method for oxidation to a methyl ester O OH OH NC O MeO electron deficient and less reactive 1. NBS DME/H2O 2. iPrONa CO2Me 388 O O CO2Me Epoxidation - selective - in polar solvent the molecule folds up such that the terminal C=C is more accessible Olefin Synthesis Dale L. Boger 4. Johnson Synthesis: J. Am. Chem. Soc. 1968, 90, 6225. R NaH, THF R Br O CO2Me CO2Me 1. Ba(OH)2 MeOH CO2R 2. H+, H2O O R=H R = CO2Me NaH (MeO)2CO Julia Olefin Synthesis Cornforth Nucleophilic Addition O R = CO2Me CH2N2 65% ZnBr2 NaBH4 MeOH CO2Me R PBr3, LiBr collidine Et2O, 0 °C Et2O, 0 °C CO2Me O EtOH, 0 °C R Cl CuCl2–LiCl DMF, 45% O MeMgCl Me HO THF, –75 °C R=H R = Cl CO2Me H Cl O O Na, EtI O K2CO3 HCl KOH Br Et Et Br vs. H R H Br R Br O CO2Me H CO2H O Cl O MeOH, 25 °C Me diastereoselective 92:8 Cornforth nucleophilic addition CO2Me O O O 95:5 (t,t:t,c) Ba(OH)2 2. LDA, THF 5% HMPA O CO2Me Br Cyclopropylcarbinyl– homoallylic alcohol rearrangement R = OH R = Br 1. NaI, HMPA 25 °C O R=H R = Me O 1. NBS 2. MeOH cat. H2SO4 Br CO2Me Cyclopropylcarbinyl Bromide Rearrangement - highly stereoselective modification of Julia olefin synthesis - Johnson J. Am. Chem. Soc. 1968, 90, 2882 - Julia Bull. Soc. Chim., Fr. 1960, 1072. - ring opening concomitant with ionization - antiperiplanar arrangement of the C–Br and cleaved cyclopropane bond is necessary Cl O R Et H MeMgBr Cornforth Nucleophilic Addition - J. Chem. Soc. 1959, 112, 2539. - earliest generalization of the Felkin model of nucleophilic addition to a carbonyl group in acyclic systems 389 Modern Organic Chemistry The Scripps Research Institute J. Am. Chem. Soc. 1970, 92, 6635, 6636. 5. Corey Synthesis: 1. nBuLi 2. (CH2O)n 3. Ac2O H H Lindlar Catalyst Alkyne Reduction 1,5-Hydrogen Migration β-Oxido Ylide Reaction Diimide Reduction H2SO4 OH CH2I2, Cu–Ag 4. H2/Pd-BaSO4 5. NaOH OH Allylic alcohol directed Simmons–Smith Lindlar catalyst hydrogenation OH H OHC 350 °C NaBH4 96% 65% H HO 1,5-H Shift dictates olefin stereochemistry - Alternatively OTHP OTHP PPh3 1. n 2. BuLi 3. (CH2O)n CHO OTHP PBr3 OH Br Me2CuLi or Me3FeLi β-Oxido ylide modification of Wittig reaction OTHP OTHP + 1. H3O+ 2. TsCl 3. NaI/acetone 4. Ph3P PPh3I (50:50) with Cu (100:0) with Fe Me HO 1. nBuLi Me PPh3I OH OTHP 1. H+, DHP 1. MnO2 2. 3. sBuLi 4. (CH2O)n H 2. O3, Zn, HOAc O Me OTHP β-Oxido ylide 2. Ph3P=CH2 Wittig reaction 1. H+ 2. [O] (c.f. 1968) HN=NH Me 3. epoxidation Me OTHP Me CO2Me O OTHP Diimide reduction Ph3P O PPh3 + R + R'CHO R' R β-Oxido Ylide Modification H H 390 OH H sBuLi OH –O H R' PPh3 (CH2O)n R –O H R' PPh3 R H R' – O 1,5-H Shift Diimide Reduction - less substituted C=C reduced more rapidly - generated in-situ O PPh3 R H R' –O HO N N H H R R N N H H R H R H H H R Olefin Synthesis Dale L. Boger 6. Johnson Synthesis: J. Am. Chem. Soc. 1970, 92, 4463. H+, toluene CO2Me + OH MeO OMe 1 NaBH4 CO2Me 100 °C O 87:13 trans:cis Olefinic ketal Claisen reaction 1. 1, H+, toluene 100 °C cis (13%) removed after reduction SN2' reaction Olefinic ketal Claisen reaction 51% CO2Me and 12% Cl 1. NBS H2O/THF NaBH4, DMSO CO2Me 1,5-hexadiyne 50 °C 2. K2CO3, MeOH, 35% and chlorine impurity CO2Me CH3CO2H MeOH, 0 °C OAc H+ CO2Me OMe H CO2Me OH 100 °C OH CO2Me Olefinic Ketal Claisen Reaction - selectivity dependent on 1,3-interaction in chair-like T.S. - second Claisen more selective due to larger R group vs. CO2Me CO2Me H+ O OMe 81% CO2Me H+, tol + OMe O Me K2CO3 CO2Me (CH3CO)2O O O –MeOH Me Me CO2Me vs. O R OH hexane, 0 °C 85% Cl OH MeO CO2Me MeOH, 0 °C SOCl2 CO2Me 2. NaBH4 MeOH, 0 °C 70% [3,3]-Sigmatropic Rearrangements Claisen Reaction Cope Reaction Oxy-Cope Reaction H H O R H H CO2Me CO2Me O O 87 : CO2Me 13 391 Modern Organic Chemistry The Scripps Research Institute 7. Stotter–Kondo Synthesis: S J. Am. Chem. Soc. 1973, 95, 4444. Dihydrothiopyran Strategy: J. Chem. Soc., Chem. Commun. 1972, 1311. Cyclic Precursors to Trisub. Olefins Stabilized Allylic Anions Desulfurization, Benkeser Red. Sulfur Ylides Cyclopropane Synthesis Epoxide Synthesis S 1. MeMgBr 2. POCl3, C6H6 Me pyr, 90% O S S sBuLi Me2S+(O)CH2– S DABCO –20 °C, THF Me S 75–90% overall OH S SOCl2, pyr S Me 75% O O Sulfur ylide epoxidation sBuLi 1 or 2 DABCO cyclic precursors dictate trisubstituted olefin stereochemistry S S Li/EtNH2 Me Me OR R = THP, 60% R = Li, 90% R=H Ra–Ni 55–70% SH –78 °C SH Me Me OH Benkeser reduction dissolving metal reduction Me [O], see Corey 1968 Me OH Me CO2Me Me Trost Intermediate HOCl HOCl Me Cl nBuLi OLi DHP, H+ Me Cl 2 OTHP 1 thermodynamic E product Cl S O O Cl N DABCO N ** ** Convergent Route - symmetrical intermediate * S *** DABCO - accelerates slow deprotonation - breaks up Li aggregates Site of Deprotonation - at carbon activated by both S and vinyl Sulfur Ylides: Trost, Melvin Sulfur Ylides: Emerging Synthetic Intermediates, Academic Press, 1975. Benkeser Reduction Synthesis 1972, 391. 392 Olefin Synthesis Dale L. Boger S Use of Cyclic Precursors - control olefin geometry - insert S, remove with Ra–Ni S Me S Specific Deprotonation Site - kinetically preferred site due to sterics - the thermodynamic and kinetic product - alkylation occurs cleanly α, not γ, to heteroatom (a well established trend) S Me - Li/NH3 Birch Reduction (blue solution), –33 °C at refluxing NH3 temperatures - Li/EtNH2 or MeNH2 Benkeser Reduction, more strongly reducing because of higher reaction temperature S e– S e– EtNH2 S H3O+ S SH H H protonation no protonation, more hindered, olefin geometry maintained restricted rotation of allyl anion π-system - 1,4-Addition of sulfur ylides -> cyclopropanes Ph2S-CH2CH3 Ph2S + EtI ICH2CH3 I– AgBF4 AgI + Ph2S-EtBF4 Me O Ph2S O Me Me R' = H Me R' Me O Ph2S Me R' = Me R' O - This reaction is sensitive to substitution pattern on the α,β-unsaturated carbonyl Me Me R' - In addition, a substituted sulfur ylide increases propensity for epoxide formation over cyclopropane formation 393 Modern Organic Chemistry The Scripps Research Institute Tetrahedron Lett. 1979, 593. 8. Still Synthesis: [2,3]-Sigmatropic Rearrangement tBuLi, OHC Br Et2O –78 to 0 °C THF, –78 °C + 93% Li Br OR OHC OH KH, THF nBuLi, OR Bu3SnCH2Cl 88% O O SnBu3 SnBu3 OR OH OH OH OH THF –78 to –20 °C 79% OR [2,3]-Sigmatropic rearrangement OTs OTs LiAlH4 TsCl, pyr Et2O, 0 °C 98% 0 °C, 93% OR OR H2O–HOAc 45 °C, 92% Me Me R J. Am. Chem. Soc. 1978, 100, 1927. R O OLi one isomer, Z Li R H O Me H H R O– R H O– Me H vs. H R Me O H H severe allylic 1,2-strain 394 R = CH(CH3)OCH2CH3 R=H Me Note: Me substitution on olefin provides Z selectivity. Organocuprate and Conjugate Addition Reactions Dale L. Boger XII. Conjugate Additions: Organocuprate 1,4-Additions Reviews: House Acc Chem Res., 1976, 9, 59. Ashby Chem Rev., 1975, 75, 521. Comprehensive Org. Syn., Vol. 4, 169. O Review: Lipshutz Org. React. 1992, 41,135. Posner Org. React. 1975, 22, 253. Posner Org. React. 1972, 19, 1. HO RMgX or R RLi 1,2-addition - But Kharasch observed 1,4-addition with added Cu(I) salt: OM O O RMgX cat. Cu(I) 1,4-addition R R Kharasch J. Am. Chem. Soc. 1941, 63, 2308. - This led to the development of stoichiometric organocuprate reagents: ether or MeLi + CuI (1 equiv) THF MeLi (1.0 equiv) Me-Cu-Me Li "ate" complex colorless, soluble, stable even at 25 °C Me-Cu + LiI insoluble, bright yellow organocopper reagent House, Whitesides J. Org. Chem. 1966, 31, 3128. - "ate" complexes incorporating Li+ were first described by Gilman (J. Org. Chem. 1952, 17, 1630) and consequently such reagents are often referred to as "Gilman reagents". - Most organometallics, including organocuprates, are susceptible to β-elimination: H CH R –40 to H R Cu H R + CH2 –20 °C CH2 Cu Li - So most organocuprates are best handled at temperatures lower than ca. –40 °C. R 1. Scope - Relative ease of ligand transfer from Cu follows the order: , Ph > Me > Et > iPr > tBu >> PhS, R2N, RC C Dummy ligands for mixed cuprates - In addition, the size of the migrating group also affects the conversion: R O R=H R=H R = CH3 R = CH3 R = CH3 R = CH3 R = CH3 Me2CuLi Ph2CuLi Et2CuLi iPr CuLi 2 t Bu2CuLi Ph2CuLi CuLi 60–80% 25% 55–65% 58% 40% 0% 0% 1,2-addition observed 2 395 Modern Organic Chemistry The Scripps Research Institute - Effect of substrates: O O O > OR O >> CN O– RO OR O Me2CuLi O t Bu Me 96% tBu - Unsaturated esters are less reactive than enones. - β,β-Disubstitution slows reaction. O OCH3 OCH3 Me2CuLi O tBu Me tBu δ BF 3 BF3•OEt2 - unreactive substrates will react if Lewis acids are added to activate substrate toward nucleophilic addition. // δ O 53% OCH3 tBu - also note the alternative use of higher order cuprates [R2CuCN]Li2. Maruyama J. Am. Chem. Soc. 1977, 99, 5652. Yamamoto J. Am. Chem. Soc. 1978, 100, 3240. RCu•BF3 Yamamoto J. Am. Chem. Soc. 1980, 102, 2318. Yamamoto J. Org. Chem. 1979, 44, 1745. MeCu•BF3 88% O O Me2CuLi Review: Yamamoto Angew. Chem., Int. Ed. Eng. 1986, 25, 947. // Me2CuLi•BF3 70% Me2CuLi−TMSCl Corey Tetrahedron Lett. 1985, 26, 6015. O O O Me2CuLi Me2CuLi TMSCl O 396 O O Organocuprate and Conjugate Addition Reactions Dale L. Boger - Conjugate addition to α,β-unsaturated aldehydes is typically problematic but successful examples have been reported. O Me Me3CuLi2 H O H 81% Still Tetrahedron Lett. 1976, 2659. Meyer Org. Prep. Proceed. 1979, 11, 97. Clive J. Chem. Soc., Chem. Commun. 1981, 643. (Me5Cu3Li2) Clive J. Org. Chem. 1982, 47, 2572. Conjugate Addition/Alkylation (stereochemistry) Posner J. Org. Chem. 1979, 44, 3661. Review: Comprehensive Org. Syn., Vol. 4, pp 237–268. Conjugate Addition/Aldol Heng Tetrahedron 1979, 35, 425. - Cuprates can also be prepared from other organometallic reagents which have greater compatibility with reactive groups: e.g. activated Cu(o)/RBr, RZnI, RSnBu3/Me2Cu(CN)Li2, RCH=CH2/ Cp2Zr(H)Cl then CuBr•SMe2 O Cp2Zr O 1. H 2. CuBr•SMe2 Cl ZrCp2 Cl hydrozirconation Lipshutz Tetrahedron Lett. 1992, 33, 5857. 25 °C, 1h 79% - Useful in the regiospecific trap and subsequent generation of enolates. R2CuLi TMSCl LiO O R TMSO MeLi LiO R R Stork J. Am. Chem. Soc. 1974, 96, 7114. Stork J. Am. Chem. Soc. 1961, 83, 2965. Horiguchi Tetrahedron Lett. 1989, 30, 7087. - Asymmetric 1,4-addition O + R2Zn cat. Cu(OTf)2 O > 95% ee cat. O P N O Ph Ph Feringa Acc. Chem. Res. 2000, 33, 346. 397 Modern Organic Chemistry The Scripps Research Institute - Additions to acetylenes R' R' R2CuLi CO2CH3 CO2CH3 cis addition of "RCu" R R' = Et Cu R = CH3 THF at –100 °C 97:3 THF at –78 °C 92:8 cis:trans toluene (3 h) 92.5:7.5 ether (3 h) 24:76 lower stereoselectivity due to configurational instability of alkenyl copper reagent see also: Alexakis Bull. Chim. Soc., Fr. 1977, 693. Cahiez Synthesis 1976, 245. Alexakis Tetrahedron Lett. 1976, 2313. Truce J. Org. Chem. 1978, 43, 2252. Marfat J. Am. Chem. Soc. 1977, 99, 253. R' R CO2CH3 –30 °C to 0 °C R' Cu R Cu CO2CH3 25 °C rapid 0 °C slow –30 °C observable Corey, Katzenellenbogen J. Am. Chem. Soc. 1969, 91, 1851. Fried J. Am. Chem. Soc. 1969, 91, 1853. Klein J. Chem. Soc., Perkin Trans. 2 1973, 1971. - Alkenyl copper intermediates can be subsequently trapped: R' R CO2CH3 E+ E+= H+ (H2O), Br+ (NBS) Cu R' R CO2CH3 E - Also, used in displacement of leaving groups (addition/elimination reactions). via β-elimination from intermediate enolate R2CuLi X CO2CH3 R CO2CH3 X = SPh, Br, OAc (good leaving group) CO2CH3 X CO2CH3 R cis addition X R net retention of stereochemistry CO2CH3 H Cu trans elimination X R CO2CH3 H Cu X = SPh Corey J. Am. Chem. Soc. 1969, 91, 1851. Casey Tetrahedron Lett. 1974, 925. Mukaiyama Chem Lett. 1974, 705. 398 Organocuprate and Conjugate Addition Reactions Dale L. Boger - Examples: CO2CH3 CO2CH3 R2CuLi AcO Coates J. Org. Chem. 1974, 39, 275. Coates J. Am. Chem. Soc. 1971, 93, 1027. Corey Tetrahedron Lett. 1973, 3817. R AcO CO2CH3 R R2CuLi CO2CH3 O X = SPh, Cl, Br, OAc (but not for OCH3) X O OLi Me SPh O –PhS Me2CuLi SPh Me OLi Me Me2CuLi O RX Me R Me Me O Li0 Cl Cl Li Li Et2O 0 °C 1. CuSPh –78 to –15 °C O 2. Wender Org. Syn. 1992, 70, 204. Cl - Selective preparation of ketones from carboxylic acid derivatives. O R' R2CuLi O // Cl R' O Cl tBu R' R (tBu)2CuLi 60% Et2O, 0 °C O OLi R R no overaddition to give 3° alcohol tBu tBu no epimerization of axial carbonyl group - Additions to terminal alkynes. R H R'Cu cis addition H+ R R R' Cu R' E+ R E R' 399 Modern Organic Chemistry The Scripps Research Institute - Alkylation reactions Me Br 2 Me2CuLi H Br H Me H H H H Me2CuLi H Br H Me H substitution reactions proceed with retention of configuration H O P OR O OR Me Me2CuLi a) Li/NH3 H b) H+ - Mechanism: O P OR O OR e– O– P OR O OR H e– H - Also can be conducted with aryl and enol triflates OSO2CF3 Me Me2CuLi functional group reactivity~ RCOCl > CHO > tosylates > epoxides > bromides > ketones > esters > nitriles 400 Organocuprate and Conjugate Addition Reactions Dale L. Boger 2. Mechanism reversible π-complex a) Me Cu Me O oxidative addition O (I) Me Cu(III) Li Me Me Cu Me (I) reductive Me-Cu(I) + OLi OLi elimination Me Cu(III) Me Me or b) Me2CuLi + O electron O Me2Cu + Li radical anion transfer Me2CuLi O -Evidence for mechanism b) i. Isomerization and recovery of substrates without 1,4-addition tBu CO2tBu tBu CO2tBu < 1 equiv Me2CuLi CO2tBu vs. tBu tBu Me OH MeLi tBu no isomerization of recovered starting material via OLi tBu tBu evidence for electron transfer mechanism 401 Modern Organic Chemistry The Scripps Research Institute ii. Cation is essential for the reaction Me2Cu Li - if crown ethers are added to reaction mixture, reaction is slowed or prevented - Li+ complexes with carbonyl oxygen and activates substrate to conjugate addition (Ouannes Tetrahedron Lett. 1977, 815.) iii. Retention of stereochemistry of cuprate alkyl group that is transferred e.g. O O tBu // Cu retention of configuration // Cu tBu O O Whitesides J. Org. Chem. 1972, 37, 3718. Whitesides J. Am. Chem. Soc. 1969, 91, 6542. - So reaction cannot be proceeding through a free-radical Cu tBu O would get mixture - Retention also observed for alkenyl cuprates: Br 0.5 equiv CuI Li CH3 CH3 O CuLi 2 O CH3 Casey Tetrahedron Lett. 1971, 2455. Configurationally stable - Not true for free radical H H H 402 H Organocuprate and Conjugate Addition Reactions Dale L. Boger - Additional evidence for radical anion mechanism: Me Me2CuLi + O O O Marshall Tetrahedron Lett. 1971, 2875. 55% 39% may be formed via intermediate radical anion Me2CuLi + O O O 43% 49% - but CO2tBu Me2CuLi OtBu OtBu // k = 10–2 s–1 OLi OLi not observed Me2CuLi CO2tBu tBu O tBu // OLi tBu LiO - So half-life of intermediate radical anion is very short. - Subsequent coupling with cuprate reagent (after e– transfer) is faster than other radical reactions in some cases. - However, competitive single electron reductions with cuprates have been observed and they may be used to effect reductive elimination reactions in manner analogous to dissolving metal or Zn reductions. 403 Modern Organic Chemistry The Scripps Research Institute iv. Trap of intermediate radical anion OTs H+ Me2CuLi, –78 °C H2O MO O O 96% Ac2O AcO - no conjugate or homo-conjugate addition observed, only intramolecular trap of intermediate radical anion Hannah Tetrahedron Lett. 1975, 187. OTs LiO OTs O O e– - Key piece of evidence for electron transfer mechanism. Ac2O AcO LiO v. House J. Am. Chem. Soc. 1972, 94, 5495. - Rate and ease of conjugate addition to the substrate correlate with the polarographic reduction potential while they do not always correlate with propensities for Michael addition. Eo Me2CuLi + e– CuLi CuLi + e– 2 2 Ph2CuLi Ph2CuLi CuLi 2 404 Me2CuLi –2.35 v –2.1 v + e– –2.3 v CuLi + e– –2.4 v 2 But these are not experimentally determined Eo values. Organocuprate and Conjugate Addition Reactions Dale L. Boger - And for conjugate addition with Me2CuLi Ered Ered O –1.63 v Ph CO2Et nPr CO2Me –2.26 v O –2.13 v CO2Et –2.25 v tBu MeO2C –2.14 v COMe O OCH3 tBu –2.12 v –2.33 v O O –2.35 v –2.20 v OCH3 All can accept an e– (undergo reduction) by Me2CuLi. O Eo = –2.35 v - But these substrates do not react with Me2CuLi: CO2CH3 OBu –2.43 v –2.50 v t Bu O CN CO2CH3 Note that for –2.55 v –2.54 v tBu tBu E the ease of organocuprate conjugate addition decreases in the order: E = COR > CO2R > CN House Acc. Chem. Res. 1976, 9, 59. 405 Modern Organic Chemistry The Scripps Research Institute -House estimation of O R3 O R1 R4 base value = –1.8 v R2 base value = –1.9 v R1 R2 substituent R1 R2 R3/R4 substituent R1 R2 alkyl alkoxy phenyl –0.1 –0.3 +0.4 –0.1 0 +0.1 –0.1 –0.3 +0.4 alkyl alkoxy –0.1 –0.3 –0.1 --- R CN R R base value = –2.3 v vi. Kinetic preference for 1,2-addition for standard organometallic (and other) nucleophiles suggests something unique about 1,4-addition of organocuprates O O // // R-CuX R-M vii. 13C NMR detection of reaction intermediates - Mechanism of organocuprate conjugate addition: observation of cuprate–olefin complexes and Li-coordinated intermediates in the reaction of lithium dimethyl cuprate with 10-methyl∆1,9-2-octalone. Robin and Smith J. Am. Chem. Soc, 1989, 111, 8276. Cu(III) intermediate observed directly O O O XLi O (CuMe2)nLin 2 4 See also: Corey Tetrahedron Lett. 1990, 31, 1393. O M O 5 CuMe2 The intermediates 1–5 were observed at –78 °C in Et2O-d6 by 13C NMR LiX viii. Isolation of the π-complex and conversion on to product Corey Tetrahedron Lett. 1985, 26, 6015. 406 Li 3 (CuMe2)nLin 1 6 Organocuprate and Conjugate Addition Reactions Dale L. Boger 3. Homoconjugate Addition CO2Et Me2CuLi Me CO2Et CO2Et CO2Et - Can also use O O O O -These reactions work well with Me2CuLi, and probably vinyl cuprates and aryl cuprates (no problem with β elimination) but not as well for simple alkyl cuprates (less stable, must keep < –30 °C) - Application to prostaglandin synthesis: O O O O CO2CH3 O N2 OTHP CO2CH3 CuLi 2 O CO2CH3 OTHP OTHP Corey J. Am Chem. Soc. 1972, 94, 4013. and CO2CH3 O CO2CH3 O N2 Me CO2CH3 O OSiMe2tBu R OSiMe2tBu R – 2Cu 2 O CuLi R O 407 Modern Organic Chemistry The Scripps Research Institute 4. Competitive Reduction and Rearrangement a) Interception of radical–anion intermediate OTs Me2CuLi O O b) Reduction e– OLi OLi O // CH3O Me OCH3 CH3O OCH3 OCH3 Also observed with γ-acyloxy enones: O OLi OLi Me2CuLi R = Ac OR Ruden Tetrahedron Lett. 1975, 2043. R = CH3 R = THP OR Note: This is cited as further support of the electron transfer mechanism. poorer leaving groups via OLi OLi OAc R2CuLi X = Cl reduction 408 OLi O OLi X R2CuLi X = OCH3 R conjugate addition X Organocuprate and Conjugate Addition Reactions Dale L. Boger 5. Mixed Organocuprates - For dialkylcuprates, one alkyl substituent (ligand) is lost: O R R2CuLi 2RI O + RCu lost - Mixed cuprates have been developed in which one ligand will not transfer: Corey J. Org. Chem. 1978, 43, 3418. Cu Cu RS Cu R2N Cu C5H11 Cu CH3O - With these reagents, only the non-transferable reagent is lost Cu Me Li Cu + MeLi CH3O CH3O - Also: addition of Li salts forms cuprate reagents from alkyl copper reagents ("ate" complexes) MeCu O MeCu LiI No reaction 1,4-addition (MeCuILi) MeCu LiCN 1,4-addition (MeCuCNLi) House J. Org. Chem. 1966, 31, 3128. These are more reactive and also very good for sluggish reactions e.g., epoxide openings, alkylations. Higher Order Cuprates R2CuLi 2RLi + CuCN LiCN R2Cu(CN)Li2 R2Cu(CN)Li2 See: Lipshutz Org. React. 1992, 41, 135. Lipshutz Synthesis 1987, 325. Lipshutz Tetrahedron 1984, 40, 5005. 409 Modern Organic Chemistry The Scripps Research Institute - Representative Mixed Cuprates RLi, CuI, R3P (1:1:2) Suzuki Tetrahedron Lett. 1980, 1247. (COD)RCuMgX Leyendecker Tetrahedron Lett. 1980, 1311. RCu(SPh)Li, RCu(OtBu)Li, RCu(NMe2)Li Posner J. Am. Chem. Soc. 1973, 95, 7788. RCu(SPh)Li Alexakis Tetrahedron Lett. 1976, 3461. Org. Prep. Proc. Int. 1976, 8, 13 RCu(C CtBu)Li and RCu(CN)Li Boeckman J. Org. Chem. 1977, 42, 1581. Marino J. Org. Chem. 1976, 41, 3213. RCu(CN)Li Acker Tetrahedron Lett. 1977, 3407. Miyaura Tetrahedron Lett. 1977, 3369. RCu(C CPr)Li Corey J. Am. Chem. Soc. 1972, 94, 7210. RCu(C CC(OMe)Me2)Li Corey J. Org. Chem. 1978, 43, 3418. 6. Functionalized Organocuprate Reagents - Examples O O H H Cu•TMEDA•LiI CO2Et O O TMSCl, –78 °C, 3 h H H 92% CO2Et Configurationally stable (better than higher order cyano cuprate): prepared from the corresponding Bu3Sn reagent/nBuLi then CuI/TMEDA. Linderman J. Org. Chem. 1991, 56, 5491. 410 Organocuprate and Conjugate Addition Reactions Dale L. Boger - Other representative functionalized organocuprate reagents )2CuLi Kojima, Wakita and Kato Tetrahedron Lett. 1979, 4577. O EtO )2CuLi Me3Si )2CuLi R2CuLi R = nBu, Ph, CH2=CH, sBu R = tBu, Me, CH2=CHCH2 N R X N ) CuLi 2 R X Cu(SPh)Li Doyle and West J. Org. Chem. 1975, 40, 3821. Nordlander and Haky J. Org. Chem. 1979, 45, 4780. Schollkopf and Haenssle Justus Liebigs Ann. Chem. 1972, 763, 208. Baldwin, Hoefle and Lever J. Am. Chem. Soc. 1974, 96, 7125. Huynh and LinstrumelleTetrahedron Lett. 1979, 1073. House and Wilkins J. Org. Chem. 1978, 43, 2443. Corey and Enders Tetrahedron Lett. 1976, 11. Corey and Boger Tetrahedron Lett. 1978, 4597. Gawley, Termine, and Aube Tetrahedron Lett. 1980, 21, 3115. X = NMe2, OCH3 (RCH=CHCH2)2CuLi (MeO)2CH Cu(C CtBu)Li [(EtO)2P(O)CH2]2CuLi ) CuLi 2 )2CuLi PhSCu(Li)CH2(CH2)nCH2Cu(Li)SPh Miginiac, Daviaud and Gerard Tetrahedron Lett. 1979, 1811. Depezay and Le Merrer Tetrahedron Lett. 1974, 2751. Boeckman and Rammaiah J. Org. Chem. 1977, 42, 1581. Cyano cuprate: Marino and Farina J. Org. Chem. 1976, 41, 3213. Thiophenyl cuprate: Grieco, Wang, and Majetich J. Org. Chem. 1976, 41, 726. Savignac and Mathey Tetrahedron Lett. 1976, 2829. Mathey and Savignac Synthesis 1976, 766. Wender and Filosa J. Org. Chem. 1976, 3490. Marino and Browne J. Org. Chem. 1976, 3629. Piers, Lau and Nagakura Tetrahedron Lett. 1976, 3233. Piers and Nagakura Tetrahedron Lett. 1976, 3237. Marino and Browne Tetrahedron Lett. 1976, 3241. Marino and Browne Tetrahedron Lett. 1976, 3245. Wender and Eck Tetrahedron Lett. 1977, 1245. 411 Modern Organic Chemistry The Scripps Research Institute Y ((RO)2PCH2)2CuLi, Y= O, S )2CuLi Savignac and Mathey Tetrahedron Lett. 1976, 2829. Fargeas Tetrahedron 1996, 52, 6613; 1994, 35, 7767. Bu3Sn Me2NCH2 ) 2CuLi O Corey, Cane and Libit J. Am. Chem. Soc. 1971, 93, 7016. Ireland J. Org. Chem. 1975, 40, 973. CuLi )2CuLi Wollenberg J. Am. Chem. Soc. 1977, 99, 7365 Schlosser, M. J. Org. Chem. 1978, 43, 1595. OEt ) 2CuLi Linstrumelle Tetrahedron Lett. 1979, 1073. Me3Si Cu(Li)C CPr OR (n = 1, R = THP) Corey J. Am. Chem. Soc. 1976, 98, 222. (n = 3, R = TBDMS) Corey Tetrahedron Lett. 1976, 4701 and 4705 . n Me Cu(Li)C C(Me)2OMe Corey Tetrahedron Lett. 1978, 1051. Corey J. Am. Chem. Soc. 1978, 100, 2916. THPO R(Li)Cu C5H11 OR 412 Corey J. Am. Chem. Soc. 1972, 94, 7210. Corey Tetrahedron Lett. 1983, 24, 5571. Corey Tetrahedron Lett. 1986, 27, 2199 and 3585. Organocuprate and Conjugate Addition Reactions Dale L. Boger 7. Stereochemistry of Organocuprate Conjugate Addition Reactions A. Cyclic Substrates Cyclic enones: intraannular diastereoselectivity Ref. 2,3-diastereoselectivity O O Me2CuLi Me 1 Me Me O O condition dependent: cis preferred, but isomerization to trans is facile. H Me2CuLi Me 3,4-diastereoselectivity O O R1 R1 Me Me Et iPr Ph R2CuLi 2 R R1 R trans:cis R1 72:28 78:22 88:12 96:4 (87:13) Et R trans:cis Me Ph iPr Me Et 77:23 89:11 89:11 92:8 3-substituted enones O O R2CuLi 3 R R R 3,5-diastereoselectivity O O 4 R1 R trans:cis Me Me 98:2 (99:1) (93:7) trans only R2CuLi R1 R1 R Me CH2Ph 3,4-diastereoselectivity vs 3,5-diastereoselectivity O O Ph2CuLi 4 Ph Ph Ph Ph Ph O O This will be dependent on the relative size of the C-3 and C-4 substituents. CuLi 2 Me Me CO2Et Me 3,6-diastereoselectivity O 5 Me 80 : 20 CO2Et OSiMe3 Me2CuLi R R Me 413 Modern Organic Chemistry The Scripps Research Institute Exocyclic enones and esters Ref. CHCOMe Me CHCOMe 96% 6 Me2CuLi tBu tBu O O Me Me2CuLi 7 tBu tBu Bicyclic enones and related substrates R R Me2CuLi 8 R = H, Me O O Me R Me Me2CuLi 9 O O H MeMe Me H H H N Me2CuLi O N O OTHP Me Me OTHP Me Me2CuLi O O H H CuLi 2 10 O O R Me R1 Me O R1 R N R2CuLi 11 414 Me O O H N R2CuLi O H Organocuprate and Conjugate Addition Reactions Dale L. Boger ref. Me H Me H Me H Me H Me2CuLi 12 O Me2CuLi O 1 Me O O Me Me 1,6-addition 13 R2CuLi O Me 2 rate: 2 > 1 (>20:1) O R R trans:cis Me 93:7 Et 98:2 iPr 100:0 tBu 100:0 Medium-sized rings Me Me O Me2CuLi 14 > 100:1 Me O Me Me2CuLi O O Me Me Me 14 O Me2CuLi O 99:1 96:4 Me Me BUT Me 14 O Me Me2CuLi O Me Me O Me2CuLi 96:4 96:4 Me O Me 415 Modern Organic Chemistry The Scripps Research Institute B. Acyclic Substrates O 12 O H Me Me2CuLi Ph Ph H OMOM Ph > 30:1 Bu 15 Ph (Bn)2N H Bu2CuLi CO2Et > 30:1 H Ph H OMOM Ph (Bn)2N H H H CO2Et + Ph (Bn)2N H H Bu CO2Et H > 95: <5 Bu 15 Ph (Bn)2N H CO2Et Bu2CuLi > 30:1 CO2Et Ph (Bn)2N H H H CO2Et + Ph (Bn)2N H CO2Et Bu CO2Et CO2Et < 5: >95 OBOM 16 R2CuLi TBDPSO H CO2Me H OR CO2Et H R' TMSCl, THF –78 °C, 3 h OBOM TBDPSO R - favorable interaction between alkoxy and π system. - free of 1,2-allylic strain. - increased stabilization of the α,β-unsaturated system via interaction between low-level π* orbital and high-level σR'–C orbital. R2CuLi NCO2R O CO2Me CO2Me TMSCl, THF –78 °C, 3 h NCO2R O R R O N H O 416 73–93% > 50:1 R = Me R = Et R = Bu 70–90% yield > 50:1 R = Me CO2Me R = Et R = Bu O H CO2Et H - favorable interaction between parallel σC–R and σ*C–Cu orbitals. - possibility of chelation between carbamate and ester may overide 1,2-allylic strain as well as bulk of γ-substituent. Organocuprate and Conjugate Addition Reactions Dale L. Boger Stereochemistry of Organocuprate Conjugate Addition Reactions (References) Books and Reviews Kozlowski, J. A. in Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 4, pp 169–198. Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135–631. Posner, G. H. Org. React. 1972, 19, 1–113. March, J. Asymmetric Synthesis, Vol. 4, Academic: New York, New York, 1983. Taylor, R. J. K. Synthesis 1985, 4, 364. Kharasch, M. S.; Reinmuth, O. Grignard Rections of Nonmetallic Substances, Prentice-Hall: Englewood Cliffs, NJ, 1954, pp. 196–239. Endocyclic enones 2,3-diastereoselectivity 1. Pesaro, M.; Bozzato, G.; Schudel, P. J. Chem. Soc., Chem. Commun. 1968, 1152. Siscovic, E.; Rao, A. S. Curr. Sci. 1968, 37, 286. Boeckman, R. K. J. Org. Chem. 1973, 38, 4450. Coates, R. M.; Sandefur, L. O. J. Org. Chem. 1974, 39, 275. Posner, G. H.; Sterling, J. J.; Whitten, C. E.; Leutz, C. M.; Brunelle, D. J. J. Am. Chem. Soc. 1975, 97, 107. Posner, G. H. Isr. J. Chem. 1984, 24, 88. Piers, E.; Karunaratne, V. J. Chem. Soc., Chem. Commun. 1983, 935. 3,4-diastereoselectivity 2. Luong-Thi, N. T.; Riviere, H. Compt. rend. 1968, 267, 776. Riviere, H.; Tostain, J. Bull. Soc. Chim., Fr. 1959, 568. Zimmerman, H. E.; Morse, R. L. J. Am. Chem. Soc. 1968, 90, 954. Luong-Thi, N. T.; Riviere, H. Tetrahedron Lett. 1971, 587. 3-substituted enones 3. Buchi, G.; Jeger, O.; Ruzicka, L. Helv. Chim. Acta 1948, 31, 241. House, H. O.; Fischer, W. F. J. Org. Chem. 1968, 33, 949. Stotter, P. L.; Hill, K. A. J. Org. Chem. 1973, 38, 2576. 3,5-diastereoselectivity 4. House, H. O.; Fischer, W. F. J. Org. Chem. 1968, 33, 949. Allinger, N. L.; Riew, C. K. Tetrahedron Lett. 1966, 1269. Wheeler, O. H.; de Rodriguez, E. G. J. Org. Chem. 1964, 29, 718. Eliel, E. L.; Biros, F. J. J. Am. Chem. Soc. 1966, 88, 3334. Ellis, J. W. J. Chem. Soc., D 1970, 406. Kharasch, M. S.; Tawney, P. O. J. Am. Chem. Soc. 1941, 63, 2308. House, H. O.; Giese, R. W.; Kronberger, K.; Kaplan, J. P.; Simeone, J. F. J. Am. Chem. Soc. 1970, 92, 2800. Siscovic, E.; Rao, A. S. Curr. Sci. 1968, 37, 286. Cacchi, S.; Caputo, A.; Misiti, D. Indian J. Chem. 1974, 12, 325. Hoye, T. R.; Magee, A. S.; Rosen, R. E. J. Org. Chem. 1984, 44, 3224. Posner, G. H.; Sterling, J. J.; Whitten, C. E.; Leutz, C. M.; Brunelle, D. J. J. Am. Chem. Soc. 1975, 97, 107. 417 Modern Organic Chemistry The Scripps Research Institute 3,6-diastereoselectivity 5. Stork, G.; Hudrlik, P. F. J. Am. Chem. Soc. 1968, 90, 4462. Stork, G. Pure Appl. Chem. 1968, 17, 383. Exocyclic enones and esters 6. House, H. O.; Respess, W. L.; Whitesides, G. M. J. Org. Chem. 1966, 31, 3128. Coates, R. M.; Sowerby, R. L. J. Am. Chem. Soc. 1971, 93, 1027. Foulon, J. P. J. Organometal. Chem. 1982, 228, 321. 7. House, H. O.; Chu, C. Y.; Wilkins, J. M.; Umen, J. J. Org. Chem. 1975, 40, 1460. Corey, E. J.; Boger, D. L. Tetrahedron Lett. 1978, 9 and 13. Bicyclic enones and polyenones 8. Birch, A. J.; Robinson, R. J. Chem. Soc. 1943, 501. Ireland, R. E.; Pfister, G. Tetrahedron Lett. 1969, 2145. Piers, E.; Keziere, R. J. Tetrahedron Lett. 1968, 583. Marshall, J. A.; Roebke, H. J. Org. Chem. 1968, 33, 840. Birch, A. J.; Smith, M. Proc. Chem. Soc. 1962, 356. Marshall, J. A.; Fanta, W. I.; Roebke, H. J. Org. Chem. 1966, 31, 1016. Filler, R.; Rao, Y. S. J. Org. Chem. 1962, 27, 3348. Settepani, J. A.; Torigoe, M.; Fishman, J. Tetrahedron 1965, 21, 3661. Piers, E.; Britton, R. W.; deWaal, W. J. Chem. Soc., D 1969, 1069. Piers, E.; deWaal, W.; Britton, R. W. J. Am. Chem. Soc. 1971, 93, 5113. Piers, E.; Keziere, R. J. Can. J. Chem. 1969, 47, 137. Corey, E. J.; Carney, R. L. J. Am. Chem. Soc. 1971, 93, 7318. 11. Marshall, J. A.; Brady, S. F. Tetrahedron Lett. 1969, 1387. Marshall, J. A.; Brady, S. F. J. Org. Chem. 1970, 35, 4068. Wechter, W. J. Tetrahedron 1965, 21, 1625. Marshall, J. A. Tetrahedron Lett. 1971, 3795. Piers, E.; deWaal, W.; Britton, R. W. Can J. Chem. 1969, 47, 4299. Marshall, J. A.; Andersen, N. H. J. Org. Chem. 1966, 31, 667. Piers, E.; deWaal, W.; Britton, R. W. Can J. Chem. 1969, 47, 4307. Wiechert, R.; Kerb, U.; Kieslich, K. Chem. Ber. 1963, 96, 2765. Marshall, J. A.; Warne, T. M. J. Org. Chem. 1971, 36, 178. Slosse, P.; Hootelé, C. Tetrahedron Lett. 1979, 4587. 12. Corey, E. J.; Hannon, F. J. Tetrahedron Lett. 1990, 1393. 1,6-addition 13. Marshall, J. A.; Roebke, H. J. Org. Chem. 1966, 31, 3109. Campbell, J. A.; Babcock, J. C. J. Am. Chem. Soc. 1959, 81, 4069. Atwater, N. W. J. Org. Chem. 1961, 26, 3077. Birch, A. J.; Smith, M. Proc. Chem. Soc. 1962, 356. Marshall, J. A. Tetrahedron Lett. 1971, 3795. Medium-sized Rings 14. Still, W. C.; Galynker, I. Tetrahedron 1981, 37, 3981. Acyclic Substrates 15. Reetz, M. T.; Röhrig, D. Angew. Chem., Int. Ed. Eng. 1989, 28, 1706. 16. 418 Hanessian, S.; Sumi, K. Synthesis 1991, 1083. Organocuprate and Conjugate Addition Reactions Dale L. Boger 8. Origin of Diastereoselectivity A. 2,3-Diastereoselection determined by protonation of enolate Destabilizing 1,3-diaxial interaction developing. H+ pseudo equatorial H H pseudo axial R R H O R Li H R O Li H H H+ this is preferred axial protonation, chair-like transition state, cis to C3 R-substituent. axial protonation, chair-like transition state, trans to C3 R-substituent. O O R R readily epimerizes to more stable product. R' most stable product observed R' - Examples: O O Me2CuLi axial, through chair-like transition state 1:1 H H H H O Me2CuLi O Me H Me Li // O H equatorial, through boat-like transition state Posner J. Org. Chem. 1973, 38, 4459. 419 Modern Organic Chemistry The Scripps Research Institute B. 3,4-Diastereoselection O O O R'2CuLi + R' R R R'MgX + cat. CuI R = Me R = Et R = iPr R' R major (trans) R' Ratio Me 72:28 minor (cis) increasing size of R' increasing amount of trans Et 78:22 iPr 88:12 Ph 87:13 (75%) 96:4 (PhCu) R' Ratio Me 77:23 Et 89:11 R' Ratio Me 89:11 Et 92:8 equatorial delivery, boat-like transition state; cis to C4 R-substituent increasing size of R increasing amount of trans axial delivery, chair-like transition state; cis to C4 R-substituent H // H R R vs. O O H preferred // H H H axial delivery, chair-like transition state; trans to C4 R-substituent // but remember: reactive intermediate may be radical anion R H H O H H 420 Organocuprate and Conjugate Addition Reactions Dale L. Boger C. 3,5-Diastereoselectivity O O O R2CuLi + Me Me R Me trans (major) R cis (minor) House J. Org. Chem. 1968, 33, 949. R = Me 93 : 7 (MeMgI, cat, CuI) >90% 98 : 2 (Me2CuLi) 99 : 1 (Me2CuLi + LiI) Posner J. Am. Chem. Soc. 1975, 97, 107. R = CH2Ar trans only unaffected by C3 substitution Posner J. Am. Chem. Soc. 1975, 97, 107. O O Me Me2CuLi Br 4 Me - equatorial delivery of group, grows into boat conformation of enolate. // O CH3 H two nearly equally populated conformations H ~ = A B axial delivery of group grows into chair form of enolate CH3 H // H no destabilizing interactions in the ground state for axial Me group but cannot achieve axial delivery of Nu– through chair-like transition state: severe Me/Me1,3-diaxial interaction. O H equatorial delivery but would grow into boat conformation of enolate Me R O enone with alkyl substituent in the equatorial position is the reactive conformation. 421 Modern Organic Chemistry The Scripps Research Institute D. 3,4- vs 3,5-Diastereoselectivity 3,4 > 3,5 O O Ph2CuLi Ph Ph Ph Ph Ph axial delivery, chair-like transition state but destabilizing 1,2-steric interaction equatorial delivery boat-like transition state // // H Ph Ph Ph O O H H 1,2-interaction > 1,3-interaction Ph equatorial delivery requires boat-like transition state axial delivery, 1,3-destabilizing steric interactions but chair-like transition state. preferred again, it may be viewed as a radical anion intermediate equatorial axial // // H Ph Ph O Li Ph OLi H H H Ph axial equatorial E. 3,6-Diastereoselectivity O O R R R equatorial delivery, boat-like transition state axial delivery, chair-like transition state H H // H H R more stable ground state H axial delivery, chair-like transition state cis product predominates H // H 422 O O R equatorial delivery, boat-like transition state Organocuprate and Conjugate Addition Reactions Dale L. Boger F. Exocyclic enones O O t Bu tBu CH3 // equatorial attack would require boat-like transition state O tBu tBu O H axial attack proceeds through chair-like transition state axial protonation (observed even when tBu replaced with H, see alkylation section). H OLi tBu H+ tBu H O R G. Fused enones H R relative to B ring this is equatorial delivery of the nucleophile. R decelerates conjugate addition this steric interaction is a CH3 1,2-interaction or torsional strain (eclipsing interaction) H O H // H R H H Cuprate behaves as large nucleophile preferring equatorial attack (1,2-interactions) to axial attack (1,3-interactions) on the exocyclic olefin. axial delivery of nucleophile suffers severe steric interactions (1,3-diaxial interactions) -May really want to consider radical-anion conformation 1,2-torsional interaction large reagent (Cuprate) Me H LiO H H small reagent (H+) (e.g., Birch reduction) 1,3-steric interactions 423 Modern Organic Chemistry The Scripps Research Institute Me O Me O Me H - cis ring fusion. - protonation from least hindered face of enolate, also most stable product. O H Me Me Piers Can. J. Chem. 1969, 47, 137. Me2CuLi Me O cis fusion N N H H OTHP OTHP Me2CuLi O O Me H H CuLi 2 O O Corey J. Am Chem. Soc. 1971, 93, 7318. - but 1,6-addition R2CuLi O O H R R = Me Et iPr tBu O R 93:7 98:2 100:0 100:0 axial delivery of nucleophile Me2CuLi –78 oC O O CuLi 2 O O 96% H O 1. H CuLi 2 2. Me3SiCl 1. O3, 1 equiv. Me3SiO 2. BH4– 74% Clark Tetrahedron Lett. 1974, 1713. [for vernolepin] 424 H O O 80% Organocuprate and Conjugate Addition Reactions Dale L. Boger H. Exocyclic enones Me 96% O tBu O tBu steric 1,3-diaxial interaction // H H H O tBu H O H Me tBu H H H Cuprate behaves as a large reagent preferring equatorial attack torsional strain eclipsing 1,2-interaction Felkin model i) Acyclic systems H CO2Et Ph Bn NBn2 CO2Et CO2Et Ph H NBn2 NBn2 Bn H > 95:5 H Ph CO2Et NBn2 CO2Et Ph Bn CO2Et NBn2 CO2Et NBn2 CO2Et Ph H CO2Et minimizes A 1,3-strain 425 Modern Organic Chemistry The Scripps Research Institute 426 Synthetic Analysis and Design Dale L. Boger XIII. Synthetic Analysis and Design Design: Corey The Logic of Chemical Synthesis, Wiley: New York, 1989. Warren Organic Synthesis: The Disconnection Approach, Wiley: New York, 1982. Fuhrhop, Penzlin Organic Synthesis: Concepts, Methods, Starting Materials, VCH: Weinheim, 1994. Total Synthesis: Nicolaou, Sorensen Classics in Total Synthesis, VCH: Weinheim, 1996. Hanessian Total Synthesis of Natural Products: The Chiron Approach, Pergamon: Oxford, 1983. Lindberg Strategies and Tactics in Organic Synthesis, Vol. 1-3; Academic: San Diego. ApSimon The Total Synthesis of Natural Products, Vol. 1-9; Wiley: New York. Turner The Design of Organic Synthesis, Elsevier: Amsterdam, 1976. Fleming Selected Organic Syntheses, Wiley: New York, 1973. Bindra Creativity in Organic Synthesis, Academic: New York, 1975. Bindra Art in Organic Synthesis, Wiley: New York, 1988. Lednicer, Mitscher, Georg The Organic Chemistry of Drug Synthesis, Vol. 1-4; Wiley: New York. Nakanishi Natural Products Chemistry, Vol. 1-3; Academic: New York. Koskinen Asymmetric Synthesis of Natural Products, Wiley: New York, 1993. Danishefsky and Danishefsky Progress in Total Synthesis, Meredith: New York, 1971. Key Reviews: Corey Science 1969, 166, 178; 1985, 228, 408. Chem. Soc. Rev. 1988, 17, 111. Pure. App. Chem. 1967, 14, 19; 1990, 62, 1209. Angew. Chem., Int. Ed. Eng. 1991, 30, 455. (Nobel Prize Lecture) E. J. Corey received the 1990 Nobel Prize in Chemistry for his development of the theory and methodology of organic synthesis. His development and systemization of retrosynthetic analysis transformed organic synthesis from inspired recognition of a route into a precise and logical science. As the modern techniques of structure determination emerged (NMR, IR, X-ray), Corey applied his retrosynthetic analysis to some of the most challenging syntheses of the time. The application of computer analysis with LHASA (Logic and Heuristics Applied to Synthetic Analysis), the development of practical synthetic methodology for individual transformations based on clear mechanistic rationales, and the more than 100 natural product total syntheses that followed transformed modern organic synthesis. Corey, Cheng The Logic of Chemical Synthesis, Wiley: New York, 1989. Corey, Wipke Science 1969, 166, 178-192. Protecting Groups: Greene, Wuts Protecting Groups in Organic Synthesis, 3rd Ed., Wiley: New York, 1999. Note: The material in this book was first assembled in conjunction with the LHASA project (Corey) and composed the Ph.D. dissertation for T. W. Greene. Computer Assisted Analysis: Corey, Wipke (LHASA: Logic and Heuristics Applied to Synthetic Analysis), Science 1969, 166, 178. Corey, Long J. Org. Chem. 1978, 43, 2208. Jorgensen (CAMEO: Computer Assisted Mechanistic Evaluation of Organic Reactions): Pure App. Chem. 1990, 62, 1921. Hendrickson J. Chem. Inf. Comput. Sci. 1992, 32, 209. Acc. Chem. Res. 1986, 19, 274. 427 Modern Organic Chemistry The Scripps Research Institute A. Classifications 1. Linear Synthesis - The target compound is made through a series of linear transformations. A B 5 steps overall yield 90%/step 70%/step 59% 17% 2. Convergent Synthesis - Individually prepared compounds are convergently brought together to make the target compound. 5 steps C E D F B overall yield 90%/step 70%/step 73% 34% Advantages of a convergent synthesis - shorter - simpler to execute - higher overall yields - better material balance and supply - Triply Convergent Synthesis -three major components are brought together in a single step to make the target compound. D F H C E G I 3. Divergent Synthesis - For a class of compounds, it is advantageous to prepare a common intermediate and use this common intermediate to prepare all members of the class of agents. - Examples: prostaglandins O O OH PGF1α R2 PGF2α RO CHO PGF3α HO R2 OH Variations lie only in the side chains - Rather than use a linear synthesis for all agents, a divergent synthesis allows the use of a common intermediate to prepare structurally related products. - The divergent synthesis is a very good strategy if structure–activity studies are the ultimate goal. 428 Synthetic Analysis and Design Dale L. Boger Note: Though widely used, the discussion of this strategy was first formally presented in the literature along with a disclosure of a strategy for divergent aromatic annulation in conjunction with the total synthesis of a series of azafluoranthene alkaloids. Today, the divergent introduction of diversity is the basis of most combinatorial chemistry methods. Boger J. Org. Chem. 1984, 49, 4050; see also J. Org. Chem. 1984, 49, 4033 and 4045. OMe OMe OMe MeO N MeO MeO MeO N MeO N MeO R1 O O OR OMe Imerubrine 1 R = CH3, R = H Rufescine R = H, R1 = H Norrafescine R = CH3, R1 = OCH3 Imeluteine Boger J. Am. Chem. Soc. 1995, 117, 12452. Boger J. Org. Chem. 1984, 49, 4050. 4. Total Synthesis - Start with readily available materials and build up to the target molecule from simple, common materials. 5. Partial Synthesis - This is technically not a total synthesis. - Start with a naturally occurring compound or an advanced intermediate and independently convert that to the target molecule. - Examples partial synthesis HO HO OH Previtamin D3 - For commercialization, it would be hard to match the synthesis starting with cholesterol. H2N R H S N O H N H S O CO2H Penicillins, available by fermentation at Lilly, as an inexpensive bulk chemical OAc N partial synthesis O CO2H Cephalosporins - not as accessible through fermentation Eduard Buchner, who worked in the laboratories of both E. Erlenmeyer and A. von Baeyer, received the 1907 Nobel Prize in Chemistry for his biochemical research and discovery of cell-free fermentation. Not only did this mark the beginning of the modern era of biochemistry but his greatest legacy might be the development of today's fermentation industry which provides us with not only foods and beverages, but also antibiotics and other important biological products. Anne S. Miller, the first person to be saved by penicillin in the US (1942) died on May 27, 1999 at the age of 90. Hospitalized, sometimes delirious, with a temperature that spiked at 107 °F, and having not responded to treatment with sulfa drugs, blood transfusions, or surgery, a dose of the experimental drug penicillin provided a quick cure and recovery. 429 Modern Organic Chemistry The Scripps Research Institute 6. Formal Total Synthesis vs. Total Synthesis O O O(CH2)8CO2H HO O(CH2)8CO2H HO O O m-CPBA known transformation HO HO O Pseudomonic Acid Pseudomonic Acid A Rogers Tetrahedron Lett. 1980, 21, 881. Kozikowski J. Am. Chem. Soc. 1980, 102, 6577. H H OR Formal Total Synthesis HO intermediate OH HO Me O O CO2H Gibberellic acid Independent synthesis of this precursor would constitute a formal total synthesis of gibberellic acid since the conversions have been previously accomplished. In this case, the key intermediate is so far from the final target that most would not "claim" such an accomplishment unless the final conversions were also developed within their own laboratories. 7. Biomimetic (Total) Synthesis - Presumably, nature will not be using a process that is intrinsically difficult or impossible. It is believed that one can effectively mimic the conditions provided by nature, and conduct the same reaction in a flask. - Two important considerations 1 - The reaction must be capable of occurring 2 - The biogenetic process is under a great deal of control (enzymatic) and a similar level of contro in lab may be difficult, but necessary - Classic example : Steroid synthesis Extensively studied and many good chemists failed before the experimental parameters were sufficiently defined to mimic the cation–olefin cyclization. R Steroids Biomimetic Synthesis O 430 Synthetic Analysis and Design Dale L. Boger B. Retrosynthetic Analysis - Work backwards from the target compound to generate a set of intermediates which can be made from available starting materials. T11 T1 Target Structure antithetic direction working backwards T12 T13 T2 synthetic direction building up materials toward the target T3 These less complicated building blocks in organic synthesis were called synthons in the early years. Now they are referred to as retrons. Objectives: 1. Generate a large number of potential approaches in order to obtain an optimal route. 2. Strive to generate simpler, less complex intermediates which can be obtained from readily available materials. 3. All steps are subject to reevaluation - this allows for design of a better or optimized synthesis. Steps in Design and Execution of a Synthesis 1. Selection of a problem more time is or should be devoted to 2. Selection of goals to be achieved through synthesis steps 1 and 2 than most may realize 3. Simplification 4. Generation of synthetic pathways steps 3 and 4 constitute 5. Evaluation of synthetic pathways --> assignment of merit retrosynthetic analysis 6. Selection of specific reactions and reagents for each step 7. Selection of specific reaction conditions and design of experiments 8. Execution and analysis of results Because of the amount of time and effort involved in the execution, it is important to be meticulous in evaluating the potential synthetic pathways. 1. Selection of a problem - One of the most important considerations. - Should be the first consideration, independent of all others. This assures that it is a problem that you want to address. - Recognize the time and effort involved in the actual conduct of the synthesis. - This will depend on the setting, circumstances and interests of the individual. 2. Selection of goals OH CO2H SR SRS-A (Slow Reacting Substance of Anaphylaxis) a. Structure determination of SRS-A: the initial intent. The R group on the thiol was not known, so the first synthesis was designed to facilitate the introduction of different R groups permitting a comparison with the endogenous product to confirm the structure. b. Once the structure was determined, objectives included providing sufficient material for biological testing. c. Determination of absolute configuration - the chiral centers were unambiguously established through synthesis. d. Development of a route amenable to analogue preparation: want to inhibit the action of SRS-A (an antagonist development). e. Biomimetic synthesis (follows the biosynthetic generation of materials) - might constitute a simplification. 431 Modern Organic Chemistry The Scripps Research Institute f. g. h. i. j. Development of commercially viable processes. Demonstration of improvements in current methodology. Novel, interesting structures. Common intermediate for a class of structures (divergent synthesis). Mechanism of action of a class of compounds - devise partial structures of the parent compound to define the mechanism of action. k. Chemistry of a class of compounds. l. Properties of a class of compounds. The specific goals are established prior to the generation of the retrosynthetic pathway. The goals will play an important role in the assignment of relative merit of each potential pathway in the retrosynthetic analysis. 3. Simplification and Background Chemistry a. Recognition of symmetry elements present in a structure. i.e, Squalene CHO CHO - two identical halves - build out from a central core by conducting each of the steps twice and simultaneously - Johnson J. Am. Chem. Soc. 1970, 92, 741. SO2Ar Br OH + - combines two halves prepared from a common intermediate at the end of the synthesis. - Grieco J. Org. Chem. 1974, 39, 2135. CO2CH3 CH3O2C OH CH3O N CH3 CH3O CH3O2C HO N CH3 O O CH3O N CH3 CH3O CH3O2C N CH3 CO2H CO2H N N CH3O2C CH3O CH3O Isochrysohermidin 432 Boger J. Am. Chem. Soc. 1993, 115, 11418. CO2CH3 N N OCH3 OCH3 Synthetic Analysis and Design Dale L. Boger - The recognition of symmetry elements is not always so obvious by initial examination of the agent. e.g., Juncusol Me Me OH OH X HO HO Me HO Me Me Kende J. Am. Chem. Soc. 1979, 101, 1857. now symmetrical - simplification of the synthetic problem O or start with the central ring and build out in a similar symmetrical fashion Boger J. Org. Chem. 1984, 49, 4045. O e.g., Carpanone Me Me H O O O Me Me Me H O O O Dimerize O O O O O O O OH O Chapman J. Am. Chem. Soc. 1971, 93, 6696. - biomimetic synthesis of this agent allows for simplification. - this is a very good example where the symmetry elements are not obvious by looking at the agent. e.g., Rifamycin Me Me Me Me O RO Me AcO H H Me OAc OH OH OH O H Me N Me Me Me RO Me S C O OR1 OR2 OR3 S H O O O O Me O - this agent does not contain symmetry in the entire molecule but a subunit is symmetrical. O Me S Me H S Corey Tetrahedron Lett. 1979, 335. 433 Modern Organic Chemistry The Scripps Research Institute e.g., Usnic Acid COMe O HO Me OH HO O Me OH Oxidative Dimerization COMe COMe OH Me OH Barton J. Chem. Soc. 1956, 530. e.g., Porantherine H H N N Me N Me Me Me H H O O H O O H Me H O H HN Me O Me Me N O H NH2 O Me Me O Corey J. Am. Chem. Soc. 1974, 96, 6516. - the symmetry elements are tucked more deeply into the structure b. Background Chemistry - Information available in the literature will provide very important insights required to effectively design a synthesis. e.g., Quassin OMe MeO O O Me Me Me H H Me H H O Grieco J. Am. Chem. Soc. 1980, 102, 7586. O - 7 stereocenters but 3 are epimerizable centers and the natural product possesses the most stable configuration, so a synthesis without stereocontrol of these 3 centers can be used (epimerize later). Need only worry about control of 4 of the 7 stereocenters. 434 Synthetic Analysis and Design Dale L. Boger c. Recognize and Remove Reactive Functionality - Another key to simplification derived from background chemistry e.g., Vernolepin OH O O H OH O O H O O O remove as well - α-Methylene lactone in a trans fused 5-membered ring This is extraordinarily reactive to nucleophiles (Michael). It will not stand up to many synthetic steps/reagents. - the final step should be introduction of the reactive group. O Danishefsky J. Am. Chem. Soc. 1976, 98, 3028. Grieco J. Am. Chem. Soc. 1976, 98, 1612. Danishefsky J. Am. Chem. Soc. 1977, 99, 6066. e.g., Precursor to aromatic amino acids CO2– O CO2H O H+ O O OH– O OCH3 CO2CH3 O decarboxylation loss of the OH HO H HO + H H - acid sensitive (derived from background chemistry). - a successful approach must involve generation under basic conditions. Danishefsky J. Am. Chem. Soc. 1977, 99, 7740. e.g., PGI2 (prostacyclin) CO2H O H H+, H2O OH CO2H O C5H11 HO C5H11 HO OH OH - enol ether sensitive to acid-catalyzed hydrolysis. Corey J. Am. Chem. Soc. 1977, 99, 2006. U. von Euler, B. Katz, and Julius Axelrod received the 1970 Nobel Prize in Medicine for the discovery of hormonal transmitters in the nerve terminals and the mechanism for their storage, release, and inactivation. S. K. Bergstrom, Bengt I. Samuelsson, and J. R. Vane shared the 1982 Nobel Prize in Medicine for their discovery of the prostaglandins and related biologically active substances. 435 Modern Organic Chemistry The Scripps Research Institute e.g., Thromboxane A2 (TXA2) OH CO2H O O C5H11 pH = 7.0 t1/2 = 32 sec CO2H HO C5H11 O OH OH The strained acetal should be introduced late in the synthesis e.g., PGH2 (R = H) PGG2 (R = OH) TXB2 Still J. Am. Chem. Soc. 1985, 107, 6372. O CO2H C5H11 O pH = 7.0 t1/2 = 4–5 min Reduction / Acid-catalyzed Rearrangement OR Reactive cyclic peroxide is sensitive to nucleophilic attack - introduce late in the synthesis Porter J. Am. Chem. Soc. 1980, 102, 1183. Salomon J. Am. Chem. Soc. 1979, 101, 4290. Porter J. Am. Chem. Soc. 1979, 101, 4319. e.g., Mitomycin C - stable as the quinone O H2N OCH3 CH3 OH CH2OCONH2 N NH O note vinylogous amide H2 reduction H2N OCH3 CH3 OH CH2OCONH2 N NH H2N CH3 CH2OCONH2 Nu– N NH OH OH hydroquinone - basic, nucleophilic free amine - intermediate less stable steer clear of such synthetic intermediates There are only two total syntheses of mitomycin C to date Kishi J. Am. Chem. Soc. 1977, 99, 8115. Fukuyama J. Am. Chem. Soc. 1989, 111, 8303. Absolute configuration established in J. Am. Chem. Soc. 1967, 89, 2905 by a single crystal X-ray structure (INCORRECT). But in the early 1980's, additional X-ray structures on related agents gave the opposite and correct absolute configuration. Take home message: Evaluate the quality of the background chemistry and assess the level of confidence and committment you want to place on it. The earlier X-ray was not on a heavy atom derivative and preceded the advances in direct methods we take for granted today. Hirayama J. Am. Chem. Soc. 1983, 105, 7199. A number of Nobel Prizes have chronicled the achievements of X-ray crystallography including the contributions of: J. Kendrew and M. Perutz (1962, heavy atoms and structure of hemoglobin). D Hodgkin (1964, X-ray structure determinations including vitamin B-12, penicillin and insulin). O. Hassel (1969, chair conformation of cyclohexane reported in 1930). W. N. Lipscomb (1976, borane structures and chemical bonding, structure of carboxypeptidase A in 1967). A. Klug (1982, elucidation of nucleic acid–protein complexes). H. A. Hauptman and J. Karle (1985, direct methods). J. Deisenhofer, R. Huber, and H. Michel (1988, structure of photosynthetic reaction center (> 10,000 atoms) and first membrane protein structure determination). 436 Synthetic Analysis and Design Dale L. Boger - The background chemistry can provide keys to the design of a synthetic strategy. O MeO MeO NH Me N Me O OCONH2 OMe MeO H N O Me Mitomycin Rearrangement e.g., Thienamycin N H O Isomitomycin was isolated and characterized and provided the basis for Fukuyama's total synthesis. N O OCONH2 OMe N H O OCONH2 OMe OH O H OHH H H SR N trans preferred A. Fleming, H. W. Florey, and E. B. Chain received the 1945 Nobel Prize in Medicine for the discovery of penicillin and its curative effects in various infectious diseases. N SR NH2 CO2H CO2H OH S N O H O H CO2H cis less favored must protect the amine throughout the synthesis. unusual trans H–H relationship - easily epimerizable center and fortunately, trans is most stable configuration. Grieco J. Am. Chem. Soc. 1984, 106, 6414. Georg J. Am. Chem. Soc. 1987, 109, 1129. Yet - almost all the early syntheses went to great length to control this relative stereochemistry and it often, unnecessarily, added to their length. e.g., Coriolin OH OH H O H Me O O Me H Me O Me OH Me introduce reactive functionality last Me H Me OH Danishefsky J. Am. Chem. Soc. 1981, 103, 3460. 4. Generation of Synthetic Pathways (Retrosynthesis) (General strategies employed in working backwards) Covered in detail in Corey The Logic of Chemical Synthesis, Wiley: New York, 1989, pp 1–98. a. Transform-based strategies - powerful, simplifying transformation that reduces complexity. - usually very key reactions in the synthesis that dominate the approach - formation of a key intermediate (i.e., the Diels–Alder transform, the aldol transform). b. Structure-goal strategies - oldest approach. - in working backwards from the target molecule to the various intermediates, an intermediate may actually be located that is already in the literature or commercially available. e.g., Prostaglandins O O O OH HO CO2H C5H11 HO OH OR R'O HO abundant 437 Modern Organic Chemistry The Scripps Research Institute c. Topological strategies - strategic bond disconnections (J. Am. Chem. Soc. 1975, 97, 6116). - recognize strategic bonds and remove them in the retrosynthetic direction. d. Stereochemical strategies - strategies which remove the stereocenters. - simplifying the stereochemistry of the product may be related to: 1. substrate - features of the substrate will permit you to solve the stereochemical problems. 2. mechanism - reaction mechanism will permit relative or absolute stereocontrol. e. Functional group strategies 1. Functional group interconversion (FGI) - don't gain much but it permits you to get from one point to another. 2. Functional group combination (FGC) - combine pairs of functional groups. - usually a ring forming reaction in the retrosynthetic direction to give you one FG rather than two. O ozonolysis H H O X fragmentation O OH O OH O O Baeyer–Villiger OH O 3. Functional group addition (FGA) - hard to recognize while working in the reverse direction. - for example, introduce a double bond which then may key the recognition of a Diels–Alder reaction. O O O O Br CO2Me OH Bromo-lactonization O CO2Me CO2Me Diels–Alder CO2Me 438 CO2Me MeO2C Synthetic Analysis and Design Dale L. Boger i.e., Diels–Alder reaction CH2OH FGA CH2OH DA CH2OH + CH2OH cat H2 CH2OH not optimal CH2OH unreactive dienophile neutral unreactive diene FGI (reduction) O O DA + O O optimal O O reactive dienophile neutral unreactive diene O CH2OH CO2R O CH2OH CO2R more reactive due to EWG reevaluation: isomerization may occur about the C=C. O further enhances reactivity, assures stereochemistry. But: There is an alternative and still better Diels–Alder pathway that most would miss without careful consideration. CH2OH CH2OH FGA cat H2 CH2OH CH2OH FGI CO2R reduction CH2OH FGI O hydrolysis O O Intramolecular O Diels–Alder 439 Modern Organic Chemistry The Scripps Research Institute 5. Evaluation of Pathways and Assignment of Merit a. excellent knowledge of organic chemistry b. suspect reactions must be recognized - one poor step can ruin the synthesis c. control of stereochemistry is clear d. want opportunity for alternatives - reactions that look good on paper aren't always successful in lab 6. Selection of Specific Reactions and Reagents a. this also requires an excellent knowledge of organic chemistry b. check the literature for alternative reagents - it is wiser to change reagents than to change the entire synthesis if problems arise c. many reference texts are available Larock Fieser and Fieser Paquette Comprehensive Organic Transformations Reagents for Organic Synthesis Vol. 1–18 Encyclopedia of Reagents for Organic Synthesis Handbook of Reagents for Organic Synthesis: Coates, Denmark Reagents, Auxiliaries and Catalysts for C–C Bonds Burke, Danheiser Oxidizing and Reducing Agents Reich, Rigby Acidic and Basic Reagents Pearson, Roush Activating Agents and Protecting Groups Computer Databases CLF, Reaccs, Scifinder, Beilstein, Isis 7. Selection of Reaction Conditions a. reaction temperature b. solvent c. knowledge of reaction mechanism d. consult current and background literature 8. Execution of the synthesis - most difficult and time consuming element of work a. easy: setting up and conducting the reaction b. difficult: interpreting the results from the reaction C. Strategic Bond Analysis - For bridged ring systems Corey J. Am. Chem. Soc. 1975, 97, 6116. - Most desirable bond disconnections in the antithetic direction minimize: 1. appendages 2. appendage chiral centers 3. medium or large size rings 4. bridged rings Rule 1: Because it is easy to form common size rings, a strategic bond must be in a 4–7 membered primary ring. A primary ring is one which cannot be expressed as an envelope or two or more smaller rings. This is restricted to primary rings because ring forming reactions are strongly affected by the size of the smallest ring containing the newly forming bond. The six membered ring is not primary because it contains two smaller rings. Rule 2a: A strategic bond must be directly attached to another ring (i.e. exo to another ring). This is because a ring disconnection which produces two functionalized appendages is harder to utilize than one which produces one or no functionalized appendages. c or c or d non-strategic bonds two ring appendages - more complicated 440 a a or b strategic bonds d b or one ring appendage Synthetic Analysis and Design Dale L. Boger b non-strategic bond Rule 2b: b a strategic bond a A strategic bond may not be exo to a preexisting 3-membered ring. non-strategic even though exo to a ring X EWG Rule 3: anion displacement reactions don't work well on a three-membered ring Strategic bonds should be in ring(s) which exhibit the greatest degree of bridging. The maximum bridging ring is selected from the set of synthetically significant rings which is defined as the set of all primary rings plus all secondary rings which are less than 8membered. The maximum ring is that which is bridged, not fused at the greatest number of sites. Select the maximum bridging ring and disconnect the strategic bonds within that ring bridge point fusion point 5R-3B 5R-4B maximum bridging 4R-2B 6R-3B 7R-2B fusion point fusion point 5R-2B Rule 4: To avoid formation of >7-membered rings during the antithetic bond cleavage, any bond common to a pair of rings whose envelope is >7 is not strategic. non strategic 10-membered ring non-strategic H * strategic * H 441 Modern Organic Chemistry The Scripps Research Institute Rule 5: Bonds within aryl rings cannot be strategic. non-strategic R Rule 6a: If a disconnection leaves chiral atoms on the remaining arc then the disconnections cannot be strategic. * OH * H H non-strategic increased difficulty OH The stereochemistry is much harder to control on the acyclic precursor than on the cyclic precursor Rule 6b: Chiral atoms may be allowed if they appear directly at the point of attachment. NO2 Me * * Rule 7: OH NO2 b non-strategic b a HO Me a strategic * * O Me C–X Bonds (X = heteroatom) in rings will be strategic. C–X bonds are easier to form than C–C 442 NO2 Synthetic Analysis and Design Dale L. Boger D. Total Synthesis Exemplified with Longifolene Me Me 1. Strategic Bond and Retrosynthetic Analysis Me fusion point not a fusion point even though it is in a 1,2 relationship a b 5R, B2 8R, 3B 8 ring - secondary 5R, B4 * 7R, B2 - Ho disconnection (a) - Kuo disconnection (b) Fusion vs. bridge points: there must be at least one carbon (not in the ring in question) between the carbon in question and another carbon in the ring for it to be a bridgepoint. 6R, 3B * H H b c a e ** * b c d H * H 5R, B4 d * fusion point e H a H * * H * * non-strategic gives 8-membered ring - Oppolzer but via 5-membered ring Me * * non-strategic gives 8-membered ring * * H * much simpler than longifolene! - Corey and McMurry disconnection - Schultz disconnection - Simultaneous or sequential b/d bond disconnection: Brieger, Fallis (Diels–Alder), Johnson (cation–olefin). - Simultaneous a/e bond disconnection: Schultz (indirect via vinylcyclopropane rearrangement). 443 Modern Organic Chemistry The Scripps Research Institute 2. Corey Synthesis: J. Am. Chem. Soc. 1961, 83, 1251; 1964, 86, 478. Intramolecular Michael Addition (Santonin–Santonic Acid) Robinson Annulation Wittig Reaction Pinacol Ring Expansion Dithiane Reduction Chromatographic Resolution through Diastereomeric Derivatization (Product) 3. McMurry Synthesis: J. Am. Chem. Soc. 1972, 94, 7132. Intramolecular Enolate–Epoxide Addition (Alkylation) Dibromocarbene Addition, Ring Expansion Ethyl Diazoacetate Ring Expansion Organocuprate 1,4-Additions Intramolecular Aldol Reaction, Transannular Reactions Fragmentation Reaction 4. Brieger Synthesis: (attempted) J. Am. Chem. Soc. 1963, 85, 3783. Diels–Alder Reaction Intramolecular Diels–Alder Reaction 1,5-Hydrogen Migration of Cyclopentadienes 5. Johnson Synthesis: J. Am. Chem. Soc. 1975, 97, 4777. Organocuprate 1,4-Addition, Regiospecific Enolate Trap Cation–Olefin Cyclization 6. Oppolzer Synthesis: J. Am. Chem. Soc. 1978, 100, 2583. Helv. Chim. Acta 1984, 67, 1154. Enamine Acylation Photochemical [2 + 2] Cycloaddition Retro-Aldol Fragmentation Reaction Wittig Reaction Simmons–Smith Cyclopropanation Hydrogenation of Cyclopropanes Classical Resolution via Crystallization of Diastereomeric Salts 7. Schultz Synthesis: J. Org. Chem. 1985, 50, 915. Birch Reductive Alkylation Retro Cheletropic Cycloaddition 1,3-Dipolar Cycloaddition Vinylcyclopropane Rearrangement Asymmetric Synthesis via Substrate Chiral Auxiliary 8. Fallis Synthesis: J. Am. Chem. Soc. 1990, 112, 4609. J. Org. Chem. 1993, 58, 2186. Intramolecular Diels–Alder Reaction Barton Free Radical Deoxygenation Reaction Acetate Pyrolysis Chromatographic Resolution through Diastereomeric Derivatization (Starting Material) 9. Kuo Synthesis: Can J. Chem. 1988, 66, 1794. Intramolecular Aldol Addition Wagner–Meerwein Rearrangement 10. Ho Synthesis: Can J. Chem. 1992, 70, 1375. Ethyl Diazoacetate Ring Expansion Alkylative Esterification 444 Me Me Me Synthetic Analysis and Design Dale L. Boger 2. Corey Synthesis: J. Am. Chem. Soc. 1961, 83, 1251. J. Am. Chem. Soc. 1964, 86, 478. Wieland–Miescher ketone O O Me Me Intramolecular Michael Addition Robinson Annulation Wittig Reaction Pinacol Ring Expansion Dithiane Reduction Chromatographic Resolution through Diastereomeric Derivatization (Product) O O HO OH O MeCH=PPh3 H+, O cat 60% C6H6–H2O O Robinson Annulation Ketone Reactivities O O Me p-TsCl LiClO4 100% pyridine CaCO3, THF OH OH 50 °C, 2.5 d Pinacol Rearrangement OH OTs O Me O O + O 2 N HCl Me 25 °C, 6 h O 41-48% Et3N O 225 °C H Intramolecular Michael Addition 2 N HCl 100 °C, 24 h Me Me Me O ethylene glycol O Me 5% Me O Me Me O O OsO4 Dihydroxylation Stereochemistry O Wittig Reaction O O O O Me 96% O 0.95 equiv O Ph3CLi; CH3I 60% Me 10–20% Thermodynamic Enolate Me O Me HS SH BF3•OEt2 SiO2 separation Diastereomeric Derivatization and Chromatographic Resolution Me Me MeS O Me Me S Me Me Me 1. MeLi, 93% 1. LiAlH4 O 2. Na, NH2NH2 2. SOCl2, pyr 3. RuO4 Me Desulfurization Wolff–Kishner Reduction Me Me 445 Modern Organic Chemistry The Scripps Research Institute O O Osmylation - large reagent reacts preferentially with more accessible double bond and from the least hindered face. Typically, this is from the equatorial direction but one 1,3-diaxial H is removed and axial approach now observed O O OsO4 100% OH OH Me O O Selective Tosylation - rates: 1° > 2° > 3° - 3° alcohols react very slowly - MsCl and Et3N generates sulfene which will react with 1°, 2°, 3° OH to give the mesylate O O p-TsCl pyridine OH OH O H2C S O OH OTs - Also note the use of DMAP to acylate 3° alcohols via R O O O O LiClO4 O CaCO3 OH OTs 50 °C TsO R' Me R TsO H O R' O O H Me O Me O O Et3N O HOCH2CH2OH 225 °C H Me Me 10–20% Me Me O O CH3 5% 446 N Pinacol Rearrangement - LiClO4 used as source of free Li+ ion to accelerate solvolytic loss of TsO group - migration of unsaturated alkyl group observed preferentially - trans antiperiplanar arrangement O R N O O B + O A Me 5% Intramolecular Michael Addition - only cis product undergoes Michael - side products include the retro-Michael product A and the OH– addition and retro aldol product B Synthetic Analysis and Design Dale L. Boger Me Me Me O Me Me Me MeS HS SH BF3•OEt2 SiO2 separation O Me Me S O Me Me Me MeS O Me Me S Me 1. LiAlH4 O 2. Na, NH2NH2 3. RuO4 Me Me H NH H2NNH2 O Thio-ketalization (Derivatization) - other carbonyl much more hindered - diastereomers arise that are separable by conventional chromatography (–H2O) N NH N Desulfurization - direct Wolff–Kishner failed - LiAlH4 protects ketone from reduction - today: Ra–Ni better for desulfurization and would avoid need to protect ketone - Wolff–Kishner reduction of dithiane similar to Huang–Minlon protocol of Wolff–Kishner reduction for carbonyl removal (Huang, Minlon J. Am. Chem. Soc. 1946, 68, 2487; 1949, 71, 3301), van Tamelen J. Am. Chem. Soc. 1961, 83, 4302. Wolff–Kishner Wolff Justus Liebigs Ann. Chem. 1912, 394, 86. H N N H H Me Me O Me base H N NH Me 1. MeLi, 93% 2. SOCl2, pyr Me Further improvements tBuOK, DMSO, 25 °C Cram J. Am. Chem. Soc. 1962, 84, 1734. Olefination - Wittig reaction unsuccessful, ketone too hindered - two-step procedure adopted Me 447 Modern Organic Chemistry The Scripps Research Institute J. Am. Chem. Soc. 1972, 94, 7132. 3. McMurry Synthesis: O O Intramolecular Enolate–Epoxide Addition Dibromocarbene Addition, Ring Expansion Ethyl Diazoacetate Ring Expansion Organocuprate 1,4-Additions Intramolecular Aldol Reaction Transannular Reactions Fragmentation Reaction O Me O O H2, Pd–C 1. MeMgBr 85% O O 2. H2SO4 Me 5 H 69% (31% 6,7 olefin) H Catalytic Hydrogenation Robinson Annulation m-CPBA 7 6 cis Me OH Peracid Epoxidation Me O Me MeS(O)CH2Na DMSO, 93% Me O H2SO4 O tBuOK O 25 °C, 90% CHBr3 5 d, 60 °C H 43% Me Me Intramolecular Enolate– Epoxide Addition Br Me Me Br O H Carbene Addition to Olefin Me Br AgClO4 O acetone–H2O 100% Me Na/NH3 OH O Me 448 1. LiAlH4 O OH Me 2. TsCl, pyr 97% Me Me H2, Pd–C 89% OTs base H 100% Me Me Me2CuLi Me Me pyr Me O Cuprate Reaction Intramolecular Aldol Reaction CrO3 OH Dissolving Metal Reduction Me Me Me O MeOH, 62% Me Ring Expansion Methodology Me O O Me OH Me Me Me steps Me Fragmentation Reaction Synthetic Analysis and Design Dale L. Boger Me H H2, Pd–C H 85% O O H 69% O O Me 2. H2SO4 O O Acid-catalyzed Elimination - cis ring fusion prefers ∆2,3 double bond - trans ring fusion prefers ∆3,4 double bond - known from steroid chemistry H 1. MeMgBr O Hydrogenation - known conditions to give cis stereochemistry - H2 comes in from less hindered face - heteroatoms can also direct H2 to their face O O O 31% O O H Me H O H O Me Me Epoxidation - epoxidation from the least hindered face - no competitive Baeyer–Villiger at ketone - trisubstituted olefin more reactive than ketone m-CPBA Me O Me NaO H H Me OH O Intramolecular Epoxide Addition - very slow epoxide opening due to steric encumbrance of Me group - benefits from irreversible nature of epoxide opening S CH2Na CH3 Me O O O Me Me Alternate route attempted: Me O Me 1. BH3•THF –OOH O O 2. H2Cr2O7 Me Me Me Me O Ph3CLi O MeI CH2N2 AlCl3 Alternate Route - hydroboration–oxidation gave ketone - methylation conditions specifically employed to avoid over-methylation - ring expansion with CH2N2 did not proceed failed ring expansion Me 449 Modern Organic Chemistry The Scripps Research Institute major A O δ+ –O minor + N N CH2 N N O O O CH2 N N + A O δ+ major EtO2C –O N N + HC N N EtO2C OH O CO2Et + :CBr2 H R R + C R H R R R H C Br π2s H + H R R R X R disrotatory ring opening + H H H H R compact H R + R H extended H H 450 Br ω2a disrotatory ring opening X vs. C Carbene Addition and Ring Expansion - singlet carbene has electrophilic character, and undergoes stereospecific reaction with olefins (no scrambling as observed with triplet carbene) - Br can donate electrons into the empty p-orbital, thus stabilizing the singlet carbene - cheletropic cycloaddition occurs with olefin geometry maintained via a π2s + ω2a cycloaddition R H H Diazoacetate Ring Expansion - improvement over diazomethane - product in enol form and will not further react with reagent - reagent stable, transportable and readily available - ultimately employed in the later Ho synthesis no further reaction CO2Et + CHBr3 + KOtBu Diazomethane Ring Expansion - CH2N2 poor nucleophile - AlCl3 added to activate carbonyl - many side reactions possible - CH2N2 explosive, difficult to use - products equally reactive toward additional expansions/epoxidations - TMSCHN2 is a safe alternative to diazomethane CHN2, a yellow gas, which typically is prepared in situ in special apparatus to diminish the chance of detonation H2O or Nuc– R R H OH Disrotatory Ring Opening of Halocyclopropanes - leaving group will influence direction of ring opening - departure of LG simultaneous with disrotatory ring opening - substituents syn to the departing group will move towards one another while they move away from each other if anti leaving group. Since this system is confined to a 7-membered ring, the R groups must move toward each other to give the compact alkyl cation and it is the syn bromide that is lost Synthetic Analysis and Design Dale L. Boger H Br H Br H In Fused Bicyclic Systems - imposed geometry of ring controls opening and directs leaving group - nucleophile comes in trans to departing Br– - exception: bicyclo[5.1.0]octane can give the trans double bond via outward rotation - Chem. Commun. 1967, 294. - Chem. Commun. 1968, 1593. - J. Am. Chem. Soc. 1970, 92, 2566. H Br Nuc H H Br Br H Br Nuc– Br Me Me Br H O Br AgClO4 O acetone–H2O 100% OH H Me Me Me Me Br H O Br O McMurry Application - ring controls geometry of ring opening, thus only one bromine departs - nucleophile (OH2) enters trans to leaving Br - no trap at other end of allyl cation - possible assistance of C=O H OH Me Me Me Me Br OH Na/NH3 O OH H OH H Dissolving Metal Reduction - stereochemistry of reduced OH - most stable product - reduction of the vinyl halide H Me Me Me Me Me Me O Me2CuLi O OLi OH Me Me Me Me Me Me OTs base O 100% O Me H Cuprate Addition - Intramolecular Aldol Reaction - cuprate adds in Michael fashion to generate enolate - enolate then attacks carbonyl in intramolecular fashion Fragmentation - reduction occurs from least hindered face - tosylation selective for 2° > 3° Me 451 Modern Organic Chemistry The Scripps Research Institute J. Am. Chem. Soc. 1963, 85, 3783. 4. Brieger Synthesis: (attempted) Diels–Alder Reaction Intramolecular Diels–Alder Reaction 1,5-Hydrogen Migration of Cyclopentadienes Me Me Me OAc MgBr OAc HCl(g)–HOAc OAc Et2O, 0 °C 0 °C, 50% 175 °C 28% 48 h, 90% Me Me Me Me Cl Me Intramolecular Diels–Alder Reaction Me CO2Me Me Me O Me OAc Me Me OAc 0% but H Me H 94% Me Me CO2Me 90% TMSO Snowden Tetrahedron Lett. 1981, 22, 97 and 101. Me Me MgBr OAc Grignard Addition - alkylation at 3° center! - nonbasic reagent, E2/E1 elimination not observed OAc Et2O, 0 °C 28% Me Me Cl Me Me 1,5 H-Shift - proceeds at 0 °C - causes failure of desired [4 + 2] cycloaddition for longifolene above R H 1,5-H R shift H H OAc H R OAc H H OAc H H H Me Me Me Me Me 90% Me Me 452 Me OAc OAc Me Me OAc Me Me Me Me Intramolecular Diels–Alder - at 175 °C, all three 1,5-H shift products present - provide three different possible products - only one product observed Synthetic Analysis and Design Dale L. Boger J. Am. Chem. Soc. 1975, 97, 4777. 5. Johnson Synthesis: Organocuprate 1,4-Addition Regiospecific Enolate Trap Cation–Olefin Cyclization Me Me (Me CuLi 2 ArCO2NR4 MeLi Br2, 1 equiv 2. CH3COCl 84% O OAc acetone, 76% O Br Cuprate Conjugate Addition Regiospecific Enolate Trap Me Me LiAlH4 ether, 0 °C 92% CF3CO2H ether, 0 °C 75% HO O Me Me H Me Me Me O Me 2 equiv ZnBr2 NaCNBH3 94% Cation–Olefin Cyclization p-TsOH 25 °C, 0.5 h 91% Me Me HO Me RuO4 (cat.) NaIO4, 72% Me O LDA MeI Me Me steps Me Me Me CF3CO2H ether, 0 °C 75% HO Me Me HO Me Me Me Cation–Olefin Cyclization - 2° allylic alcohol for initiation site H Me Me Me 453 Modern Organic Chemistry The Scripps Research Institute J. Am. Chem. Soc. 1978, 100, 2583. Helv. Chim. Acta 1984, 67, 1154. 6. Oppolzer Synthesis: O Enamine Acylation Photochemical [2 + 2] Cycloaddition Retro-Aldol Reaction Wittig Reaction Simmons–Smith Cyclopropanation Hydrogenation of Cyclopropanes Classical Resolution via Crystallization of Diastereomeric Salts Cl HO O PhCH2O2CO O N PhCH2OCOCl O hν, pyrex pyr 87% 83% [2 + 2] Photochemical Cycloaddition Enamine Acylation O OCO2CH2Ph O 10% Pd/C , H2 O HOAc, 25 °C, 18 h Ph3P=CH2 O 88% CH2I2, 78% Simmons–Smith Cyclopropanation Retro-Aldol Me H2, PtO2 O HOAc, 96% Cyclopropane Hydrogenation Me Me Me H H2N CO2H H optically active starting material Me classical resolution recrystallization of diasteromeric salt 454 Zn–Ag Me O Me LDA Me O MeI Me steps Synthetic Analysis and Design Dale L. Boger Me Me I OMe CO2Me CH(OMe)2 OMe CO2Me Birch Reductive Alkylation Retro Cheletropic Cycloaddition 1,3-Dipolar Cycloaddition Vinylcyclopropane Rearrangement Asymmetric Synthesis via Substrate Chiral Auxiliary J. Org. Chem. 1985, 50, 915. 7. Schultz Synthesis: CH3CONHBr MeOH, 95% 2.5 equiv K in NH3 1.0 equiv tBuOH –78 to –25 °C 98% 110 °C DBN, tol OMe CO2Me MeO Br Me Me Me Me CH(OMe)2 Birch Reduction–Alkylation CH(OMe)2 Ph H2N N O CO2Me O p-TsOH CO2Me acetone, 86% Me Me Me Me CH(OMe)2 toluene, 110 °C 43% hν 366 nm – N2 Me CHO N N Me Me Me Retro-Cheletropic Cycloaddition 1,3-Dipolar Cycloaddition O CO2Me O CO Me 2 O CO Me 2 Ph Me 40% overall Me KOH, 25 °C H2, Pd/C 140 °C O xylenes O 92% MeOH–H2O 85% Me Me Me Vinylcyclopropane Rearrangement Me Me Me Me Me steps 110 °C O CO2Me CO2Me 90% from 1,3dipolar cycloadduct O toluene 86% CO2H Me O I H from (S)-proline MeOCOCl Me CH(OMe)2 N O Me H Me Me CH(OMe)2 O CHO O O 2.5 equiv K in NH3 1.0 equiv tBuOH –78 to –25 °C 98% Me Me HCl/MeOH N Me Me O CHO O O H O O OMe N H H H•HCl N O MeO CO Me 2 1. HCl, CH(OMe)3 2. NaOMe, MeOH Me Me CH(OMe)2 455 Modern Organic Chemistry The Scripps Research Institute Ph H2N N O CO2Me Ph toluene, 110 °C 43% Me Me Me CHO N N retro cheletropic cycloaddition with loss of stilbene O O CO2Me Me Ph Me N N O O CO Me 2 CO2Me Me Me Me Me N N Me 140 °C hν –N2 Me Me N Me Vinylcyclopropane Rearrangement - [1,3]-sigmatropic rearrangement O xylenes Me CO2Me Me 456 N O CO Me 2 Me Me CO2Me Ph N N Retro Cheletropic Cycloaddition and Subsequent 1,3-Dipolar Cycloaddition O CO Me 2 Me O O CO2Me CO2Me - This sequence is equivalent to adding the elements of a carbene 1,4 across a diene - Is this 4e– + 2e– cycloaddition possible? Consider the Woodward– Hoffmann rules. Synthetic Analysis and Design Dale L. Boger 8. Fallis Synthesis: Intramolecular Diels–Alder Reaction Barton Free Radical Deoxygenation Reaction Acetate Pyrolysis Chromatographic Resolution through Diastereomeric Derivatization (Starting Material) J. Am. Chem. Soc. 1990, 112, 4609. J. Org. Chem. 1993, 58, 2186. OMe O ClCd H O OH MeLi O MnO2 65% 73% 81% resolution via diastereomeric derivatization O Me OMe O Me O MeOH, BF3•OEt2 OMe 1. H2, Pd–C, 99% O heat, toluene AcO OH 2. LiAlH4, 96% 3. Ac2O, 74% Me 83 x 97% Me Me Me Me Me Me Me OMe AcO AcO 1. NaI–TMSCl Me 2. ClC(=S)OPh Bu3SnH, 50% 525 °C, 56% Me O MeLi Me 65% OH O OPh S O Me pyrolysis Me Acetate Pyrolysis Barton Free Radical Deoxygenation O Bu3SnH, 71% Barton Free Radical Deoxygenation Intramolecular Diels–Alder Reaction Me ClC(=S)OPh OH MeLi 3-exo-tet cyclization 65% AIBN O Bu3SnH SSnBu3 •SnBu3 OPh OPh Bu3SnH Barton Free Radical Deoxygenation - mild method for removal of alcohols H SSnBu3 CH3 O H O + CH3 HO O Acetate Pyrolysis - a retro ene reaction - comparable to the sulfoxide syn elimination (Trost) which is activated by an adjacent EWG - comparable to the selenoxide syn elimination (Reich) which is milder, faster and proceeds at lower temperature 457 Modern Organic Chemistry The Scripps Research Institute O Intramolecular Diels–Alder Reaction - constraints of the 6-membered ring precludes reaction from the other cyclopentadiene isomers and lactone stereochemistry dictates π-facial selectivity O O MeOH O BF3•OEt2 OMe O O OMe Me O OMe Me Me OMe O toluene Me Me Me OMe O microwave 2.5 h, 97% O O O Me Me OMe O Me Me OMe O O Me O H H Me H OH O MnO2 - MnO2 serves to oxidize cyclopropyl alcohol analogous to allylic alcohol oxidation 81% H Nu– Me Me "conjugated" cyclopropane conformation Nu– O 9:1 MeI + R O SiMe3 458 O ClCd SiMe3 R O Me R O Me H3O+ - Cadmium reagent for α-versus γ-enolate reaction - Diastereoselective addition OMe I– R O H NaI–TMSCl deprotection - dealkylative SN2 methyl ether deprotection Synthetic Analysis and Design Dale L. Boger 1. Br2, HBr, HOAc 2. Br2, ClSO3H O Intramolecular Aldol Addition Wagner–Meerwein Rearrangement Can J. Chem. 1988, 66, 1794. 9. Kuo Synthesis: I O 70 °C LDA, –78 °C 1. HCl 2. PDC, CH2Cl2 O Br 2. K, HMPA O MeO MeO O TMSO O NaCN, DMSO 3. Zn, HOAc O 4. KI, DMSO, 110 °C 5. TMSCl, HOCH2CH2OH TMSO 1. LDA NC MeO O TMSCl TiCl4, –78 °C MeO TMSO 3. HC(OMe)3, CeCl3 1. BBr3, NaI 1. Ca/NH3 O H 2. Ac2O, DMAP MeO Intramolecular Mukaiyama Aldol MeO 2. PDC, CH2Cl2 OAc Et2Zn H 3. Ph3P=CHBr, CH2I2 OH BuLi, –78 °C 4. LiAlH4 PCC H2/Pt H CH2Cl2 H HOAc, 2.5 atm OH LiAlH4 O OH Me Me MeSO2Cl, pyr HO DMAP, 100 °C Wagner–Meerwein Rearrangement H Me Me Me MeSO2Cl, pyr HO Wagner–Meerwein Rearrangement DMAP, 100 °C H Me Me Me H MsO * H * Me 459 Modern Organic Chemistry The Scripps Research Institute 10. Ho Synthesis: Ethyl Diazoacetate Ring Expansion Alkylative Esterification Can J. Chem. 1992, 70, 1375. O O benzene + O 80 °C, 67% O CO2H H2SO4 53% O MeOH, 100% O O O H2SO4 Eaton's Acid H2, Pd–C O CO2Me O NaOMe O CO2Me MeOH, reflux 98% O Me3SO3H O CO2Me 93% O P2O5 65 °C, 82% Acylium ion Cation– Olefin Cyclization Me2CuLi N2CHCO2Et 0 °C, 96% BF3•OEt2, 100% O CO2Me Me O CO2Me Me O CO2H both isomers present Me O CO2Me Ring Expansion both isomers present Me Me LiI, H2O CO2Et Me Me collidine reflux, 90% O CO2Et K2CO3 1. NaBH4, 82% NaI, Zn MeI, acetone 2. MsCl, Et3N, 85% reflux 95% O CO2Me both isomers present O Me OMs CO2Me both isomers present O Me Me Me KOH 1. MeLi. 87% reflux 2. CF3CO3H. 48% 3. NaOH, 93% 4. PCC, 86% 100% CO2Me CO2H <50% OMs Me O longifolene Baeyer–Villiger Me I– CO2Et O CO2Me 460 Me Me LiI, H2O K2CO3 collidine MeI, acetone O reflux, 90% HO2C 95% Me O CO2Me - SN2 Dealkylative Deesterification followed by decarboxylation of the β-keto acid - Alkylative Esterification Combinatorial Chemistry Dale L. Boger XIV. Combinatorial Chemistry Combinatorial Chemistry Reviews • A Practical Guide to Combinatorial Chemistry; Czarnik, A. W. and DeWitt, S. H., Eds.; ACS: Washington, D. C., 1997. • Molecular Diversity and Combinatorial Chemistry: Libraries and Drug Discovery; Chaiken, I. N.; Janda, K. D., Eds.; ACS: Washington, D. C., 1996. • Balkenhohl, F. et al. Combinatorial Synthesis of Small Organic Molecules, Angew. Chem. Int. Ed. Eng. 1996, 35, 2288. • Ellman, J. A. et al. Synthesis and Applications of Small Molecule Libraries, Chem. Rev. 1996, 96, 555. • Gordon, E. M. et al. Applications of Combinatorial Technologies to Drug Discovery. 1. Background and Peptide Combinatorial Libraries, J. Med. Chem. 1994, 37, 1233. • Gordon, E. M. et al. Applications of Combinatorial Technologies to Drug Discovery. 2. Combinatorial Organic Synthesis, Library Screening Strategies, and Future Directions, J. Med. Chem. 1994, 37, 1385. • Pavia, M. R., Sawyer, T. K. and Moos, W. H., Eds.; The Generation of Molecular Diversity, Bioorg. Med. Chem. Lett. Symposia-in-print no. 4. 1993, 3, 381. (First Review Treatment of Field). • Combinatorial Peptide and Nonpeptide Libraries: a Handbook; Jung, G., Ed.; VCH: Weinheim, 1996. • Combinatorial Chemistry; Terrett, N. K.; Oxford Univ. Press: Oxford, UK, 1998. • Obrecht, D.; Villalgordo, J. M.; Solid-Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Libraries; Pergamon/ Elsevier, 1998. • Boger, D. L., Ed.; Combinatorial Chemistry, Bioorg. Med. Chem. Lett. Symposia-in-print no. 14. 1998, 8, 2273. • An Information Revolution, Science 2000, 287, 1951–1981. 461 Modern Organic Chemistry The Scripps Research Institute Solid Phase Peptide Synthesis R1 Cl O NHCBz • Attach first amino acid to (chloromethylated) polymer bead NHCBz • Deprotect (HBr), Couple (DCC), Cap (acetic anhydride) O R1 O O O R1 O O O N H R1 O HO O N H H N R2 O H N R2 O N H R2 R3 O NHCBz N H R4 • Repeat coupling cycle R3 O N H NH2 R4 • Deprotect, Saponify, Purify • Allows excess use of reagents and reactants to force reaction to completion • Removal of reagents, reactants and byproducts by filtration Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149. Nobel Prize, 1984 "for his development of methodology for chemical synthesis on a solid matrix" Additional Highlights in Solid Phase Synthesis • 1965: Letsinger and Khorana, the application of solid supports for the synthesis of oligonucleosides (J. Am. Chem. Soc. 1965, 87, 3526 and 1966, 88, 3182) • 1967: J. Frechet, a highly loaded trityl resin (2.0 mmol/g) • 1967: Wilkinson et al., polymer-bound tris(triphenylphosphine)chlororhodium as hydrogenation catalyst (J. Chem. Soc. A 1967, 1574) • 1969: Solid-phase synthesis of Ribonuclease (J. Am. Chem. Soc. 1969, 91, 501) • 1971: Frechet and Schuerch pioneered solid-phase chemistry in the field of carbohydrate research (J. Am. Chem. Soc. 1971, 93, 492) • 1973: Leznoff et al., the use of polymer supports for the mono-deprotection of symmetrical dialdehydes, describing oxime formation, Wittig reaction, crossed aldol condensation, benzoin condensation, and Grignard reaction on solid support (Can. J. Chem. 1973, 51, 3756) • 1974: F. Camps et al., the first synthesis of benzodiazepines on solid support (An. Quim. 1974, 70, 848) • 1976: Rapoport and Crowley, published a review and raised three important questions • degree of separation of resin-bound functionalities • analytical methods to follow reactions on solid support • nature and kinetics of competing side reactions (Acc. Chem. Res. 1976, 9, 135) • 1976–1978: Leznoff et al., the synthesis of insect sex attractants (Can. J. Chem. 1977, 55, 1143) • 1979: Leznoff et al., a chiral linker for the asymmetric synthesis of (S)-2-methylcyclohexanone in 95% ee (Angew. Chem. 1979, 91, 255) 462 Combinatorial Chemistry Dale L. Boger Tea-Bag Method .......... .......... .......... .......... .......... .......... .......... .......... Seal XXX Code • 10 to 20 mg of 248 different 13-residue peptides Mesh Opening • Sequence 1. Deprotection 2. Wash 3. Coupling 4. Wash 5. HF Cleavage Resin Repeat Houghten, R. A. Proc. Natl. Acad. Sci. USA 1985, 82, 5131. Multipin Peptide Synthesis Pin reagents, reactants in wells • Synthesize on polyacrylategrafted polyethylene rods • Utilize conventional solid phase synthesis methods growing peptide on a pin • Preparation of up to 10,000 spatially separate compounds using inexpensive equipment and readily available automation Individual pins 96-Well Plate with crowns (1 to 7 µmol loading capacity) Geysen, H. M. et al. Proc. Natl. Acad. Sci. USA 1984, 81, 3998. Zuckermann, R. N. et al. Bioorg. Med. Chem. Lett. 1993, 3, 463. 463 Modern Organic Chemistry The Scripps Research Institute Split and Mix Solid Phase Synthesis (Split-Method, Portioning-Mixing Method) A1 A1 A2 A3 A2 B1 B2 A3 - Mix - Split - React B3 A1B1 A1B2 A1B3 A2B1 A2B2 A2B3 A3B1 A3B2 A3B3 C1 C2 • Solid support is divided before each coupling cycle • Equimolar mixtures of peptides • Cannot conduct direct mixture synthesis on solid phase due to differential reaction rates • One unique peptide on each bead N = n1 x n2 x n3 x ..... nm - Mix - Split - React C3 N = number of products after each cycle n = number of reactants in each cycle A1B1C1 A1B1C2 A1B1C3 A2B1C1 A2B1C2 A3B1C1 A3B1C2 A2B1C3 Furka, A. et al. Bioorg. Med. Chem. Lett. 1993, 3, 413. A3B1C3 Furka, A. et al. Int. J. Peptide Prot. Res. 1991, 37, 487. A1B2C1 A1B2C2 A1B2C3 Split synthesis A3B3C1 A3B3C2 A3B3C3 Portion-mixing Hruby, V. J. et al. Nature 1991, 354, 82. Divide, couple, and recombine Houghten, R. A. et al. Nature 1991, 354, 84. Generation of Combinatorial Antibody Libraries Use of bacteriophage lambda vector to express in E. coli a combinatorial library of Fab fragments Sequence: First step: Separation of heavy and light chain libraries which are constructed in λHc2 and λLc1 Second Step: Combination of two libraries are combined at the antisymmetric Eco R sites present in each vector This results in a library of clones each of which potentially coexpresses a heavy and a light chain Lerner, R. A. et al. Science 1989, 246, 1275. 464 Combinatorial Chemistry Dale L. Boger Phage Display • The general concept is one in which a library of peptides is presented on the surface of a bacteriophage such that each phage displays a unique peptide and contains within each genome the corresponding DNA sequence Helper Phage Infection Extrusion Outer Membrane Periplasmic Space • Introduction of randomized DNA into gene III of filamentous phage Expression of the corresponding peptides at the N terminus of the absorption peptide (pIII) Peptide-pIII pIII Inner Membrane ssDNA • Very quick and efficient generation of large combinatorial libraries of peptide fragments PeptidepIII • Screen by panning and enrichment Peptide Library Phage DNA • Identify by DNA sequence pIII Phagemid DNA Smith, G. P. et al. Science 1990, 249, 386. Very Large Scale Immobilized Polymer Synthesis (VLSIPS) Lithographic Mask hν X–A PhotoX X X X NH NH NH NH X Deprotection NH2 NH2 X NH NH Chemical Coupling • Light-directed spatially addressable parallel chemical synthesis • Nitroveratryloxycarbonyl (NVOC) as a photolabile protecting group hν X A NH X A NH X X NH X A NH X X X X A A B B NH Repeat NH NH NH NH X A NH X NH X NH E F E F C D C D A A B B NH NH NH NH Chemical Coupling OMe O X–B X= O OMe O2N • Binary masking yields 2n compounds in n chemical steps Fodor, S. P. A.; Pirrung, M. C. et al. Science 1991, 251, 767. 465 Modern Organic Chemistry The Scripps Research Institute Solid Phase Synthesis of 1,4-Benzodiazepines • Application of solid-phase combinatorial synthesis to non-oligomeric compounds R1 O : solid phase attached to linker Si SnMe3 1) R1 NHBoc 2) TFA, CH2Cl2 Cl Pd0 Si O NH2 O NHFmoc 1) F "traceless" linker R2 2) Piperidine R1 R1 Si N R2 N R3 R1 N HF Me2S 1) 5% HOAc, 65 °C R2 N R3 O 2) Ph O N O 3) R3I, Si O NH OLi NH2 O DMF R2 Ellman, J. A. et al. J. Am. Chem. Soc. 1992, 114, 10997. DeWitt, S. H. et al. Proc. Natl. Acad. Sci. USA 1993, 90, 6909. Resin Release Only of Product First Example: Rapoport, H.; Crowley, J. I. J. Am. Chem. Soc. 1970, 92, 6363. (Dieckmann condensation) R1 R2 R1 R2 O NHBOC O O 1. TFA NH O HN R3 2. R3 NCO R1 R2 HCl, ∆ O NH N R3 O Hydantoins The desired products are formed by acid-catalyzed cyclization and only with cleavage off the solid support • Insures product purity without deliberate purification and independent of overall conversion R1 O R1 O ∆ NH2 O NH N TFA, ∆ R2 NHR4 R3 R3 R4 N O O R2 O NHR4 R3 R1 N R2 Benzodiazepines DeWitt, S. H. et al. Proc. Natl. Acad. Sci. USA 1993, 90, 6909. 466 Combinatorial Chemistry Dale L. Boger Nucleotide Encoding 1. A1 2. N1 N1 A1 1. A3 2. N3 1. A2 2. N2 N2 CPG beads Linker Unit A2 N3 A3 mix 1. A1 2. N1 PCR Primer A1, A2, A3: Amino Acids N1, N2, N3: Encoding Nucleotides 1. A3 2. N3 1. A2 2. N2 • Tag attached to molecule, not bead N1N1 A1A1 N2N1 A1A2 N3N1 N1N2 A2A1 N2N2 A2A2 N3N2 N1N3 A3A1 N2N3 A3A2 N3N3 A1A3 • PCR enrichment: sensitivity and screening by panning and enrichment A2A3 A3A3 • Bonus: nucleotide tagging could be used for identification as well Janda, K. D. et al. J. Am. Chem. Soc. 1993, 115, 9812. Brenner, S.; Lerner, R. A. Proc. Natl. Acad. Sci. USA 1992, 89, 5381. Split Synthesis ENCODED with Tagging Molecules ( T1–T4 ) T1 Separate Beads into 3 Groups OH A+ C+ B+ 1%T1 1% T1 + 1% T2 1% T2 T1 T2 OB OA T2 OC Mix Beads and Divide again into 3 Groups T1 T1 OA T2 OB T2 OC X+ 1% T3 T1 T3 O-AX T2 T3 O-BX T1 O-CX T2 T3 Y+ 1% T4 T1 T4 T2 T4 T1 T2 O-AY O-BY O-CY T4 Z+ 1% T3 + 1% T4 T T3 1 O-AZ T4 T T3 2 O-BZ T4 T T2 1 O-CZ T3 T4 Tagging Molecules 1. Chemically inert 2. Encoding by attachment to the beads 3. After release, analyzed by Capillary Gas Chromatography using Electron Capture Detection (ECGC) on femtomolar scales from single beads 4. Identity only (CH2)n N2CHCO O Clm O OMe O O HOOC O ( )n n = 2–11 m = 2–5 O Ar NO2 Electrophoric Tag Linker Cl Cl Cl Ar = H Cl Cl Cl Cl H Cl Cl H F Cl H Still, W. C. et al. Proc. Natl. Acad. Sci. USA 1993, 90, 10922; Acc. Chem. Res. 1996, 29, 155. 467 Modern Organic Chemistry The Scripps Research Institute Peptide Encoding Fmoc Ddz Distribute resin into n portions Deprotect Fmoc Couple "binding" monomer Bn B1 Ddz B2 Ddz Bn Ddz B: Fmoc protected, base-labile monomers C: Ddz-protected, acid-labile monomers, which give reproducibly strong signals upon Edman sequencing = FmocHN NHMoz O Deprotect Moz or Ddz Couple "coding" monomer Cn O Resin HN MeO B1 C1 B2 C2 Bn Cn OMe Repeat • Identity only Mix Zuckermann, R. N. et al. J. Am. Chem. Soc. 1993, 115, 2529. Electronic Encoding • Radiofrequency memory chips allow libraries to be tagged in a machine-readable form • The chips (8 x 1 mm) can be incorporated into various reaction platforms (e.g. beads, tubes, bags, pins or cans) Control logic Transmitter and receiver Antenna Rectifier Glass Housing Memory encoding A B C Nova, M. P.; Nicoloau, K. C. et al. Angew. Chem. Int. Ed. Eng. 1995, 34, 2289. Armstrong, R. W. et al. J. Am. Chem Soc. 1995, 117, 10787. 468 Combinatorial Chemistry Dale L. Boger Noncovalent Color-Coding Strategy A1 A8 A1B1 • 8 different subunits A1–A8 are linked to resin • each A is then partitioned into 12 Porous Containers (PCs) with different cap colors • a small amount of colored bead (one color for each A) is added to each PC • the PCs are grouped by cap color and subunit B is attached A1B12 A8B1 A8B12 • all 96 PCs are combined • subunit C is added to each bead color 96-well plate • compounds are sorted individually by cap and bead color A2B1C A1B1C • resin is cleaved • products are filtered into a separate 96-well plate cap color A1B2C A8B12C Guiles, J. W. et al. Angew. Chem., Int. Ed. 1998, 37, 926. Fourier Transform Combinatorial Chemistry • Cotton thread wrapped around a cylinder Thread library evaluation Fluorescence • 3 sectors exposed to 3 different reagents A C A B C A B C B A Thread length Screening and Evaluation B Fourier Transform Coupling with 4 other compounds D Fluorescence FT Library Spectrum Frequency G E Reverse F.T. at a given frequency F A B C A B C A B D E F G D E F G "Fitness Profile" of a sub-molecular unit Schwabacher, A. W. et al. J. Am. Chem. Soc. 1999, 121, 8669. 469 Modern Organic Chemistry The Scripps Research Institute Toward Larger Chemical Libraries: Encoding Fluorescent Colloids Solid support bead with numerous silica particles ("reporter") • The fluorescent "reporter" is introduced during the Split & Pool synthesis • Each particle contains a fluorescent dye (or a combination) coding for a single monomer • "Decoding" the bead (by fluorescence microscopy) allows identification of the compound Trau, M. et al. J. Am. Chem. Soc. 2000, 122, 2138. Microarray Screening: Immobilized Target or Compound Membrane Printing: the SPOT technique 1 • Peptide synthesis on paper using "Fmoc/tBu" scheme DNA Microarray: Printing oligonucleotide2 Fluorophore probe • The molecule or synthesis is arrayed by dispensing small droplets in pre-defined areas • Covalent immobilization of the compound on the glass surface support • Covalent immobilization of • Automation of the technique oligonucleotides on support allows miniaturization of the with high-density arrays process and creates • Detection of DNA/DNA high-through put systems or DNA/RNA interactions for expression analysis, genomics, and cellular response to small molecules 1 Frank, Printing small molecules on a glass surface3 • Incubation with the target • Detection by fluorescence > 1000 spots per cm2 R. et al. in Peptide and Nonpeptide Libraries, Jung, G., Ed., 1996, 363. Niemeyer, C. M. et. al. Angew. Chem. Int. Ed. 1999, 38, 2865. 3 Schreiber, S. L. et. al. J. Am. Chem. Soc. 1999, 121, 7967. 2 470 Combinatorial Chemistry Dale L. Boger Screening Mixtures of Beads (Compounds) • Super permeable resin for organic combinatorial chemistry (SPOCC) fully compatible with organic chemistry and enzyme assays (polyether polymer) HO O O O n O O OH n O O O Meldal, M. et al. J. Am. Chem. Soc. 1999, 121, 5459. O O O O • Peptide substrates contain a fluorescent dye and a quencher for use in fluorescent resonance energy transfer (FRET) assay n • Cleavage of the resin bound substrates leads to formation of strongly fluorescent beads • Identification of active compounds by MALDI-MS of fluorescent beads Meldal, M. Tetrahedron Lett. 1992, 33, 3077. Meldal, M. et al. Proc. Natl. Acad. Sci. USA 1994, 91, 3314. Meldal, M. et al. Biochem. J. 1997, 323, 427. One-Step Mixture Synthesis and Deconvolution "Activated Core Approach" + Core molecules: 3 Tetraacid chlorides Building blocks: 19 amino acids Library size: A1: 11,191 A2: 65,341 A3: 1,330 Deconvolution by Omission Resynthesis 1. Libraries A1–A3 to find best core molecule 2. Sublibraries B1–B6 to find best 9 building block amino acids (AA) 3. Sublibraries C1–C7 to check if the selected 9 AA are the best combination 4. Sublibraries D1–D9 to find the best 5 AA 5. Sublibraries E1–E7 to find the best 3 or 4 groupings of the 5 AA 6. Sublibraries F1–F6 to find the best relative position of the 4 AA on the core 7. Single compounds G1–G3 synthesized and the best inhibitor of trypsin determined Rebek, J. Jr., et al. Chem. Biol . 1995, 2, 171. 471 Modern Organic Chemistry The Scripps Research Institute Multicomponent One-Step Mixture Synthesis O R1 NH2 solid support R2 CHO R1 O OH O N CN R3 R N H 2 R3 removal from resin affords pure compounds H • 4 components 20 structural variants/input O N N H R2 resin capture excess/unreacted starting materials and byproducts removed by filtration • Libraries of single compounds R1 O R1 O H R3 O N N H R2 resin capture • 160,000 compounds generated OH AcCl new synthesis O H N R1 O O R2 Armstrong, R.W. et al. Acc. Chem. Res. 1996, 29, 123. Ugi, I. et al. Endeavour 1994, 18, 115. Multistep Solution Phase Synthesis of Combinatorial Libraries Purification via Liquid/Liquid or Liquid/Solid Extraction O CO2H BOC N EDCI BOC N • Solvent, reagent byproducts, excess reagents and reactants removed through extraction with acid and/or base O CO2H O 1st diversification R1NH2 CO2H BOC N CONHR1 2nd diversification R2NH2 CONHR 2 • Products pure irrespective of yield BOC N PyBOP HCl CONHR1 • 25–50 mg of products CONHR2 • Multistep synthesis in format of: HCl•HN CONHR1 3rd diversification • Liquid/solid extraction using ion exchange resins R3CO2H O PyBOP R3 CONHR2 N - individual compounds - small mixtures - large mixture synthesis CONHR1 Boger, D. L. et al. J. Am. Chem. Soc. 1996, 118, 2567. 472 Combinatorial Chemistry Dale L. Boger Multistep Convergent Solution Phase Combinatorial Synthesis BOC N O CO2H EDCI BOC N CO2H BOC N O R1HNOC (1) HCl R1NH2 O (2) PyBrOP R2HNOC CO2H BOC N CO2H R1HNOC R2HNOC R3HNOC R4HNOC N N N O O N BOC O O N X N O N CONHR1 CONHR2 CONHR1 R2NH2 CO2H PyBOP BOC N CONHR1 CONHR2 • The synthesis of large molecules is possible in only a few steps • Purification at each step by acid/base extractions or solid/liquid extractions N CONHR1 • Solution phase only CONHR2 • Multiplication of diversity O N CONHR3 • Final dimerization has been achieved via peptide coupling with diacids or olefin metathesis CONHR4 Boger, D. L. et al. Tetrahedron 1998, 54, 3955. Boger, D. L. et al. Bioorg. Med. Chem. 1998, 6, 1347. Linear, divergent synthesis with mutiplication of diversity (solid or solution phase) Sequential, linear oligomer synthesis Sequential, linear template functionalization FG3 FG4 FG3 FG2 FG1 FG2 FG1 FG4 FG2 FG3 FG2 FG4 Convergent synthesis with multiplication of diversity (solution phase only) receptor activation FG3 FG3 agonists antagonists FG3 FG2 FG3 FG4 FG3 FG1 FG3 FG2 Boger, D. L. et al. Tetrahedron 1998, 54, 3955; J. Am. Chem. Soc. 1998, 120, 7220. 473 Modern Organic Chemistry The Scripps Research Institute 10 compounds O CO2H EDCI BOC N BOC N 100 compounds CONHA1-n A1−A10 BOC N BOC N O CO2H PyBOP 86% CO2H O 1) HCl−dioxane 2) CH2=CH(CH2)nCON(CH2CO2H)2 PyBrOP A1-nHNOC n = 3, 4, 7, 8 (C1−C4) 63% O N N CONHB1-n CONHA1-n B1-nHNOC ( )n O O CONHA1-n B1−B10 N RuCl2(PCy3)2CHPh N CONHA1-n N N O CONHA1-n ( )n O CONHB1-n O 55% CONHB1-n CONHB1-n O 20,200 compounds A1-nHNOC ( )n O O N N N CONHB1-n • Multistep, convergent, mixture synthesis CONHB1-n TsNHNH2/NaOAc or • Deletion synthesis deconvolution provided identity of active constituent CONHA1-n H2, Pd−C, 98% CONHA1-n • Positional scanning not suitable for identification of unsymmetrical combinations B1-nHNOC N CONHA1-n N N O ( )n O CONHB1-n O Boger, D. L. et al. J. Am. Chem. Soc. 1998, 120, 7220. O 114,783,975 compounds A1-nHNOC N ( )n O O N N CONHB1-n CONHA1-n CONHB1-n Identification of Potent Inhibitors of Angiogenesis via Inhibition of MMP2 Binding to Integrin αVβ3 60 mixtures of 10 compounds R1HN O N O O R3 O NHR1 N R2HN NHR2 O O screen for inhibition of MMP2 binding to αVβ3 600-member O mixture library deconvolute and evaluate analogs to optimize binding and improve properties MMP2 α V β3 disruption of angiogenesis small molecule antagonist α V β3 O R N H R H N O CO2H O O CF3 • Blocks angiogenesis and tumor growth on the chick chorioallantoic membrane (CAM) without directly inhibiting αVβ3 or MMP2 Boger, D. L. et al. J. Am. Chem. Soc. 2001, 123, 1280. 474 NH R= Combinatorial Chemistry Dale L. Boger Application of Multistep Solution Phase Synthesis of Libraries via Liquid−Liquid and Liquid−Solid Extraction Distamycin A: Naturally occurring polyamide composed of repeating heterocyclic amino acids and a basic side chain H N H O A subunit H N 8 step total synthesis of distamycin A: 40% overall >95% purity at each step B subunit H N Solution phase combinatorial chemistry O C subunit N using 10–12 different heterocyclic amino H NH2 N acids and liquid−liquid acid/base extraction for purification Me O N Comparison of results from testing in different formats: NH Me O Small mixture libraries Large mixture scanning libraries N Me 1320 compounds (10 x 11 x 12) (132 mixtures of 10 compounds each) 1000 compounds (10 x 10 x 10) (30 scanning library mixtures of 100 compounds each) First generation libraries of potential DNA binding agents Derivatization of mixture libraries with a basic side-chain 2640 analogs in prototype library Second generation libraries of potential DNA binding agents with increased affinity Boger, D. L.; Fink, B. E.; Hedrick, M. P. J. Am. Chem. Soc. 2000, 122, 6382. Rapid, High Throughput Screen for DNA Binding Affinity and Establishment of DNA Binding Selectivity Identify compounds with affinity for single sequence of interest or define sequence selectivity of a compound against library of all sequences • Establish relative or absolute binding constants DNA affinity is measured as a decrease in relative fluorescence indicating binding and displacement of prebound ethidium bromide • Libraries used at a single concentration during first round of testing or at several concentrations to determine binding constant Use of a 96-well fluorescence plate reader allows screening of 100s of libraries in a matter of minutes • Library of compounds against a single sequence in form of hairpin oligonucleotide • Single compound assayed against a full library of hairpin oligonucleotide sequences to establish DNA binding selectivity (Profiling DNA binding selectivity) • Library of compounds assayed against a library of DNA sequences Boger, D. L.; Fink, B. E.; Hedrick, M. P. J. Am. Chem. Soc. 2000, 122, 6382. Boger, D. L.; Fink, B. E.; Tse, W.; Hedrick, M. P. J. Am. Chem. Soc. 2001, 123, 5878. 475 Modern Organic Chemistry The Scripps Research Institute Rapid, High Throughput Screen for DNA Binding Affinity and Establishment of DNA Binding Selectivity 5'-CGATGCACA 3'-GCTACGTGA 100 90 80 A A A all possible 5 base pair sites 70 60 50 40 DNA affinity is measured as a decrease in relative fluorescence indicating binding and displacement of prebound ethidium bromide 30 20 10 0 1 26 51 76 101 126 151 176 201 226 251 276 301 326 351 376 401 426 451 476 501 512 Use of a 96-well fluorescence plate reader allows screening of 100s of libraries in a matter of minutes H H N H Distamycin A O N N H Me O N N H Me O N NH2 N NH Me O Boger, D. L.; Fink, B. E.; Hedrick, M. P. J. Am. Chem. Soc. 2000, 122, 6382. Boger, D. L.; Fink, B. E.; Tse, W.; Hedrick, M. P. J. Am. Chem. Soc. 2001, 123, 5878. 512 Hairpin Oligonucleotides 80 70 60 50 40 30 K = 9.3 x 107 M –1 K = 7.8 x 10 6 M –1 K = 5.4 x 10 6 M –1 ataa t aa ttt aa ata aa atg aa aa a atatt aa ttc aa ttg aa atc aa att atag t aa aa t aa ta t aa ta c ca att aa ac a aa ta g aa tg a aa ca a aa ca t atttg aa tg t aa aa c ca aa t aa tta atttc aa ga t aa ag a aa ag t aa ga c aa ta a ataa a aa aa g aa gtc aa gtt atta a ca ttt aa gta aa ag g ac aa a atctt aa ca g aa ag c atttt atata aa gc a ataa g ac ata atta g aa ctt 90 K = 6.5 x 10 7 M –1 20 10 0 Application of Multistep Solution Phase Synthesis of Libraries via Liquid−Liquid and Liquid−Solid Extraction Azatriostin A: cyclic octapeptide, close analogue of the natural occurring depsipeptide Triostin A, an antitumor antibiotic which binds to DNA by bisintercalation N R1 = O R N O N N NH H HN R O N R1 O S O O S O R1 N O R NH H HN N N O R O HUN-7293: cyclic heptadepsipeptide potent inhibitor of cell adhesion molecule expression exhibiting anti-inflammatory properties CN O O N O NH N N OMe O H N O O O NH N O Azatriostin A: Boger, D. L.; Lee, J. K. J. Org. Chem. 2000, 65, 5996. HUN-7293: Boger, D. L.; Chen, Y. Bioorg. Med. Chem. Lett. 2000, 10, 1741. 476 Combinatorial Chemistry Dale L. Boger Multistep Solution Phase Synthesis of Nonamide-Based Libraries with Purification by Liquid–Liquid Extractions O BOCN 3 Grignard reagents BOCN O O CO2H NaBH(OAc)3 R1–MgX O 5 amines R2–NH2 R1 EDCI 97% avg 87% avg R1 BOCN R1 N R2 210 electrophiles O N 3 R –CO2H R3–SO2Cl R3–OCOCl R3–NCO O • Isolation and purification by liquid–liquid acid/base extractions • 25–50 mg of final products • >95% purity, irrespective of yield • Potent inhibitors of LEF-1/β-catenin mediated gene transcription N R2 R3 5´ O 350 individual piperazinone products HCl−EtOAc RCO2H, EDCI 80% avg 3´ LEF-1 c-fos Luciferase binding promoter sites 67% avg overall yield, >95% pure Boger, D. L. et al. Helv. Chim. Acta, 2000, 83, 1825. Polymer-supported Scavenging Reagents I. polymer-supported reagent A XB A–B + (> 1eq) • Addresses the purification problem in solution phase synthesis filter X A–B • Entrain impurities upon completion of solution-phase reactions, either covalently or ionically II. polymer-supported catalyst A + B X (< 1eq) A–B + X filter A–B • Covalent scavengers: nucleophile–electrophile III. polymer-supported scavenging reagent • Ionic scavengers: a series of anion and (excess reagents, starting materials) cation exchange resins (liquid–solid extraction) A + B A–B + A–B + Y filter Side Products A–B Reviews: Booth, R. J.; Hodges, J. C. Acc. Chem. Res. 1999, 32, 18. Flynn, D. L.; Parlow, J. J. Curr. Opin. Drug Discovery Dev. 1998, 1, 41. X Boger, D. L. et al. J. Am. Chem. Soc. 1996, 118, 2567. Flynn, D. L. et al. J. Am. Chem. Soc. 1997, 119, 4874. Hodges, J. C. et al. J. Am. Chem. Soc. 1997, 119, 4882. Kaldor, S. W. et al. Tetrahedron Lett. 1996, 37, 7193. 477 Modern Organic Chemistry The Scripps Research Institute Solution Phase Combinatorial Synthesis of Biaryl Libraries Employing Heterogeneous Conditions for Catalysis and Isolation O NHR O RHN NHR 10% Pd–C Et3N I O O R1 2 R meta, para RHN purify by size exclusion chromatography R1 • final purification possible by size exclusion chromatography HN O R1 I • purification by acid/base liquid–liquid or liquid–solid (ion exchange) extractions and filtration of catalyst O NHR remove by acid extraction remove by filtration H N O 10% Pd–C Et3N • convergent, mixture synthesis RHN O O NH R2 6 R1 groups 6 R2 groups 10 linkers R2 • scanning and deletion synthesis deconvolution libraries prepared 64,980 compounds Boger, D. L.; Jiang, W.; Goldberg, J. J. Org. Chem. 1999, 64, 7094. Boger, D. L.; Goldberg, J.; Andersson, C.-M. J. Org. Chem. 1999, 64, 2422. Resin Capture of Product ("Fishing Out" Principle) • Libraries of β-amino alcohols are synthesized by parallel synthesis in solution • Purification is achieved by "fishing out" the desired products with a PEG-bound dialkylborane • Precipitation of the polymer-bound product allows the removal of unreacted starting materials and any byproducts • Treatment with HCl releases the product from the polymer support in high purity O Cl R2 R1 R1 phenol or sulfonamide H B O NH2 R1 1° or 2° amine OH N H R2 Impure mixture (Not purified) R1 O B N R2 HCl R1 OH (PEG Polymer) purify by PEG precipitation/filtration N H R2 Pure product Janda, K. D. et al. J. Org. Chem. 1998, 63, 889. Ugi reaction with polymer bound carboxylic acid: Armstrong, R. W. Tetrahedron Lett. 1996, 37, 1149. 478 Combinatorial Chemistry Dale L. Boger Resin Release Only of Product OH O • A wide range of 3° amines can be synthesized on solid support Cl R1 HN R2 O O O • The product is released via β-elimination R1 N R2 O • Only the activated (quaternary) product is released, ensuring purities >95% R3X i Pr2NEt O R1 O R3 N R2 + R1 N 2 R R3 • After cleavage of product, the resin is regenerated and can be reused Morphy, J. R. et al. J. Am. Chem. Soc. 1997, 119, 3288. Iterative Deconvolution SURF Deconvolution (Synthetic Unrandomization of Randomized Fragments) • Iterative deconvolution was first applied to peptide libraries XXX • The SURF procedure was described for nucleotide libraries • Libraries are synthesized on solid phase by split synthesis AXX + BXX CXX _ _ • Repetitive synthesis and screening of increasingly simplified sets • At each step of the deconvolution an additional position is known AAX ABX _ _ ACX + • Activity increases at each step, enhancing the accuracy of identification • Most potent library member guaranteed to be found and multiple hits lead to multiple parallel deconvolutions ACA + ACB _ ACC _ • Time between synthesis of libraries and hit identity long and cumbersome Houghten, R. A. et al. Nature 1991, 354, 84. Ecker, D. J. et al. Nucleic Acids Res. 1993, 21, 1853. 479 Modern Organic Chemistry The Scripps Research Institute Recursive Deconvolution • The library (XXX) is synthesized by split synthesis • At each stage 1/3 of the material is stored and labeled as a partial library • These stored partial libraries are used to deconvolute the full library XXA + XXB _ XXC Test 3 pools for activity _ Couple A to saved and catalogued XA, XB, and XC XAA _ XBA + XCA Test 3 pools for activity _ Couple BA to saved and catalogued A, B and C ABA + BBA _ CBA Test 3 pools for activity _ Janda, K. D. et al. Proc. Natl. Acad. Sci. USA 1994, 91, 11422. Positional Scanning of Synthetic Peptide Combinatorial Libraries • Deconvolution libraries produced upfront for testing O1 X X X X X-NH2 • Identifies most active residue at each position in one round of testing X O2 X X X X-NH2 • Screen looking for increases in activity X X O3 X X X-NH2 X X X X X • This combination is not always the most potent (ca. 20–40% of time) • Best for identifying multiple hits in a library including weak activities • Requires mixture synthesis, not suited for solid phase X X O4 X X-NH2 X X O5 X-NH2 X X X O6-NH2 O = individual component X = mixture Houghten, R. A. et al. Nature 1991, 354, 84. 480 Combinatorial Chemistry Dale L. Boger Scanning Deconvolution Applications Proliferative response of TL 5G7 to MBP and scanning peptide libraries A: the response to a sizing scan with completely randomized libraries ranging in length from 6 to 15 amino acids B: the response to peptide sublibraries with fixed amino acid in position 1 to 11 phenylalanine (F), lysine (K), asparagine (N), or glycine (G) • Mixture analysis so the number of compounds assayed can be very large • Identified single peptides 104−105x more active than well known natural autoantigen Hemmer, B. et al. J. Exp. Med. 1997, 185, 1651. (Multiple sclerosis) Hemmer, B. et al. Nature Med. 1999, 5, 1375. (Lyme disease) Deletion Synthesis Deconvolution • Deconvolution libraries produced upfront for testing dA1 X X X X X dC1 X • Identifies most active residues at each position in one round of testing dA2 X X X X X dC2 X dA3 X X X X X dC3 X • Screen library for loss of activity versus full mixture dA4 X X X X X dC4 X X dB1 X X X X X dD1 X dB2 X X X X X dD2 X dB3 X X X X X dD3 X dB4 X X X X X dD4 • Best at identifying potent hits in a library, poor at identifying weak or multiple hits • Requires mixture synthesis, not suited for solid phase • Also suited for symmetrical libraries not capable of being addressed by scanning deconvolution dA1 X = mixture minus A1 (delete A1) = mixture Boger, D. L. et al. J. Am. Chem. Soc. 1998, 120, 7220. 481 Modern Organic Chemistry The Scripps Research Institute Test Case Comparisons of Scanning and Deletion Synthesis Deconvolution 6 R1 groups O O 20 R2 groups O O NHR2 N NHR2 N CO2H CONHMe R1 R1 Library 1 (120 compounds) Library 2 (120 compounds) Each individual compound and the scanning and deletion deconvolution sublibraries were prepared and tested side by side to establish which would identify the newly discovered leads Cytotoxic Activity (L-1210 IC50) of Mixture, Scanning, and Deletion Deconvolution Sublibraries scanning deconvolution deletion deconvolution scanning deconvolution deletion deconvolution B7 B13 B17 A5 A4 B7 B13 A5 B6 B14 B17 A5 B17 6 and 20 compd mix 100 and 114 compd mix gain in activity loss in activity Cytotoxic Activity (IC50, µM) for Individual Compounds A4 A5 B7 5 >100 B13 26 19 B17 25 28 A5 B6 44 B14 71 B17 5 Deletion synthesis more effective at identifying most potent compound in library Scanning deconvolution more sensitive and capable of identifying weak activities Combination more powerful than either technique alone Boger, D. L.; Lee, J. K.; Goldberg, J.; Jin, Q. J. Org. Chem. 2000, 65, 1467. Assay and Deconvolution by Mass Spectrometry Target-assisted isolation of mixture components Separation of target–ligand complex by: size exclusion chromatography ultrafiltration capillary electrophoresis affinity chromatography Identification of the bound ligand after dissociation of the complex by: ESI-MS: exceptional ability to detect ions present in solution with little fragmentation MALDI-MS: advantages over ESI-MS are its tolerance against impurities, buffer salts and formation of primarily singly charged ions Analysis of mixtures, so numbers of compounds evaluated can be large Direct detection and identification of target–ligand complexes Study of intact non-covalent complexes is possible by FTICR-MS (FTICR: Fourier Transform Ion Cyclotron Resonance). Advantages of FTICR-MS are its high sensitivity due to the accumulation of certain ions in the trap that allows the study of minor mixture components Review: Eliseev, A. V. Curr. Opin. Drug Discovery Dev. 1998, 1, 106. 482 Combinatorial Chemistry Dale L. Boger Active Protein-Binding Compounds Through SAR by NMR • use of 15 N-labeled target proteins makes it possible to study the ligand–protein complex by 15N-HSQC, even at high ligand concentrations screen and optimize first ligand • less time consuming compared to the combinatorial approach where a large number of linked compounds have to be synthesized. • linked ligands with nano molar binding constants screen and optimize derived from individual ligands with micro molar binding constants second ligand link ligands Shuker, S. B.; Hajduk, P. J.; Meadows, R. P.; Fesik, S. W. Science 1996, 274, 1531. Assay and Deconvolution by NMR Direct detection and identification of target– ligand complexes (detect bound ligand) Diffusion encoded spectroscopy (DECODES): combination of pulse field gradient (PFG) NMR and total correlation spectroscopy (TOCSY). Under PFG conditions, all resonances of low molecular weight ligands disappear from spectrum while signals of target-bound ligand remain. Approach is only applicable for low molecular weight molecules (200–400 Da) as targets and ligands. Lin, M.; Shapiro, M. J.; Wareing, J. R. J. Am. Chem. Soc. 1997, 119, 5249. Indirect detection and identification of target– ligand complexes (detect unbound ligands) 1D relaxation edited NMR and 1D difusion edited NMR: Difference spectrum of the 1D edited library-, protein- and mixture of protein with library-spectrum contains only signals from the bound ligand. There is no need for deconvolution of the library to identify active compounds. By removing the signals of the biomolecule there is no broadening or obscuring of the ligand's signals by the macromolecule. Hajduk, P. J.; Olejniczak, E. T.; Fesik, S. W. J. Am. Chem. Soc. 1997, 119, 12257. 483 Modern Organic Chemistry The Scripps Research Institute Combinatorial Target-Guided Ligand Assembly • no structural or mechanistic information required for this combinatorial method 1. prepare a set of potential binding elements with a common chemical linkage group X X X X X X • accomplished in 4 straightforward steps X • prelude to target assembled tight binding ligand from combinatorial mixture? 2. screen potential binding elements to identify elements that bind to target X X Target X Target X Ellman, J. A. et al. Proc. Natl. Acad. Sci. USA 2000, 97, 2419. Target 3. prepare library of all possible combinations of linked binding elements with variations in the link 4. screen library of linked X X X X X X X binding elements to identify the tightest binding ligands X X Target Solid Phase or Solution Phase Combinatorial Synthesis? Solid Phase Solution Phase + Simple removal of excess reagents and reactants + Chemistry not limited by support or linker + Automation straightforward + Monitor by traditional techniques + Split and mix synthesis + Purification possible after each step + – Pseudo-dilution effects + + Unlimited amounts (scales) available – + Automation by liquid–liquid techniques Reaction monitoring difficult – No purification possible Mixture or parallel synthesis – + + Linear, cannot conduct convergent synthesis – Removal of excess reagents and reactants limits scope – – 484 Adapt chemistry to solid phase and develop linking/cleaving strategies Limited scale Cannot conduct mixture synthesis Avoids extra steps for linking, etc Convergent or linear synthesis Combinatorial Chemistry Dale L. Boger Combinatorial Synthesis Using Soluble Polymers • Reactions were performed in the homogeneous liquid-phase solution using a soluble polymer (MeO-PEG: polyethylene glycol monomethyl ether) • Homogeneous reaction conditions overcome the difficulties of solid-phase combinatorial synthesis • Isolation can be accomplished by precipitation of PEG polymer at each stage • Intermediates can also be purified by conventional means (e.g. chromatography) • Analysis of intermediates is possible by conventional means (e.g. NMR) MeO-PEG-OH + O C O O S N Cl O O MeO-PEG-O cat. Dibutyltinlaurate CH2Cl2 HN S Cl O R−NH2, pyridine CH2Cl2 O O H2N S O MeO-PEG-O 0.5 N NaOH S HN NHR NHR O O Janda, K. D. et al. Proc. Natl. Acad. Sci. USA 1995, 92, 6419. Review: Janda, K. D. et al. Chem. Rev. 1997, 97, 489. Fluorous-phase Combinatorial Synthesis • Fluorous liquids: Immiscible in both water and organic solvents • Simple purification of products by three-phase liquid−liquid extraction • Accomplishment of a series of radical additions by homogeneous fluorous-phase combinatorial synthesis Early applications of fluorous bound substrate included • Ugi reaction • Biginelli reaction • Stille coupling • Solid-phase extraction with fluorous reverse-phase silica gel Curran, D. P.; Luo, Z. J. Am. Chem. Soc. 1999, 121, 9069. Reagents on fluorous phase or Substrates on fluorous phase (C6F13CH2)3SnH, AIBN R I + E E CF3 PhCO2C3H7 + PhCH2OH C8H17CH=CH2 + CO R 72–92% Fluorinert Fluid F-77 tol/c-C6H11CF3 C6H13CH2CH2CF3)3P Rh(CO)2(acac) PhCO2CH2Ph + C3H7OH C8H17CH(CHO)CH3 + C10H21CHO Curran, D. P. et al. J. Am. Chem. Soc. 1996, 118, 2531; Chemtracts, Org. Chem. 1996, 9, 75. Science 1997, 275, 823; Angew. Chem. Int. Ed. 1998, 37, 1174. 485 Modern Organic Chemistry The Scripps Research Institute A Combinatorial Approach to Materials Discovery Application of the combinatorial approach to the discovery of new solid-state materials with novel physical or chemical properties such as magnetoresistance or high-temperature superconductance. Substrates: polished MgO or LaAlO3 single crystals Sputtering Targets: CuO, Bi2O3, CaO3, PbO, SrCO3, Y2O3, and BaCO3 Generation of a 128-member binary library using 7 deposition-masking steps Superconducting materials: BiSrCaCuOx and YBa2Cu3Ox (Binary masks used for library synthesis) Schultz, P. G. et al. Science 1995, 268, 1738. Comparison of Combinatorial Chemistry Techniques Technique Single compound /mixture Speed of synthesis SAR retrieval Utility parallel synthesis single slow fast lead optimization mixture synthesis (scanning/deletion deconvolution) mixture fast slow (fast) lead identification parallel arrayed mixture mixture moderate moderate lead identification split and mix mixture (one compound per bead) moderate slow lead identification lead optimization chemically encoded mix and split mixture (one compound per bead) moderate moderate lead identification lead optimization mix and sort (microreactors) single moderate fast lead optimization lead identification Guiles, J. W. et al. Angew. Chem. Int. Ed. 1998, 37, 926. 486