C-C BOND FORMATION

72

Carbon- Carbon Bond Formation 1. Alkylation of enolates, enamines and hydrazones C&S: Chapt. 1, 2.1, 2.2 problems Ch 1: 1; 2; 3, 7; 8a-d; 9; 14 Ch. 2: 1; 2; 4) Smith: Chapt. 9 2. Alkylation of heteroatom stabilized anions C&S :Chapt. 2.4 - 2.6) 3. Umpolung Smith: Chapt. 8.6 4. Organometallic Reagents C&S: Chapt. 7, 8, 9 problems ch 7: 1; 2; 3, 6; 13 Ch. 8: 1; 2 Smith: Chapt. 8 5. Sigmatropic Rearrangements . C&S Chapt. 6.5, 6.6, 6.7 # 1e,f,h,op Smith Chapt. 11.12, 11.13 Enolates Comprehensive Organic Synthesis 1991, vol. 2, 99. - -deprotonation of a ketone, aldehyde or ester by treatment with a strong nonnucleophillic base. - carbonyl group stabilizes the resulting negative charge.
O H H H R B: O H H R H H OR

- Base is chosen so as to favor enolate formation. Acidity of C-H bond must be greater (lower pKa value) than that of the conjugate acid of the base (C&S table 1.1, pg 3)
O H 3C O H 3C CH3 O CH2 OEt

pKa = 20

MeO- pKa = 15 tBuO- pKa = 19

unfavorable enolate concentration more favorable enolate concentration

pKa = 10

- Common bases: NaH, EtONa, tBuOK, NaNH2, LiNiPr2, M N(SiMe3)2, Na CH2S(O)CH3 Enolate Formation: - H+ Catalyzed (thermodynamic)
O H+ OH

- Base induced (thermodynamic or kinetic)

O H

:B

O-

B:H

Regioselective Enolate Formation Tetrahedron 1976, 32, 2979. - Kinetic enolate- deprotonation of the most accessable proton (relative rates of deprotonation). Reaction done under essentially irreversible conditions.
O LDA, THF, -78C O - Li+

C-C BOND FORMATION typical conditions: strong hindered (non-nucleophilic) base such as LDA R2NH pKa= ~30
N Li

73

Ester Enolates- Esters are susceptible to substitution by the base, even LDA can be problematic. Use very hindered non-nucleophillic base (Li isopropylcyclohexyl amide)
O OR' R LDA, THF, -78C E+ N R O- Li+ OR' R N Li THF, -78C R OR' O

- Thermodynamic Enolate- Reversible deprotonation to give the most stable enolate: more highly substituted C=C of the enol form
O - K+ O tBuO- K+, tBuOH O - K+

kinetic

thermodynamic

typical conditions: RO- M+ in ROH , protic solvent allows reversible enolate formation. Enolate in small concentration (pKa of ROH= 15-18 range) - note: the kinetic and thermodynamic enolate in some cases may be the same - for ,-unsaturated ketones
thermodynamic site O kinetic site

Trapping of Kinetic Enolates - enol acetates

Ph O 1) NaH, DME 2) Ac2O kinetic Ph O O isolatable separate & purify

Ph O O

CH3Li, THF

CH3Li, THF

Regiochemically pure enolates

Ph O- Li+

Ph O- Li+

- silyl enolethers
Ph O

Synthesis 1977, 91.

1) LDA 2) Me3SiCl kinetic Ph

C-C BOND FORMATION Acc. Chem. Res. 1985, 18, 181.

+
OTMS isolatable separate & purify CH3Li, THF -orBu4NF -or- TiCl4 CH3Li, THF Ph OTMS

74

Geometrically pure enolates

Ph O- M+

Ph O- M+

- tetraalkylammonium enolates- "naked" enolates - TMS silyl enol ethers are labile: can also use Et3Si-, iPr3Si- etc. - Silyl enol ether formation with R 3SiCl+ Et3N gives thermodyanamic silyl enol ether - From Enones
1) Li, NH3 2) TMS-Cl O TMSO 1) MeLi 2) E+ O H
O TMS-Cl, Et3N TMS-OTf Et3N O Li, NH3, tBuOH TMS-Cl OSiMe3

OSiMe3

OSiMe3

- From conjugate (1,4-) additions

O (CH3)2CuLi O- Li+ E+ O E

Trap or use directly

- From reduction of -halo carbonyls

O Br Zn or Mg O- M+

Alkylation of Enolates (condensation of enolates with alkyl halides and epoxides) Comprehensive Organic Synthesis 1991, vol. 3, 1. 1 alkyl halides, allylic and benzylic halides work well 2 alkyl halides can be troublesome 3 alkyl halides don't work

C-C BOND FORMATION

O a) LDA, THF, -78C b) MeI O Me

75

- Rate of alkylation is increased in more polar solvents (or addition of additive)

O (Me2N)3P HMPA O R NMe2 R= H DMF R-CH3 DMA H 3C O S CH3 CH3N O CH3N O NCH3 Me2N TMEDA NMe2

DMSO

Mechanism of Enolate Alkylation: SN2 reaction, inversion of electrophile stereochemistry

X C

180
M+ -O

Alkylation of 4-t-butylcyclohexanone:
O R O E R

equitorial anchor H E tBu R B E B tBu E R O- M+ H O Twist Boat Chair O

E H tBu R A

A favored

on cyclohexanone enolates, the electrophile approaches from an "axial" trajectory. This approach leads directly into a chair-like product. "Equitorial apprach leads to a higher energy twist-boat conformation. Alkylation of ,-unsaturated carbonyls
O- M+ R1 O R1 H H R1 H Thermodynamic R2 O- M+ R2 E R1 H E O R2 Kinetic H R2 E R1 E H O R2

C-C BOND FORMATION Stork-Danheiser Enone Transposition: - overall -alkylation of an ,-unsaturated ketone
O LDA PhCH2OCH2Cl OMe O PhO OMe CH3Li PhO OMe J. Org. Chem. 1995, 60, 7837. HO CH3 H3O
+

76

CH3 PhO O

Chiral enolates- Chiral auxilaries. D.A. Evans JACS 1982, 104 , 1737; Aldrichimica Acta 1982,15 , 23. Asymmetric Synthesis 1984, 3, 1. - N-Acyl oxazolidinones
O R N Me O R N O H 2N O OH O H 2N O Me Ph Ph norephedrine OH

valinol
O R N Me O N O LDA, THF Et-I R O O Ph LDA, THF Et-I Me Ph major product (96:4) O O N O LiOH, H2O, THF R R O N O O LiOH, H2O, THF R O OH

Complimentary Methods for enantiospecific alkylations

O OH

O R

Diastereoselectivity: 92 - 98 % for most alkyl halides

major product (96:4)

Enolate Oxidation Chem. Rev. 1992, 92, 919.

O R N O O NaN(SiMe3)2, THF, -78C O Ph N SO2Ph O LDA, THF O tBuO N N O OtBu R Boc N HN Boc N O O R OH (88 - 98 % de) 1) HO2) CH2N2 3) TFA 4) Raney Ni O N O O

O R NH2 OMe

(94 - 98 % de)

C-C BOND FORMATION

O R N O O Bu2BOTf, Et3N R Bu B O N O O NBS R Br Ph O R NH2 Ph D- amino acids OH Bu O N O O N3-

77

Ph O R N3 N O O Ph 1) LiOH 2) H2, Pd/C

O R N

O O KN(SiMe3)2, THF SO2N3 Ph R N3

O N

O O

Ph

Oppolzer Camphor based auxillaries Tetrahedron, 1987, 43, 1969. diastereoselectivities on the order of 50 : 1
SO2Ph N O O R
H O O SO2N(C6H11)2 Et2CuBF3 LDA, NBS O O SO2N(C6H11)2 O Br O SO2N(C6H11)2

Ar Ar R O N O SO2Ph O

R R N S O2 O

O SO2N(C6H11)2

H HO

NH2 O

Asymmetric Acetate Aldol

O N S O 1) Br O H Br 85 %, 19:1 de TIPSO O NH2

Sn(OTf)2, CH2Cl 2, R3N, -40C 2) TIPS-OTf, pyridine 3) NH3

J. Am. Chem. Soc. 1998, 120, 591 J. Org. Chem. 1986, 51, 2391

Chiral lithium amide basess

CH3 MeO CO2Et OMe Ph N Li THF, -78C (CH3)2C=O OMe MeO O OMe O (72% ee) CH3

C-C BOND FORMATION

H O N N Ph N Li But O H N Li N (97 % ee) N Me tBu Ph OTMS

78

tBu

THF, HMPA TMSCl

Lewis Acid Mediated Alkylation of Silyl Enolethers- SN1 like alkylations

OTMS tBu-Cl, TiCl4, CH2Cl2, -40C (79%) SPh R Cl O O CH3 C(CH3)3

note: alkylation with a 3 alkyl halide

ACIEE1978, 17, 48 TL 1979, 1427 R

OTMS

SPh R Raney Ni (95 %)

TiCl4, CH2Cl2, -40C (78%)

Enamines Gilbert Stork Tetrahedron 1982, 38, 1975, 3363. - Advantages: mono-alkylation, usually gives product from kinetic enolization
O N O N can not become coplanar

"Kinetic"
O N

"Thermodynamic"
O + N R O E

O O N H H+, (-H2O)

R-I

H2O

enamine

-Chiral enamines
N O E

Imines
Ph N

Isoelectronic with ketones

Me O OMe LDA, THF, -20C Li N Ph 1) E 2) H3O+ O E E = -CH3, -Et, Pr, PhCH2-, allylee 87 - 99 %

Hydrazones

C-C BOND FORMATION isoelectronic with ketones Comprehensive Organic Synthesis 1991, 2, 503
O Me2N-NH2 H , (-H2O)
+

79

N N LDA, THF

-N -

E+

N hydrolysis E

O E

- Hydrazone anions are more reactive than the corresponding ketone or aldehyde enolate. - Drawback: can be difficult to hydrolyze. - Chiral hydrazones for asymmetric alkylations (RAMP/SAMP hydrazones- D. Enders "Asymmetric Synthesis" vol 3, chapt 4, Academic Press; 1983)
OMe N NH2 SAMP MeO N H 2N RAMP

N N OMe I

LDA OTBS

N N OMe

O3

O H

(95 % de) TBSO

TBSO

1) LDA 2) Ts-CH3, THF -95 - -20 C OMe 3) MeI, 2N HCl

O CH3 (100 % ee)

Me O Li R1 E (C,C) R2 H

MeO R1 R2 E H N N

N N Z (C,N)

Aldol Condensation
O H R

Comprehensive Organic Synthesis 1991, 2, 133, 181.

a) LDA, THF, -78C b R'CHO H R O OH R' -hydroxyl aldehyde (aldol)

- The effects of the counterion on the reactivity of the enolates can be important Reactivity Li+ < Na+ < K+ < R4N+ addition of crown ethers

C-C BOND FORMATION - The aldol reaction is an equilibrium which can be "driven" to completion.
O- M+ R R' + RCHO H R M O O R' work-up H R O OH R'

80

In the case of hindered enolates, the equillibrium favors reactants. Mg2+ and Zn2+ counterions will stabilize the intermediate -alkoxycarbonyl and push the equillibrium towards products. (JACS 1973, 95, 3310)
O- M+ PhCHO, THF O OH Ph M= Li M= MgBr 16% yield 93% yield

- Dehydration of the intermediate -alkoxy- or -hydroxy ketone can also serve to drive the reaction to the right.
O O O

tBuO- Na +, tBuOH O O H O O H

JACS 1979, 101 , 1330

Enolate Geometry - two possible enolate geometries

O LDA, THF, -78C O - Li+ H O - Li+

+
H Z - enolate

E - enolate

- enolate geometry plays a major role in stereoselection.

Z -enolate
R
1

OM R2 H

R3CHO
R

O
1

OH R R2
3

erythro (syn)

E -enolate
R
1

OM H R2

R3CHO
R
1

OH R R
2 3

threo (anti)

- Zimmerman-Traxler Transition State : Ivanov condensation JACS 1957, 79 , 1920.

+

O
-

MgBr
- +

H O Ph Ph H Mg

Br O

Ph

PHCHCO2 MgBr

OMgBr

"pericyclic" T.S.

C-C BOND FORMATION Analysis of Z-enolate stereoselectivity

R2 R3 O H H R1 M O R3 R2 O R2 M O H H R1 H H R1 R3 O M O R1 R2 O OH R3

81

erythro (syn) favored

R2 H O H R3 M R1 O O H R3 R1 R3 H R2 O M H R2 O H R1 M O R1 R2 O OH R3

threo (anti) disfavored

Analysis of E-enolate stereoselectivity

H R3 O R2 H M R1 O O R2 H R1 H R3 H H O M R
3

O R2

M R1

O R1

OH R3 R2

threo (anti) favored

H

H H O R R3
2

M R1

M O

O R2 R3

M R1

O O R1 R2 OH R3

R2

R3 R1

erthro (syn) disfavored

Analysis of Boat Transition State for Z-Enolates

R2 O R3 H H R1 Favored Chair M R1 R2 H Boat H R2 O H H R3 R1 Disfavored Chair O M R1 R2 O HO R3 staggered R3 R2 R1 H Boat: R1-R2 1,3-interaction is gone O O M R1 O R3 O HO H R3 R2 O O M

C-C BOND FORMATION Analysis of Boat Transition State for E-Enolates

H O R3 R2 H Favored Chair H O H R2 R3 R1 R1 R2 R3 staggered M O O HO R3 H R2 R1 O M O O R1 R1 R2 R2 Boat H O M HO R3 H H R1 O R3 O M

82

Disfavored Chair

Boat: R1-R2 1,3-interaction is gone

Summary of Aldol Transition State Analysis: 1. Enolate geometry (E- or Z-) is an important stereochemical aspect. Z-Enolates usually give a higher degree of stereoselection than E-enolates. 2. Li+, Mg 2+, Al3+= enolates give comparable levels of diastereoselection for kinetic aldol reactions. 3. Steric influences of enolate substituents (R1 & R2) play a dominent role in kinetic diastereoselection.
O- M+ Path A R2 H Path B O H R2 Path A R1 R2 R1 R2 O HO R3 R1

O- M+ R1

HO R3

When R1 is the dominent steric influence, then path A proceeds. If R2 is the dominent steric influence then path B proceeds. 4. The Zimmerman-Traxler like transition state model can involve either a chair or boat geometry. Noyori "Open" Transition State for non-Chelation Control Aldols Absence of a binding counterion. Typical counter ions: R4N+, K+/18-C-6, Cp2Zr2+ - Non-chelation aldol reactions proceed via an "open" transition state to give syn aldols regardless of enolate geometry. Z- Enolates:
R1 H H O R1 H R3 O ODisfavored R2 H H H R R2 3 O H R2 O OFavored R2 R3 R3 H O H R2 H O Favored R1 OH R3 R1 R2 R3 R2 R1 OR1 R3 OH R1 R2 O HO R3

Syn Aldol
O HO

R1

O-

Disfavored

Anti Aldol

C-C BOND FORMATION E- Enolate:

-

83

O H

R1 favored R2 H

O H

R1 R3 H R2 H

R1 O H R1 R3 R2 R2 HO

R3 O
-

R3

O favored
-

Syn Aldol

O H

R1 disfavored R2

R1 H

R1 O R3 R1 R3 R2 R2 HO

H O

R3

H H R3 R2 O H O disfavored

Anti Aldol

NMR Stereochemical Assignment. Coupling constants (J) are a weighted average of various conformations.
O R1 R2 HA 60 HA H O O HB R2 R1 R3 R1 O H O HB 60 HA R3 R2 R1 HB R3 O HA OH R2 H O HB R3

Syn Aldol JAB = 2 - 6 Hz

non H-bonded H

O R1

OH B R3

Anti Aldol JAB = 1 - 10 Hz

60 60 HB O R2

R2 HA HA H O O R3 R2 R1 HB R1 O H O R3 HA HB HA OH R2 R1 R3

non H-bonded

Boron Enolates:

Comprehensive Organic Synthesis 1991, 2, 239. Organic Reactions 1995, 46, 1; Organic Reactions 1997, 51, 1. OPPI 1994, 26, 3. - Alkali & alkaline earth metal enolates tend to be aggregates- complicates stereoselection models. - Boron enolates are monomeric and homogeneous - B-O and B-C bonds are shorter and stronger than the corresponding Li-O abd Li-C bonds (more covalent character)- therefore tighter more organized transition state. Generation of Boron Enolates:
O R2B-X iPrEtN OBR2 X= OTf, I R= Bu, 9-BBN

C-C BOND FORMATION

R3N: R1 H _ + BL2OTf O R2 R1 Z-enolate OBL2 R2

84

R3N: R1 R2
O

_ + BL2OTf O H R1

OBEt2

R2 E-enolate
OBR2 R

R 3B

OSiMe3

R2B-X

OBR2 + Me3 Si-X

O R N2

R' 3B R

OBR'2 R' Hooz Reaction

Diastereoselective Aldol Condensation with Boron Enolates

O Ph Ph pure Z-enolate OBEt2 O RCHO Ph OBEt2 R

100% Syn Aldol

OBEt2 R1 R2

O R3CHO R1 R2 O R3CHO R1

OH R3 generally > 95 : 5 syn : anti

Z-enolate OBEt2 R1 R2 E-enolate

OH R3 R2 generally ~ 75 : 25 anti : syn

Asymmetric Aldol Condansations with Chiral AuxilariesD.A. Evans et al. Topics in Stereochemistry, 1982, 13 , 1-115. - Li+ enolates give poor selectivity (1:1) - Boron and tin enolates give much improved selectivity
Bu O Me N O O B Bu2BOTf, EtNiPr2 , -78 O - O + N O RCHO R Me Bu OH O N O O

> 99:1 erythro

O Me N O Ph O 1) Bu2BOTf, EtNiPr2 , -78 2) RCHO R Me OH O X

C-C BOND FORMATION

L O B _ L O
+

85

H R O

L O
+

L B _ O N O O R

L O B _

L O
+

O N O

RCHO

H R

L O
+

L B _ O N O O R

L O B _

L O
+

N O O

preferred conformation
R2 O L B L O O N H O O H R3 L B L O N O O Disfavored O O N R2 R2 H R3

R3

Favored O O N R2

OH R3

OH R3

Oppolzer Sultam
O N S O2 1) LDA 2) Bu3SnCl R3 Sn O S O N R2 S O2 L 2B N O R2 R3CHO N S O2 R2 O OH R3

O R2

R3CHO N S O2

OH R3 R2

C-C BOND FORMATION Chiral Boron

O StBu when large, higher E-enolate selectivity iPrEt2N, PhCHO,-78C BOTf Ph OH O StBu + Ph OH O StBu

86

1 : 33 (> 99 % ee)

Ph O R SPh ArO2SN B Br

Ph NSO2Ar Ph R > 95 : 5 (> 95 % ee) OH O SPh + Ph R OH O SPh

iPrEt2N, PhCHO,-78C

In general, syn aldol products are achievable with high selectivity, anti aldols are more difficult Mukaiyama-Aldol- Silyl Enol Ethers as an enolate precursors. Lewis acid promoted condensation of silyl ketene acetals (ester enolate equiv.) with aldehydes: proceeds via "open" transition state to give anti aldols starting from either E- or Z- enolates.
OSiMe3 OEt RCHO, TiCl4, CH2Cl2, -78C R OH CO2Et CH3 R= iPr (anti : syn) = 100 : 0 C6H11 94 : 6 Ph 75 : 25 RCHO, TiCl4, CH2Cl2, -78C R OEt OH CO2Et CH3 R= iPr (anti : syn) = 52 : 48 C6H11 63 : 37 Ph 67 : 33 + R OH CO2Et CH3 + R OH CO2Et CH3

OSiMe3

Asymmetric Mukiayama Aldol:

Ph H 3C O OSiMe3 NMe2 RCHO, TiCl4, CH2Cl2, -78C OH R O Rc (90-94% de) syn : anti = 85 : 15 selectivity insenstivie to enolate geometry + R OH O Rc

C-C BOND FORMATION

Ph N SO Ph 2 O OSitBuMe2 iPrCHO, TiCl4, CH2Cl2, -78C Rc CH3 O HO 96 % de anti : syn = 93 : 7

87

O OSitBuMe2 SO2N(C6H11)2

RCHO, TiCl4, CH2Cl2, -78C

O Rc

HO + Syn product CH3

E-Enolate R= Ph % de= 90 nPr 85 iPr 85 Z-Enolate R= iPr % de= 87

anti : syn = 91 : 19 94 : 6 98 : 2 anti : syn = 97 : 7

Mukaiyama-Johnson Aldol- Lewis acid promoted condensation of silyl enol ethers with acetals:
OSiMe3 O TiCl4 or SnCl4 R RCHO or RCH(OR')2 CH2Cl2, -78C
O O O TiCl4, CHCl2, -78 C HO O O

OH Mukaiyama-Johnson Aldol via Ti or Sn enolate

O O

OTMS

+
Cl4Ti O+ O Cl4Ti O

O OSiMe3

OTMS Ph

TiCl4, (CH3)2C(OEt)2 (78 %) Ph

OEt

Fluoride promoted alkylation of silyl enol ethers

OSiMe3 nBu4NF, THF, MeI O

Acc. Chem. Res. 1985, 18, 181

C-C BOND FORMATION Meyer's Oxazolines:

O N (ipc)2BOtf iPrEt2N, Et2O N (ipc)2B Ester equiv. O 1) RCHO 2) 3N H2SO4 3) CH2N2 (~ 30%) H 3C R OH CO2Me + R OH H 3C CO2Me

88

R= nPr %ee (anti) = 77 anti : syn = 91 : 9 C6H11 84 95 : 5 tBu 79 94 : 6

Anti-Aldols by Indirect Methods:

SePh O PhSe C6H11 OTBS chiral auxillary 1) TBS-Cl 2) DiBAl-H 3) TsCl 4) Ba(CN)BH3 1) (C5H7)2BOTf R3N 2) RCHO HO syn aldol CH3 R OTBS
CO2Me N 2) RCHO N CH3 MOMO O MeO N O MeO O 1) LDA, THF, -78 C 2) RCOCl MOMO N CH3 OMOM Zn(BH4)2 O O CH3 MOMO N CH3 OMOM KBEt3H, Et2O, -78 C N CH3 OMOM O HO CH3 syn : anti 97 : 3 O O 1) LDA, THF, -78 C O R

OTBS R O C6H11

1) HF 2) [O] R 3) NaIO4 4) CH2N2 HO CO2Me R HO

CO2Me

O3 R

CH3 CHO OTBS

Anti Aldol Product

1) HIO6 2) CH2N2

OH MeO2C CH3 Anti Aldol HO CH3 syn : anti 1 : 99 R

Syn Aldols by Indirect Methods:

O O N O 1) LDA, THF, -78 C O 2) RCOCl O N CH3 O O Zn(BH4)2 R O N CH3 O O OH R syn : anti = 100 : 1

C-C BOND FORMATION Aldol Strategy to Erythromycin:

O
10 11 12 15 14 13 O 1 3 9 8

89

4
7 6 5 4

1 CO2H Erythromycin seco acid

OH

OH OH

OH

OH

OH

OH

[O] syn aldol 3

[O]

Erythromycin aglycone CHO OH syn aldol 4

CO2H O syn aldol OH OH 1

CHO

+
CHO O syn aldol OH

CHO

+
CO2H

CHO O
1 HO2C OH 3 OH 5 O 9 OH 11 OH 13

CHO

O O N

LDA, CH3CH 2COCl O 83%, (96:4)

O N 1

TiCl4, iPr 2EtN, CH2Cl2 O CHO

O N

OH 5

1) Zn(BH3)2 2) (H3C)2C(OMe)2 CSA (100%)

Ph Ph

90% (> 99:1)

Ph

O O N

O 3

O 5

1) 9-BBN, THF 2) Swern oxid. 73% (85:15) O

O N

O CHO

Ph

Ph 1) Na BH(OAc)3 2) TBS-OTf, 2,6-lutidine 3) AlMe3, (MeO)MeNHHCl MeO 72% (>99:1)

O O N

Sn(OTf)2, Et3N, CH2Cl2 O CH3CH 2CHO 84% (> 96:4)

O N 9

O 11

OH 13

O N CH3

OH

OTBS

Ph O EtMgBr 86% 8 11 13 OH OTBS

Ph 1) PMBC(NH)CCl3 TfOH 2) (PhMe2Si)2NLi, TMS-Cl 48 %

PMBO TMSO

OTBS

C-C BOND FORMATION

H3C H Sn H O L O L X O X CH3 CH3
anti-syn

90

X O O OH R L L L O Ti O O H

H CH3
Disfavored

H CH3 CH3 O X

X O

H L CH3 Sn H O O L
Disfavored

OH R

H3C H

X H

H CH3 CH3 O Ti L L
J. Am. Chem. Soc. 1990,112, 866

CH3 CH3
anti-syn

H3C CH3

O L

H3C CH3

O O N

O 3

O 5 CHO 7

PMBO TMSO

OTBS 13

BF3OEt2, CH 2Cl2, -78 C O 83% (95:5)

O N

O 3

O 5

OH 7

PMBO O 9 11

OTBS 13

+
8

11

Ph O 1) Zn(BH3)2 2) DDQ 95% Ph p-MeOC 6H4 O O N O O O O O O N O O O

p-MeOC 6H4 OH O O OTBS

Ph 1) NaH, CS2, MeI 2) nBu3SnH, AIBN 70%

p-MeOC 6H4 OTBS 1) LiOOH 2) TBAF HO 63% 13 O O O O O OH Cl3C6H2COCl iPr2EtN, DMAP (86%

Ph

p-MeOC 6H4 O
10 11 12 13 9 8 7

O
9

1) Pd(OH)2, iPrOH 2) PCC 3) 1M HCl, THF

6

11

OH
5 13

O
5 4 3 2

58 % O

O
1 3

OH OH

O
1

O O

Michael Addition - 1,4-addition of an enolate to an ,-unsaturated carbonyl to give 1,5-dicarbonyl compounds

O M Ph
+

O R Ph

Organometallic Reagents Grignard reagents:

O R-Br Mg(0) THF OH R-MgBr R

O OH R-MgBr THF R + R O often a mixture of 1,2- and 1,4-addition

C-C BOND FORMATION

O OH R-MgBr THF, CeCl3
O R-MgBr

91

R
O

1,2-addition

CuI,THF, -78C R

1,4-addition

Organolithium reagents - usually gives 1,2-addition products - alkyllithium are prepared from lithium metal and the corresponding alkyl halide vinyl or aryl- lithium are prepared by metal-halogen exchange from the corresponding vinyl or aryl- haidide or trialkyl tin with n-butyl, sec-butyl or tbutyllithium.
R-Br X X= Br, I, Bu3Sn nBu-Li Et2 O Li(0) R-Li Li Et2 O

Organocuprates Reviews: Synthesis 1972, 63; Tetrahedron 1984, 40 , 641; Organic Reactions 1972, 19 , 1. - selective 1,4-addition to ,-unsaturated carbonyls
2 R-Li
O R2CuLi R

CuI, THF
O

R2CuLi

- curprate "wastes" one R group- use non transferable ligand

MeO Cu

MeO Cu R

R-Li

Li+

non-transferable ligand
Other non transferable ligands _ _ + Bu3P Cu R Li Me2S Cu R Li+ 2S Cu R CN 2Li
+

_ NC Cu R Li

_
+

F3B Cu R

Li+

Mixed Higher Order Cuprate B. Lipshutz Tetrahedron 1984, 40 , 5005 Synthesis 1987, 325.

Addition to Acetals
O R H3C O R (n-C6H13)2CuLi BF3OEt 2

Tetrahedron Asymmtetry 1990, 1, 477.

n-C6 H13 O CH3 OH 1) PCC 2 NaOEt n-C6 H13 CH3 TL 1984, 25, 3087

OH Chiral axulliary is destroyed 99 % ee LA O H R Nu O

R H

O O CH3

LA CH3 Nu: R H O O

C-C BOND FORMATION

TMS O O 1) TiCl4 2) [O] 3) TsOH JACS 1984, 106, 7588 OH

92

98 % ee

Stereoselective Addition to Aldehydes - Aldehydes are "prochiral", thus addition of an organometallic reagent to an aldehydes may be stereoselective. - Cram's Rule JACS 1952, 74 , 2748; JACS 1959, 84 , 5828. empirical rule
O R
1

M S

1) "R2 - " 2) "H + "

OH R1 R
2

M S L

O M L R1 S M

OH S R
2

R2

- Felkin-Ahn TL 1968, 2199; Nouv. J. Chim. 1977, 1 , 61. based on ab initio calculations of preferred geometry of aldehyde which considers the trajectory of the in coming nucleophile (Dunitz-Burgi trajectory).
O M L R
1

vs. R2
-

O L

R2

better

- Chelation Control Model- "Anti-Cram" selectivity - When L is a group capable of chelating a counterion such as alkoxide groups +
M O OR' R1
*

worse

OH

S M

M S

OR' "Anti-Cram" Selectivity

M+ O OR' HO OR' R2 R1 S

R2
M R
1

Umpolung - reversal of polarity Aldrichimica Acta 1981, 14, 73; ACIIE 1979, 18, 239. i.e: acyl anion equivalents are carbonyl nucleophiles (carbonyls are usually electophillic)
O R usually R O +

Benzoin Condensation
KCN PhCHO Ph OH CN

Comprehensive Organic Synthesis 1991, 1, 541.

OH Ph - CN Cyanohydrin anion PhCHO HO Ph CN OPh -O Ph CN OH Ph Ph O OH

Ph Benzoin

C-C BOND FORMATION 93 Thiamin pyrophosphate- natures acyl anion equivalent for trans ketolization reactions
NH2 H NH2

+
N H 3C N N S OPO3PO3 H 3C N N

_ +
N S OPO3PO3

H 3C

H 3C

Thiamin pyrophosphate
CHO H H H H 2C OH OH OH OPO3 H 2C OH O CHO H 2C OH O HO H OH OH OH OPO3

thiamin-PP

H H H 2C

OH OH OPO3

H H 2C

OH OPO3

H H

D-ribose-5-P (C5 aldose)

D-ribulose-5-P (C5 ketose)

glyceraldehyde-3-P (C3 aldose)

H H 2C

sedohepulose-7-P (C7 ketose)

Trimethylsilycyanohydrins
O R H

TMS-CN

TMSO R

CN H

LDA, THF

TMSO R

CN

acyl anion equivalent

O

NC OMs NaHMDS, THF, -60C CN O OEE O (72%) O O O O OEE CSA, tBuOH

Tetrahedron Lett. 1997, 38, 7471

Dithianes
B:, THF S R S H S R S R'-I S R S R' R R' Hg(II)
O

Aldehyde Hydrazones
H N N R H tBu

B:
N tBu O E R E

E+
R

Heteroatom Stabilized Anions Sulfones

Ph R O S O

(Dithiane anion is an example)

_
O Ph R O S O R' R' R' R' Ph R O S O R OH

LDA, THF

Al(Hg)

R' R'

OH

Sulfoxides
O

_
Ph R S O

R' R' R'

OH

LDA, THF

Ph R S O

R'

Raney Ni
Ph S O

R' R' R

OH

C-C BOND FORMATION Epoxide Opening Asymmetric Synthesis 1984, 5, 216.

Nu: R O Acid (SN1-like) Condition R O+ Nu H Nu
OH OH BnO OH Me2CuLi AlMe3 6:1 1:5 OH OH + BnO OH TL 1983, 24, 1377

94

Basic (SN2) Condition R

Nu

Steric Approach Control

HO

OH

Nu: attachs site that best stabilizes a carbocation

O BnO

Me3Al

JACS 1981, 103, 7520

S O _

OH S S

JOC 1974, 3645

O S Ph S _

+
(69 %) 1) TBS-Cl 2) MeI, CaCO 3, H+ Ph O OH Ph

OH

Tetrahedron Lett. 1992, 33, 931

Cyclic Sulfites and Sulfates (epoxide equivalents)

O OH R1 OH
O S O R1 O R2 Nu:

Synthesis 1992, 1035.

O S O R2 RuCl3, NaIO4 O R1 O R2 O

R2

SOCl2, Et3N

S O R1 sulfite
O S O R1 O
-

sulfate
H2O

H R2 Nu

HO R1

H R2 Nu

H2O O S O R1 O R2 O Nu: O O S O R1 OH R2 Nu Nu: Nu2 H R1 H R Nu1 2

C-C BOND FORMATION

O SO2 R1 O R2 CO2Me CO2Me NaH R1 R2 MeO2C CO2Me

95

O SO2 CO2Me O

1) (CH3)2CuLi 2) TBS-Cl
OBn

OTBS CO2Me CH3

MeO

1) H2, Rh 2) HF

O O carpenter Bee pheromone

OMe NCH3

O SO2

OMe H3C

H N

OMe OMe

OBn OMe 1) Ac2O 2) HCl

O MeO OBn meso MeO BnO OAc

OH MeO HO NCH3 OBn OMe OBn OBn MeO BnO OMe NCH3

Irreversible Payne Rearrangement

O OH O O SO2 OTBS O Bu 4NF OH O OH

Payne Rearrangement of 2,3-epoxyalcohols Sigmatropic Rearrangements Nomenclature:

bond that breaks
1 1 2 3 2 1
R H

Aldrichimica Acta 1983, 16, 60

Asymmetric Synthesis 1984, 3, 503.

1 1 2 3 4 5
R

2 3 R

2 3 R

3 R

bond that forms

[3,3]-rearrangement

2 1
H

4 5

[1,5]-Hydogen migration bond that forms

bond that breaks

3,3-sigmatropic Rearrangements Cope Rearrangemets- requires high temperatures

R

Organic Reaction 1975, 22, 1

C-C BOND FORMATION Chair transition state:

CH3 H 3C H H 220 C H 3C E CH3 Z

96

E,Z (99.7 %)

E,E (0.3 %)

Z,Z (0 %)

H H 3C H 3C H HH

CH3

CH3

H 3C H 3C E

CH3 Z

H 3C

E,Z (0 %)

E,E (90 %)

Z,Z (10 %)

"Chirality Transfer"
Ph R CH3 Ph CH3 H E S CH3 (87 %) Diastereomers Ph Ph H 3C R E H 3C Z CH3 R (13 %) H

Ph

R CH3 Z Ph

E CH3

CH3 R H

Diastereomers Ph Ph H 3C R Z H 3C Z H S CH3

- anion accelerated (oxy-) Cope- proceeds under much milder conditions (lower temperature) JACS 1980, 102 , 774; Tetrahedron 1978, 34, 1877; Organic Reactions 1993, 43, 93; Comprehensive Organic Synthesis 1991, 5, 795. Tetrahedron 1997, 53, 13971.

C-C BOND FORMATION

OH OMe O

97

KH, DME, 110C

OMe

OH

KH OO

Ring expansion to medium sized rings

OH KH, O 9-membered ring

Claisen Rearrangements - allyl vinyl ether to an ,-unsaturated carbonyl Chem. Rev. 1988, 88, 1081.; Organic Reactions 1944, 2, 1.; Comprehnsive Organic Synthesis 1991, 5, 827.

O O

OH O

O CHO

220 C
O H O

Hg(OAc)2
O H O

JACS 1979, 101 , 1330

O H O

Chair Transition State for Claisen

R H E-olefin O R X X X=H X= OEt, NMe2, etc R O X R H O O 1,3-diaxial interaction X R X Z-olefin E/Z = 90 : 10 E/Z = > 99 : 1 O

new stereogenic centers R old stereogenic center H O O X R X

C-C BOND FORMATION 98 - Chorismate Mutase catalyzed Claisen Rearrangement- 105 rate enhancement over non-enzymatic reaction
CO2H Chorismate mutase O OH Chorismate CO2H OH Prephenate HO2C O CO2H J. Knowles JACS 1987, 109, 5008, 5013

- Claisen rearrangement usually proceed by a chair-like T.S.

H HO2C O H CO2H Chair T.S HO2C O H H

OH H H O CO2H CO2H Boat T.S

OH

Opposite stereochemistry
CO2H O CO2H

H H

OH

OH
OH + OH

OH

J. Org. Chem. 1976, 41, 3497, 3512 J. Org. Chem. 1978, 43, 3435

O +

O R H O R H

s CH3 O R H

O R H s CH3

CH3

O H

CH3 CH3 O H CH3

OH

CH3

OH

CH3 OH CH3 OH

CH3 CO2R

Tocopherol 94 - 99 % ee

hydrophobically accelerated Claisen - JOC 1989, 54, 5849

C-C BOND FORMATION Johnson ortho-ester Claisen:

EtO OEt OH H3C-C(OEt)3 H+ O - EtOH O OEt [3.3] O OEt

99

Ireland ester-enolate Claisen.

O O

Aldrichimica Acta 1993, 26, 17.

OTMS LDA, THF TMS-Cl O [3.3] O OH

O O Me OBn LDA, THF TMS-Cl Me Me Me CO2H OBn JOC 1983, 48, 5221

Eschenmoser
R OH EtO BF3 R NMe2 OEt O NMe2 R O NMe2

"Chirality Transfer"
R N O Ph Ph R= Et, Bn, iPr, tBu N O Ph (86 - 96 % de) R N O R aldehyde oxidation state

[2,3]-Sigmatropic Rearrangement
H Z :X Y R R H

Comprehensive Organic Synthesis 1991, 6, 873.

H R R1 X Y: R1 :X Y H X Y: R X Y: R H E :X Y

-Wittig Rearrangement
O

Organic Reactions 1995, 46, 105

_ base HO

Synthesis 1991, 594.

SnR3

BuLi

_ O

C-C BOND FORMATION

TBDPSO H MeO O OH MeO O O SnMe3 TBDPSO H MeO O (58%)
CH3 Ph _

100

KH, 18-C-6, Me3SnCH2I

TBDPSO nBuLi H

TBDPSO H MeO O O Li

J. Am. Chem. Soc. 1997, 119, 10935

TBDPSO

+
MeO OH O (42%)

H3C H

H3C Ph

CH3 OH (87 %)

CH3 H O _ CH3 Ph H3C Ph

CH3 (13 %) OH

Sulfoxide Rearrangement
R S O
-

S O

(MeO) 3P HO O

O CO2Et (MeO) 3P

CO2Et

Ph

O-

HO

Ene Reaction Comprehensive Organic Synthesis 1991, 5, 1; Angew. Chem. Int. Ed. Engl. 1984, 23, 876; ; Chem. Rev. 1992, 28, 1021.
H H

- Ene reaction with aldehydes is catalyzed by Lewis Acids (Et2AlCl)

R H O H O H R

OH CHO Et2AlCl CH2Cl2 -78C JOC 1992, 57, 2766

Ph O

O O H SnCl4 O Ph O

O OH 99.8 % de

Ph O SnCl4

OH + syn isomer

H3C

(94 : 6)

C-C BOND FORMATION

O TiCl2 O O + H CO2Me O PhS R + H CO2Me PhS R anti (99 % ee) OH + CO2Me (9 : 1) syn (90 % ee) PhS R CO2Me OH CO2Me OH (97% ee) Tetrahedron Lett. 1997, 38, 6513

101

- Metallo-ene Reaction

Angew. Chem. Int. Ed. Engl. 1989, 28, 38

CH3 C6H13 C6H13 ClMg C6H13 H 3C H2O H 3C H 3C (> 1%) C6H13 H2O H 3C CH3 C6H13 (10 %)

CH3

Cl

MgCl ClMg

intramolecular

BrMg + MgBr + (11 : 1)

BrMg

1)

Li Cl

1) Mg(0), Et2 ) 2) 60 C MgCl

CH3 MgCl

CHO 2) SOCl2

CH3 OH SOCl2

CH3

Cl

1) Mg(0), Et2 ) 2) 60 C

CH3 MgCl O2 H 1) PCC 2) MeLi 3) O3 H3C

CH3

MgCl

OH

CH3 CHO H O

4) KOH 5) H2 6) Ph3 P=CH2

H Capnellene

C-C BOND FORMATION Synthesis of Phyllanthocin

O O Ph N CH3 O (Me3Si)2 NLi Br Ph CH3 O

102

A. B. Smith et al. J. Am. Chem. Soc. 1987, 109, 1269.

O N O 1) LAH 2) BnBr

BnO 1) O3 2) H2, Lindlar's BnO CHO BnO BnO H O H CH3 OH CHO OMEM 1) MEM-Cl 2) O3 MeAlCl

BnO

O BnO 1) ZnCl2 2) H O MEMO O

+

O O BnO O

1) 2)

O (CH3 )2S(O)CH 2-

H3O +

3) Swern

O O BnO O

1) LDA, TMSCl 2) BnMe3 NF, MeI BnO O

O O

CH O 3

1) DBU 2) H2, Pd/C 3) RuO4

O O HO2C O

O CH3 MeO2C O

O O O O CH3 Ph Phyllanthocin