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Fr182877

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This document summarizes a meeting presentation about total syntheses of the natural product FR182877. Key points include: - FR182877 is a cytotoxic natural product isolated from bacteria in 1998. It poses synthetic challenges due to its large hexacyclic structure containing multiple stereocenters. - Total syntheses of both enantiomers of FR182877 have been achieved by the Sorensen and Evans groups using Diels-Alder cascades. - The presentation discusses proposed biogenetic pathways, retrosynthetic analyses, key transformations such as Suzuki couplings and macrocyclization reactions, and studies of the stereoselectivity of the Diels-Alder cascade central to the

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Total Syntheses of FR182877 MacMillan Group Meeting October 5, 2005 Sandra Lee Key Articles: Isolation Papers: (a) Sato, B.; et. al. J. Antibiot. 2000, 53, 123; (b) Sato, B.; et. al. J. Antibiot. 2000, 53, 204; (c) Yoshimura, S.; et. al. J. Antibiot. 2000, 53, 615. Sorensen Synthesis: (a) Vosburg, D. A.; Vanderwal, C. D.; Sorensen, E. J. J. Am. Chem. Soc. 2002, 124, 4552; (b) Vanderwal, C. D.; Vosberg, D. A.; Weiler, S.; Sorensen, E. J. J. Am. Chem. Soc. 2003, 125, 5393. Evans Synthesis: (a) Evans, D. A.; Starr, J. T. Angew. Chem. Int. Ed. 2002, 41, 1787; (b) Evans, D. A.; Starr, J. T. J. Am. Chem. Soc. 2003, 125, 13531.

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FR182877 : Taxol-type HO H Me Cytotoxicity and Antimitotic Activity A Me B ! Isolation–Fujisawa Pharmaceutical Co. H H OH C O Isolated from the fermentation broth of Steptomyces 2 in 1998 with IC50 = 28-75 ng/mL cytotoxicity against DO several cell lines. Me 20 EO F H Structurally similar natural products: Hexacyclic Me Acid, Macquaimicin A, and Cochleamycin A ! Synthetic challenges (a) 19-membered Hexacyclic carbomacrocycle featuring 12 stereocenters (b) Vinlogous carbonate embedded in a 6-6-7 fused ring system (c) Instability to air oxidation (C2-C21) to form a biologically inactive epoxide ! Completed syntheses ! Ongoing synthetic efforts (+)-FR182877 by Sorensen in 2002 Armstrong in 2001: Model DF ring system (–)-FR182877 by Evans in 2002 Nakada in 2002: AB bicycle (+)-FR182877 by Sorensen in 2003 Roush in 2003: ABC tricycle Prunet in 2004: A ring Clarke in 2005: DEF ring system, B ring H O O H O Me Me O H H H H Me Me HO H OH HO H OH H H O O H VS. H H Me H H Me H Me Me (+)-FR182877 (–)-FR182877

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A Proposed Biogenetic Synthesis of FR182877 HO H Me Me OH OH Me OH H H Intramolecular Me Diels-Alder CHO reaction Me O CHO Me O (IMDA) CO2R CO2R Knoevenagel RO Me RO Me condenstation HO H Knoevenagel Me condenstation Me OH OH Me Transannular OH Diels-Alder H H Me reaction CO2R (TADA) O Me O Me Transannular CO2R Me hetero- HO Diels-Alder HO Me reaction HO HO H Me H Me Me Me OH OH H H H H O Lactonization O O Me H Me O O OR Me (–)-FR182877 OH see Classics II, p. 490 Me

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A Proposed Biogenetic Synthesis of FR182877 HO H Me Me OH OH Me OH H H Intramolecular Me Diels-Alder CHO reaction Me O CHO Me O (IMDA) CO2R CO2R Knoevenagel RO Me RO Me condenstation HO H Knoevenagel Me condenstation Me OH OH Me Transannular OH Diels-Alder H H Me reaction CO2R (TADA) O Me O Me Transannular CO2R Me hetero- HO Diels-Alder HO Me reaction HO HO H Me H Me Me Me OH OH H H H H O Lactonization O O Me H Me O O OR Me (–)-FR182877 OH see Classics II, p. 490 Me

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The Pivotal Transformation: Endo vs. Exo HO H Me Me B CO2R OH HO OH H H OH H H Me OH O Cascade TADA Me B D O H H DO Me Me O H Endo-TS Me Me (–)-FR182877 Me OH OH Me Me O CO2R HO Me AcO H Me CO2R OH HO2C B HO OH H OH OH H H Me Me Cascade TADA H O D B O H H DO OH Me O H Exo-TS Me Me Me Hexacyclinic Acid

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Evans: A Diels-Alder Cascade Strategy Suzuki HO H Me Br OR OR Transannular Me Diels-Alder OH reaction Me H H O Transannular Me O O hetero- !-ketoester alkylation Me O H Diels-Alder reaction CO2Et Me TBSO Me OR OR O O OH O OTBDPS OTBDPS OTBDPS (HO)2B O N H Me Me Bn O OR O O OH O MeO Me Me Me N O N H Me Me Br Me OTBS OTBS Bn Br

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Aldol Fragment Synthesis: Dibromide Fragment O O i. , THF i. TBSCl, DMF, imid. Me MgBr Me H OH H OTBS ii. O3/O2; PPh3 ii. triethylorthoacetate, proprionic acid, 150°C OTBS 75% iii. DIBAL, –78 °C 73% O O OH i. MeNHOMe • HCl Bu2BOTf, TEA Me3Al, THF Me O O O N ii. TBSCl, DMF, imid. 88% Me OTBS iii. TsOH:nBu4NHSO4 (1:4) O N Bn MeOH, 0 °C Me 82% Bn O OTBS i. Dess-Martin O OTBS MeO Me Periodinane, NaHCO3 MeO Me N N Me ii. CBr4, PPh3, Me Br Me Me OH CH2Cl2, NaHCO3 70% Br

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Aldol Fragment Synthesis: Boronic Acid Fragment OH i. nBuLi, THF TBDPSCl O Bu2BOTf, TEA OTBDPS HO H O O ii. SO3–Pyr, DMSO CH2Cl2, TEA 89% O N 59% Me Bn OH i. MeNHOMe • HCl O O O OH Me3Al, THF i. DIBAL, THF, –78 °C O N ii. HCCMgBr ii. TBSCl, DMF, imid. Me OTBDPS Me OTBDPS 75% >20:1 dr Bn 92% catechol-BH, OTBS OTBS Cy2BH (10 mol%) OTBS OTBS THF; 1N NaOH (HO)2B 97% Me OTBDPS Me OTBDPS

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Suzuki Coupling of the "Aldol" Fragments HO H Me O OTBS MeO Me Me OH N H H O Me Me Br 5% Pd(PPh3)4 Tl2CO3 O Me O H Br THF:H2O (3:1), rt Me 84% desired pdt OTBS OTBS OTBDPS (HO)2B 8 Me O OTBS MeO Me N OTBS OTBS Me Me OTBDPS Br Me undesired double addition product ! Highly Optimized Suzuki Coupling Conditions O OTBS The coupling was sensitive to the choice of base: MeO Me (1) strong bases (i.e. hydroxides, oxides) or less halophilic N OTBS OTBS cations resulted in slower rates and competitive Me Me OTBDP decomposition of SM via protodeborylation, oxidation, S elimination, etc. Me OTBS (2) silver bases completely decomposed products' OTBDPS TBSO (3) carbonates had the best selectivity and only Tl2CO3 Me gave good reaction at rt

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Synthesis of the Pivotal Macrocycle O OTBS O O OTBS MeO Me Me N EtO Me Me Me Br i. DIBAL, –78 °C Br ii. ethyldiazoacetate OTBS SnCl2 OTBS TBDPSO 70% TBDPSO OTBS OTBS Me Me O O OTBS Me O Me OTBS EtO EtO 2 Me Cs2CO3, * i. TBAF, AcOH, DMF THF (0.005M), rt O Me Br ii. I2, PPh3, CH2Cl2 1:1 dr Me OTBS 64% (3 steps) I TBSO OTBS Br TBSO Me

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The Diels-Alder Cascade in Action TBSO O Me OTBS Me OTBS H Me EtO EtO2C Br Ph2Se2O3, SO3-Pyr O Me OTBS O Me H H TEA, THF, rt; CO2Et Me hexanes, 50 °C Me TBSO 63% Me O H TBSO TBSO Br H TBSO Br TBSO Me single diastereomer HO HO H Me H Me i. HF-MeCN Me TMSOK, THF; Me OH OH H H H H ii. Pd(dppf)Cl (10 mol%) CO2Et NaHCO3, CH2Cl2 O Me3B3O3, Cs2CO3, O DMF:H2O (2:1), 100 °C HO Me H Cl 62% Me H O O N I 63% H Me Me Me Evans: [!]23D = -5 Fujisawa: [!]23D = -3.5

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A Closer Look at the Cyclization Sequence intermediate species were not isolable TBSO Me OTBS TBSO Me OTBS H Me EtO2C H Me EtO2C Br B O Me [O] 15 H OTBS Br 3 O Me H H OTBS H H 4 14 Me " CO2Et 5 Me CO2Et 12 Me O TBSO TBSO 9 Me O H Br TBSO Me TBSO Br H TBSO Me OTBS ! NMR analysis shows 2H-pyran equilibrium O Z 1:1 X O ! Cyclization order? The Normal-demand DA (NDA) Y OH Me OTBS or inverse-demand hetero DA (HDA)? EtO2C Keq = FMO anaylsis using calculated (Spartan 5.1) Pz orbital 1-10 coefficients of the HOMO and LUMO predicts B-ring O Me cyclization to occur first. O OTBS OH Me HOMO LUMO X O Z TBSO Br Atom Pz Atom Pz Y best overlap C9 0.38 C5 0.51 best overlap C12 -0.48 C4 -0.26 C14 -0.07 C3 -0.56 C15 0.03 O1 -0.29 Moorhoff (Syn 1997, 685): 6!-cyclization to pyran tautomer

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Studying the Inherent Stereoselectivity of the TADA Cascade ! Model IMDA study shows high endo selectivity with poor diastereofacial selectivity Sorensen's system, the enantiomer which differs only in silyl protecting groups and the Me @ C11, also observed high endo selectivity and the opposite dr 61:31 dr. This suggests that the C6-C8 stereotriad only modestly differentiates !-faces in the B-ring cyclization O OTBS TBSO TBSO MeO Me H Me H Me N 8 6 Me Me Br Br 11 OTBS OTBS Br 60 °C, CDCl3, 3h H H H H CHO CHO 37:63 dr OTBS Me O OMe Me O OMe O N N OTBS Me 18 19 Me Me TBSO Me TBSO Me desired cycloadduct ! The high face-selectivity of the TADA cycloaddition is conjectured to arise from C18,C19 stereocenters

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OMe Me OMe Modeling the TADA Endo Me CO2Me Transition States H H O Me MeO H H Me HH H O OMe H MeO OMe MeO O H H H endo TS I Br Br Me Me Nine simplified macrocycles (varied Me OMe at C18 and C19) were energy- CO2Me minimized (PM3) with distance MeO H H MeO H H Me constraints (of 2.9-2.1 Å) leading to O Me MeO Me the observed natural product (via H H OMe Br O OMe O endo TS I) or it's endo MeO Me H H diastereomer (via endo TS II). H Br endo TS II H Me For each macrocycle, five energy-minimized geometries were obtained and two energy curves were generated plotting the increasing energy penalty for !-face alignment of the approaching TS ( I and II). 18 19 Me OMe EtO2C EtO2C O Me OTBS Me O Me CHO Me Me TBSO Me MeO Br Br MeO MeO MeO Br 4.0-9.4 kcal/mol

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Analysis of the Transannular Hetero Diels-Alder Cycloaddition ! Tricyclic intermediate has two low-energy conformations Me OMe Me OMe H CO2R' Me H CO2R' H !E = H Me MeO MeO H Me O OMe H OMe HO 2 kcal/mol H H Br H Br Me kinetic conformation from 1st D-A required conformation for 2nd D-A ! Application of transition state bond constraints energetically favors desired cyclization Me OMe Me OMe H CO2R' H 3 Me CO2R' H H 3 Me MeO MeO H Me O OMe H HO OMe X 15 14 RO RO H 14 H Me 15 H H Me Br H Br Me C3-C14: at 2.2 Å = –146 kcal/mol C3-C14: at 2.2 Å = –173 kcal/mol Br Br OR OR O-C15: at 2.4 A O-C15: at 2.4 A H H H H OR CO2R' CO2R' !!G = 27 kcal/mol RO Me Me O H Me O Experiment: R = TBS, R' = Et H H Calculation: R, R' = Me Me

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HO HO H Me Me Me Me OH H OH H H O H O O O H H Me O H Me O Me Me (–)-FR182877 (+)-FR182877

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A Proposed Biogenetic Synthesis of FR182877 HO H Me Me OH OH Me OH H H Intramolecular Me Diels-Alder CHO reaction Me O CHO Me O (IMDA) CO2R CO2R Knoevenagel RO Me RO Me condenstation HO H Knoevenagel Me condenstation Me OH OH Me Transannular OH Diels-Alder H H Me reaction CO2R (TADA) O Me O Me Transannular CO2R Me hetero- HO Diels-Alder HO Me reaction HO HO H Me H Me Me Me OH OH H H H H O Lactonization O O Me H Me O O OR Me (–)-FR182877 OH see Classics II, p. 490 Me

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Sorensen: Initial Retrosynthetic Strategy Towards (+)-FR182877 featuring a D-A / Knoevenagel / D-A sequence RO H Me HO HO Me Me Me Transannular OR H H hetero- CHO Me Diels-Alder Me Knoevenagel H OH reaction H OH condenstation H O O O O Me H H H O Me O Me O Me O Me Me O RO RO H Me Me Y Me Me X OR Tandem Stille OR H H Claisen-Type Coupling- CHO Cyclization CHO IMDA Bn Bn Me O Me O N N O O X = SnBu3 or Br AcO Me O AcO Me O Y = SnBu3 or I

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Highlighted Issues in the Initial Strategy Towards (+)-FR182877 selectivity in the tandem Stille/IMDA sequence TBSO TBSO Me Me Br Bu3Sn Pd2dba3 (5 mol%), Me Me OTBS OTBS Ph3As (20 mol%), THF, reflux IMDA CHO CHO Bn Bn or Me O Me O Cl2Pd(CN)2 DMF, rt N N O O AcO Me O AcO Me O TBSO TBSO H Me H Me Me Me OTBS OTBS H H H H CHO CHO Bn Bn Me O Me O N N O O AcO Me O AcO Me O undesired endo cycloadduct

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Highlighted Issues in the Initial Strategy Towards (+)-FR182877 forming the !-keto lactone and Knoevenagel condensation TBSO TBSO H Me H Me Me Me OTBS 5 OTBS H H KHMDS ( 4 eq) H H CHO THF, –78 °C CHO Knoevenagel Bn Me O Me N O O AcO Me O Me O O HO ! Issues encountered in this approach: Me The desired !-keto lactone substrate was unstable to Stille coupling, as such the acetate imide was used. Me H OH The IMDA was not diastereoface-selective and gave 2 endo cycloadducts O O (separable by chromatography) H The Knoevenagel condensation to form the tetracycle ring was unsuccessful Me O Me revise strategy to an intermolecular Knoevenagel condensation Sorensen: Org. Lett. 1999, 1, 645 + JACS 2003, 125, 5393

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A Revised Retrosynthetic Strategy Towards (+)-FR182877 featuring a Knoevenagel / RCM approach HO HO Me Me Transannular Me hetero- Me H OH Diels-Alder H OH Ring-Closing H O reaction O Olefin Metathesis O O H H H Me O Me O Me Me RO H Me RO Me Me H OR H O Me CHO H OR Intermolecular H Condenstation O O O H O H O Me Me Me Me

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Highlighted Issues in the Revised Strategy Towards (+)-FR182877 unfruitful condensation reactions are circumvented via a HWE TESO i. TBAF, THF TESO TESO Me ii. Dess-Martin H Me H Me Periodinane, NaHCO3 Me Me Me OTES H OTES H OTES iii. NMP, rt H H OTES CHO CHO 1.9:1 dr 53% undesired product O O for IMDA rxn: Yamamoto's BLA and MacMillan's i. Et3N•3HF Me catalysts were also tried P ii. Ba(OH)2, THF, Me O O Br OMe iii. TESCl, N TEA, DMAP Me Me 6.5:1 Z:E Me TESO 65% H Me TESO H Me Me H OTES H Me Br H OTES H O O O O O O OMe Br OMe N N Me Me Me Me Me Me undesired product

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Highlighted Issues in the Revised Strategy Towards (+)-FR182877 an unexpected olefin geometry in alkylidene formation TESO TESO H Me H Me Me Me t-BuLi, H OTES OTES THF, –78 °C H H H OR O Br >90% H O Li O O Br OMe E O O O N OMe Me Me transient lithium allenoate N Me Me Me Me TESO H Me ! Issues Encountered in this Approach: Me IMDA to form the first fragment was moderately diastereoface-selective (1.9:1 H OTES desired:undesired) H The desired !-keto lactone and the acyclic !-keto ester were not amenable to the O O Knoevenagel condensation O Isomerization to the needed E geometry of alkylidene ketolactone was not Me realized though various methods Me revise strategy to form E-geometry alkylidene dicarbonyl undesired Z-olefin geometry

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A Re-revised Retrosynthetic Strategy Towards (+)-FR182877 OR Me Me OR H H HO RO Me Me CHO Transannular hetero- Diels-Alder H-W-E Me O OMe Me Me Condensation reaction H OH H OR N H O O O O Me O Me H H H Br Me O Me O O Me Me P OMe reductive C-acylation O OMe RO RO Me Me Intramolecular Me Diels-Alder Me OR OR reaction Me3Sn OTES CHO OAc !-allyl Stille coupling Me O OMe N Me O OMe Me N RO Me Me RO Me

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Highlighted Issues in the Re-revised Strategy Towards (+)-FR182877 IMDA and the HWE sequence TESO TESO O O Me Me MeO P OH MeO Me Me Br OTES OTES i. TBAF, THF, 0 °C H H i. DCC, NaHCO3 OTES CHO ii. MnO2, DMF, rt ii. Et3N•3HF, CH2Cl2 Me O OMe Me O OMe 65% (2 steps) 77% N N Me 1.6:1dr Me acylation yielded 4 spots (chromatographic separation HO Me HO Me of desired endo product) HO TESO Me Me Me Me OH OTES H H i. Ba(OH)2, THF/H2O H CHO Me Br OMe H N ii. TESCl, imid., DMAP O Me O OMe Me O O N Me Me O Me Br O * P OMe O OMe

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Highlighted Issues in the Re-revised Strategy Towards (+)-FR182877 haunted by the formation of the E-alkylidene TESO TESO HO Me Me Me Me Me Me H OTES i. t-BuLi, THF, –78 °C H OTES H OH 1 Me Br OMe H OMe H H Me 19 O N ii. PPTS, MeOH N O OLi O Me O 64% (4 steps) Me O Me O O O Me Me Me undesired Z olefin geometry confirmed by X-ray ! Issues Encountered in this Approach: IMDA gave poor diastereofacial selectivity (1.6:1 of desired:undesided cycloadduct) Key reductive lithiation cyclization step resulted in the formation of an undesired Z alkylidene dicarbonyl tetracycle. It was conjectured that the geometrical constraints of the 12-membered ring would had favored the Z isomer revise strategy in forging the C1-C19 bond and forming the !-keto lactone Sorensen: Org. Lett. 2001, 3, 4307 + JACS 2003, 125, 5393

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Sorensen: The Retrosynthetic Strategy that Worked featuring tandem TADA reactions RO OR HO Me Me lactonization Me O OMe Me O Me OR tandem RO OTMS O O H OH t-BuO TADAs H O TMSO O O OP H H Me Me Me H Me O Me O !-allyl Stille coupling Me Me Tsuji-Trost allylic alkylation OR Me OR OR O O OR Me OR OR O O O N OMe P RO HWE Me O OMe H I Bn Me SnMe3 Me OTMS O O TMSO O O AcO N AcO OMe O N Me Me Me Me Me Ph

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Synthesis of !-allyl Stille Coupling Fragment MeNHOMe • HCl O O O OH Bu2BOTf, TEA Me3Al, THF OTBS OTBS H O N O O 75% (2 steps) Me (2 steps from diol) O N Bn Me Bn OTMS i. TMSCl, DMAP, O OH Me OTBS imid, CH2Cl2 MeO OTBS N ii. LiCH2P(O)(OMe)2, O Me Me THF, –78 °C OMe P O OMe OH OTES i. Ba(OH)2, THF; Me OH i. Et2BOMe, NaBH4 Me OTES THF/H2O, 0 °C THF/MeOH O ii. TESCl, DMAP, TESO I O imid., CH2Cl2 Me I Sn(Me3) Me iii. Me3SnSnMe3, Me ii. PPTS, MeOH, rt Pd(Ph3P)4, Hünigs, 79% (4 steps) PhH, 80 °C 83% (3 steps)

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The !-allyl Stille Coupling of the Aldol Fragments O O OH i. MeNHOMe • HCl O Bu2BOTf, TEA Me3Al, THF OAc OAc H O N O O ii. TMSCl, DMAP, Me Me Me imid, CH2Cl2 O N Ph 87% (4 steps) "known aldehyde" Me Tetrahedron, 1972, 28, 2622 Ph O OTMS MeO OAc N OTES Me Me Me OTES Pd2dba3, LiCl, NMP Hünig's base, 40 °C TESO OTMS O 85% OMe OTES N Me OTES Me Me Me Me TESO Sn(Me3) Me

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Fr182877

  • 1. Total Syntheses of FR182877 MacMillan Group Meeting October 5, 2005 Sandra Lee Key Articles: Isolation Papers: (a) Sato, B.; et. al. J. Antibiot. 2000, 53, 123; (b) Sato, B.; et. al. J. Antibiot. 2000, 53, 204; (c) Yoshimura, S.; et. al. J. Antibiot. 2000, 53, 615. Sorensen Synthesis: (a) Vosburg, D. A.; Vanderwal, C. D.; Sorensen, E. J. J. Am. Chem. Soc. 2002, 124, 4552; (b) Vanderwal, C. D.; Vosberg, D. A.; Weiler, S.; Sorensen, E. J. J. Am. Chem. Soc. 2003, 125, 5393. Evans Synthesis: (a) Evans, D. A.; Starr, J. T. Angew. Chem. Int. Ed. 2002, 41, 1787; (b) Evans, D. A.; Starr, J. T. J. Am. Chem. Soc. 2003, 125, 13531.
  • 2. FR182877 : Taxol-type HO H Me Cytotoxicity and Antimitotic Activity A Me B ! Isolation–Fujisawa Pharmaceutical Co. H H OH C O Isolated from the fermentation broth of Steptomyces 2 in 1998 with IC50 = 28-75 ng/mL cytotoxicity against DO several cell lines. Me 20 EO F H Structurally similar natural products: Hexacyclic Me Acid, Macquaimicin A, and Cochleamycin A ! Synthetic challenges (a) 19-membered Hexacyclic carbomacrocycle featuring 12 stereocenters (b) Vinlogous carbonate embedded in a 6-6-7 fused ring system (c) Instability to air oxidation (C2-C21) to form a biologically inactive epoxide ! Completed syntheses ! Ongoing synthetic efforts (+)-FR182877 by Sorensen in 2002 Armstrong in 2001: Model DF ring system (–)-FR182877 by Evans in 2002 Nakada in 2002: AB bicycle (+)-FR182877 by Sorensen in 2003 Roush in 2003: ABC tricycle Prunet in 2004: A ring Clarke in 2005: DEF ring system, B ring H O O H O Me Me O H H H H Me Me HO H OH HO H OH H H O O H VS. H H Me H H Me H Me Me (+)-FR182877 (–)-FR182877
  • 3. A Proposed Biogenetic Synthesis of FR182877 HO H Me Me OH OH Me OH H H Intramolecular Me Diels-Alder CHO reaction Me O CHO Me O (IMDA) CO2R CO2R Knoevenagel RO Me RO Me condenstation HO H Knoevenagel Me condenstation Me OH OH Me Transannular OH Diels-Alder H H Me reaction CO2R (TADA) O Me O Me Transannular CO2R Me hetero- HO Diels-Alder HO Me reaction HO HO H Me H Me Me Me OH OH H H H H O Lactonization O O Me H Me O O OR Me (–)-FR182877 OH see Classics II, p. 490 Me
  • 4. A Proposed Biogenetic Synthesis of FR182877 HO H Me Me OH OH Me OH H H Intramolecular Me Diels-Alder CHO reaction Me O CHO Me O (IMDA) CO2R CO2R Knoevenagel RO Me RO Me condenstation HO H Knoevenagel Me condenstation Me OH OH Me Transannular OH Diels-Alder H H Me reaction CO2R (TADA) O Me O Me Transannular CO2R Me hetero- HO Diels-Alder HO Me reaction HO HO H Me H Me Me Me OH OH H H H H O Lactonization O O Me H Me O O OR Me (–)-FR182877 OH see Classics II, p. 490 Me
  • 5. The Pivotal Transformation: Endo vs. Exo HO H Me Me B CO2R OH HO OH H H OH H H Me OH O Cascade TADA Me B D O H H DO Me Me O H Endo-TS Me Me (–)-FR182877 Me OH OH Me Me O CO2R HO Me AcO H Me CO2R OH HO2C B HO OH H OH OH H H Me Me Cascade TADA H O D B O H H DO OH Me O H Exo-TS Me Me Me Hexacyclinic Acid
  • 6. Evans: A Diels-Alder Cascade Strategy Suzuki HO H Me Br OR OR Transannular Me Diels-Alder OH reaction Me H H O Transannular Me O O hetero- !-ketoester alkylation Me O H Diels-Alder reaction CO2Et Me TBSO Me OR OR O O OH O OTBDPS OTBDPS OTBDPS (HO)2B O N H Me Me Bn O OR O O OH O MeO Me Me Me N O N H Me Me Br Me OTBS OTBS Bn Br
  • 7. Aldol Fragment Synthesis: Dibromide Fragment O O i. , THF i. TBSCl, DMF, imid. Me MgBr Me H OH H OTBS ii. O3/O2; PPh3 ii. triethylorthoacetate, proprionic acid, 150°C OTBS 75% iii. DIBAL, –78 °C 73% O O OH i. MeNHOMe • HCl Bu2BOTf, TEA Me3Al, THF Me O O O N ii. TBSCl, DMF, imid. 88% Me OTBS iii. TsOH:nBu4NHSO4 (1:4) O N Bn MeOH, 0 °C Me 82% Bn O OTBS i. Dess-Martin O OTBS MeO Me Periodinane, NaHCO3 MeO Me N N Me ii. CBr4, PPh3, Me Br Me Me OH CH2Cl2, NaHCO3 70% Br
  • 8. Aldol Fragment Synthesis: Boronic Acid Fragment OH i. nBuLi, THF TBDPSCl O Bu2BOTf, TEA OTBDPS HO H O O ii. SO3–Pyr, DMSO CH2Cl2, TEA 89% O N 59% Me Bn OH i. MeNHOMe • HCl O O O OH Me3Al, THF i. DIBAL, THF, –78 °C O N ii. HCCMgBr ii. TBSCl, DMF, imid. Me OTBDPS Me OTBDPS 75% >20:1 dr Bn 92% catechol-BH, OTBS OTBS Cy2BH (10 mol%) OTBS OTBS THF; 1N NaOH (HO)2B 97% Me OTBDPS Me OTBDPS
  • 9. Suzuki Coupling of the "Aldol" Fragments HO H Me O OTBS MeO Me Me OH N H H O Me Me Br 5% Pd(PPh3)4 Tl2CO3 O Me O H Br THF:H2O (3:1), rt Me 84% desired pdt OTBS OTBS OTBDPS (HO)2B 8 Me O OTBS MeO Me N OTBS OTBS Me Me OTBDPS Br Me undesired double addition product ! Highly Optimized Suzuki Coupling Conditions O OTBS The coupling was sensitive to the choice of base: MeO Me (1) strong bases (i.e. hydroxides, oxides) or less halophilic N OTBS OTBS cations resulted in slower rates and competitive Me Me OTBDP decomposition of SM via protodeborylation, oxidation, S elimination, etc. Me OTBS (2) silver bases completely decomposed products' OTBDPS TBSO (3) carbonates had the best selectivity and only Tl2CO3 Me gave good reaction at rt
  • 10. Synthesis of the Pivotal Macrocycle O OTBS O O OTBS MeO Me Me N EtO Me Me Me Br i. DIBAL, –78 °C Br ii. ethyldiazoacetate OTBS SnCl2 OTBS TBDPSO 70% TBDPSO OTBS OTBS Me Me O O OTBS Me O Me OTBS EtO EtO 2 Me Cs2CO3, * i. TBAF, AcOH, DMF THF (0.005M), rt O Me Br ii. I2, PPh3, CH2Cl2 1:1 dr Me OTBS 64% (3 steps) I TBSO OTBS Br TBSO Me
  • 11. The Diels-Alder Cascade in Action TBSO O Me OTBS Me OTBS H Me EtO EtO2C Br Ph2Se2O3, SO3-Pyr O Me OTBS O Me H H TEA, THF, rt; CO2Et Me hexanes, 50 °C Me TBSO 63% Me O H TBSO TBSO Br H TBSO Br TBSO Me single diastereomer HO HO H Me H Me i. HF-MeCN Me TMSOK, THF; Me OH OH H H H H ii. Pd(dppf)Cl (10 mol%) CO2Et NaHCO3, CH2Cl2 O Me3B3O3, Cs2CO3, O DMF:H2O (2:1), 100 °C HO Me H Cl 62% Me H O O N I 63% H Me Me Me Evans: [!]23D = -5 Fujisawa: [!]23D = -3.5
  • 12. A Closer Look at the Cyclization Sequence intermediate species were not isolable TBSO Me OTBS TBSO Me OTBS H Me EtO2C H Me EtO2C Br B O Me [O] 15 H OTBS Br 3 O Me H H OTBS H H 4 14 Me " CO2Et 5 Me CO2Et 12 Me O TBSO TBSO 9 Me O H Br TBSO Me TBSO Br H TBSO Me OTBS ! NMR analysis shows 2H-pyran equilibrium O Z 1:1 X O ! Cyclization order? The Normal-demand DA (NDA) Y OH Me OTBS or inverse-demand hetero DA (HDA)? EtO2C Keq = FMO anaylsis using calculated (Spartan 5.1) Pz orbital 1-10 coefficients of the HOMO and LUMO predicts B-ring O Me cyclization to occur first. O OTBS OH Me HOMO LUMO X O Z TBSO Br Atom Pz Atom Pz Y best overlap C9 0.38 C5 0.51 best overlap C12 -0.48 C4 -0.26 C14 -0.07 C3 -0.56 C15 0.03 O1 -0.29 Moorhoff (Syn 1997, 685): 6!-cyclization to pyran tautomer
  • 13. Studying the Inherent Stereoselectivity of the TADA Cascade ! Model IMDA study shows high endo selectivity with poor diastereofacial selectivity Sorensen's system, the enantiomer which differs only in silyl protecting groups and the Me @ C11, also observed high endo selectivity and the opposite dr 61:31 dr. This suggests that the C6-C8 stereotriad only modestly differentiates !-faces in the B-ring cyclization O OTBS TBSO TBSO MeO Me H Me H Me N 8 6 Me Me Br Br 11 OTBS OTBS Br 60 °C, CDCl3, 3h H H H H CHO CHO 37:63 dr OTBS Me O OMe Me O OMe O N N OTBS Me 18 19 Me Me TBSO Me TBSO Me desired cycloadduct ! The high face-selectivity of the TADA cycloaddition is conjectured to arise from C18,C19 stereocenters
  • 14. OMe Me OMe Modeling the TADA Endo Me CO2Me Transition States H H O Me MeO H H Me HH H O OMe H MeO OMe MeO O H H H endo TS I Br Br Me Me Nine simplified macrocycles (varied Me OMe at C18 and C19) were energy- CO2Me minimized (PM3) with distance MeO H H MeO H H Me constraints (of 2.9-2.1 Å) leading to O Me MeO Me the observed natural product (via H H OMe Br O OMe O endo TS I) or it's endo MeO Me H H diastereomer (via endo TS II). H Br endo TS II H Me For each macrocycle, five energy-minimized geometries were obtained and two energy curves were generated plotting the increasing energy penalty for !-face alignment of the approaching TS ( I and II). 18 19 Me OMe EtO2C EtO2C O Me OTBS Me O Me CHO Me Me TBSO Me MeO Br Br MeO MeO MeO Br 4.0-9.4 kcal/mol
  • 15. Analysis of the Transannular Hetero Diels-Alder Cycloaddition ! Tricyclic intermediate has two low-energy conformations Me OMe Me OMe H CO2R' Me H CO2R' H !E = H Me MeO MeO H Me O OMe H OMe HO 2 kcal/mol H H Br H Br Me kinetic conformation from 1st D-A required conformation for 2nd D-A ! Application of transition state bond constraints energetically favors desired cyclization Me OMe Me OMe H CO2R' H 3 Me CO2R' H H 3 Me MeO MeO H Me O OMe H HO OMe X 15 14 RO RO H 14 H Me 15 H H Me Br H Br Me C3-C14: at 2.2 Å = –146 kcal/mol C3-C14: at 2.2 Å = –173 kcal/mol Br Br OR OR O-C15: at 2.4 A O-C15: at 2.4 A H H H H OR CO2R' CO2R' !!G = 27 kcal/mol RO Me Me O H Me O Experiment: R = TBS, R' = Et H H Calculation: R, R' = Me Me
  • 16. HO HO H Me Me Me Me OH H OH H H O H O O O H H Me O H Me O Me Me (–)-FR182877 (+)-FR182877
  • 17. A Proposed Biogenetic Synthesis of FR182877 HO H Me Me OH OH Me OH H H Intramolecular Me Diels-Alder CHO reaction Me O CHO Me O (IMDA) CO2R CO2R Knoevenagel RO Me RO Me condenstation HO H Knoevenagel Me condenstation Me OH OH Me Transannular OH Diels-Alder H H Me reaction CO2R (TADA) O Me O Me Transannular CO2R Me hetero- HO Diels-Alder HO Me reaction HO HO H Me H Me Me Me OH OH H H H H O Lactonization O O Me H Me O O OR Me (–)-FR182877 OH see Classics II, p. 490 Me
  • 18. Sorensen: Initial Retrosynthetic Strategy Towards (+)-FR182877 featuring a D-A / Knoevenagel / D-A sequence RO H Me HO HO Me Me Me Transannular OR H H hetero- CHO Me Diels-Alder Me Knoevenagel H OH reaction H OH condenstation H O O O O Me H H H O Me O Me O Me O Me Me O RO RO H Me Me Y Me Me X OR Tandem Stille OR H H Claisen-Type Coupling- CHO Cyclization CHO IMDA Bn Bn Me O Me O N N O O X = SnBu3 or Br AcO Me O AcO Me O Y = SnBu3 or I
  • 19. Highlighted Issues in the Initial Strategy Towards (+)-FR182877 selectivity in the tandem Stille/IMDA sequence TBSO TBSO Me Me Br Bu3Sn Pd2dba3 (5 mol%), Me Me OTBS OTBS Ph3As (20 mol%), THF, reflux IMDA CHO CHO Bn Bn or Me O Me O Cl2Pd(CN)2 DMF, rt N N O O AcO Me O AcO Me O TBSO TBSO H Me H Me Me Me OTBS OTBS H H H H CHO CHO Bn Bn Me O Me O N N O O AcO Me O AcO Me O undesired endo cycloadduct
  • 20. Highlighted Issues in the Initial Strategy Towards (+)-FR182877 forming the !-keto lactone and Knoevenagel condensation TBSO TBSO H Me H Me Me Me OTBS 5 OTBS H H KHMDS ( 4 eq) H H CHO THF, –78 °C CHO Knoevenagel Bn Me O Me N O O AcO Me O Me O O HO ! Issues encountered in this approach: Me The desired !-keto lactone substrate was unstable to Stille coupling, as such the acetate imide was used. Me H OH The IMDA was not diastereoface-selective and gave 2 endo cycloadducts O O (separable by chromatography) H The Knoevenagel condensation to form the tetracycle ring was unsuccessful Me O Me revise strategy to an intermolecular Knoevenagel condensation Sorensen: Org. Lett. 1999, 1, 645 + JACS 2003, 125, 5393
  • 21. A Revised Retrosynthetic Strategy Towards (+)-FR182877 featuring a Knoevenagel / RCM approach HO HO Me Me Transannular Me hetero- Me H OH Diels-Alder H OH Ring-Closing H O reaction O Olefin Metathesis O O H H H Me O Me O Me Me RO H Me RO Me Me H OR H O Me CHO H OR Intermolecular H Condenstation O O O H O H O Me Me Me Me
  • 22. Highlighted Issues in the Revised Strategy Towards (+)-FR182877 unfruitful condensation reactions are circumvented via a HWE TESO i. TBAF, THF TESO TESO Me ii. Dess-Martin H Me H Me Periodinane, NaHCO3 Me Me Me OTES H OTES H OTES iii. NMP, rt H H OTES CHO CHO 1.9:1 dr 53% undesired product O O for IMDA rxn: Yamamoto's BLA and MacMillan's i. Et3N•3HF Me catalysts were also tried P ii. Ba(OH)2, THF, Me O O Br OMe iii. TESCl, N TEA, DMAP Me Me 6.5:1 Z:E Me TESO 65% H Me TESO H Me Me H OTES H Me Br H OTES H O O O O O O OMe Br OMe N N Me Me Me Me Me Me undesired product
  • 23. Highlighted Issues in the Revised Strategy Towards (+)-FR182877 an unexpected olefin geometry in alkylidene formation TESO TESO H Me H Me Me Me t-BuLi, H OTES OTES THF, –78 °C H H H OR O Br >90% H O Li O O Br OMe E O O O N OMe Me Me transient lithium allenoate N Me Me Me Me TESO H Me ! Issues Encountered in this Approach: Me IMDA to form the first fragment was moderately diastereoface-selective (1.9:1 H OTES desired:undesired) H The desired !-keto lactone and the acyclic !-keto ester were not amenable to the O O Knoevenagel condensation O Isomerization to the needed E geometry of alkylidene ketolactone was not Me realized though various methods Me revise strategy to form E-geometry alkylidene dicarbonyl undesired Z-olefin geometry
  • 24. A Re-revised Retrosynthetic Strategy Towards (+)-FR182877 OR Me Me OR H H HO RO Me Me CHO Transannular hetero- Diels-Alder H-W-E Me O OMe Me Me Condensation reaction H OH H OR N H O O O O Me O Me H H H Br Me O Me O O Me Me P OMe reductive C-acylation O OMe RO RO Me Me Intramolecular Me Diels-Alder Me OR OR reaction Me3Sn OTES CHO OAc !-allyl Stille coupling Me O OMe N Me O OMe Me N RO Me Me RO Me
  • 25. Highlighted Issues in the Re-revised Strategy Towards (+)-FR182877 IMDA and the HWE sequence TESO TESO O O Me Me MeO P OH MeO Me Me Br OTES OTES i. TBAF, THF, 0 °C H H i. DCC, NaHCO3 OTES CHO ii. MnO2, DMF, rt ii. Et3N•3HF, CH2Cl2 Me O OMe Me O OMe 65% (2 steps) 77% N N Me 1.6:1dr Me acylation yielded 4 spots (chromatographic separation HO Me HO Me of desired endo product) HO TESO Me Me Me Me OH OTES H H i. Ba(OH)2, THF/H2O H CHO Me Br OMe H N ii. TESCl, imid., DMAP O Me O OMe Me O O N Me Me O Me Br O * P OMe O OMe
  • 26. Highlighted Issues in the Re-revised Strategy Towards (+)-FR182877 haunted by the formation of the E-alkylidene TESO TESO HO Me Me Me Me Me Me H OTES i. t-BuLi, THF, –78 °C H OTES H OH 1 Me Br OMe H OMe H H Me 19 O N ii. PPTS, MeOH N O OLi O Me O 64% (4 steps) Me O Me O O O Me Me Me undesired Z olefin geometry confirmed by X-ray ! Issues Encountered in this Approach: IMDA gave poor diastereofacial selectivity (1.6:1 of desired:undesided cycloadduct) Key reductive lithiation cyclization step resulted in the formation of an undesired Z alkylidene dicarbonyl tetracycle. It was conjectured that the geometrical constraints of the 12-membered ring would had favored the Z isomer revise strategy in forging the C1-C19 bond and forming the !-keto lactone Sorensen: Org. Lett. 2001, 3, 4307 + JACS 2003, 125, 5393
  • 27. Sorensen: The Retrosynthetic Strategy that Worked featuring tandem TADA reactions RO OR HO Me Me lactonization Me O OMe Me O Me OR tandem RO OTMS O O H OH t-BuO TADAs H O TMSO O O OP H H Me Me Me H Me O Me O !-allyl Stille coupling Me Me Tsuji-Trost allylic alkylation OR Me OR OR O O OR Me OR OR O O O N OMe P RO HWE Me O OMe H I Bn Me SnMe3 Me OTMS O O TMSO O O AcO N AcO OMe O N Me Me Me Me Me Ph
  • 28. Synthesis of !-allyl Stille Coupling Fragment MeNHOMe • HCl O O O OH Bu2BOTf, TEA Me3Al, THF OTBS OTBS H O N O O 75% (2 steps) Me (2 steps from diol) O N Bn Me Bn OTMS i. TMSCl, DMAP, O OH Me OTBS imid, CH2Cl2 MeO OTBS N ii. LiCH2P(O)(OMe)2, O Me Me THF, –78 °C OMe P O OMe OH OTES i. Ba(OH)2, THF; Me OH i. Et2BOMe, NaBH4 Me OTES THF/H2O, 0 °C THF/MeOH O ii. TESCl, DMAP, TESO I O imid., CH2Cl2 Me I Sn(Me3) Me iii. Me3SnSnMe3, Me ii. PPTS, MeOH, rt Pd(Ph3P)4, Hünigs, 79% (4 steps) PhH, 80 °C 83% (3 steps)
  • 29. The !-allyl Stille Coupling of the Aldol Fragments O O OH i. MeNHOMe • HCl O Bu2BOTf, TEA Me3Al, THF OAc OAc H O N O O ii. TMSCl, DMAP, Me Me Me imid, CH2Cl2 O N Ph 87% (4 steps) "known aldehyde" Me Tetrahedron, 1972, 28, 2622 Ph O OTMS MeO OAc N OTES Me Me Me OTES Pd2dba3, LiCl, NMP Hünig's base, 40 °C TESO OTMS O 85% OMe OTES N Me OTES Me Me Me Me TESO Sn(Me3) Me