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. - a -deprotonation of a ketone, aldehyde or ester by treatment with a strong non- nucleophillic base. - carbonyl group stabilizes the resulting negative charge.

O O O - B: H H - H R R R H H H H

- 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 MeO- pK = 15 unfavorable enolate pK = 20 a H C CH a - concentration 3 3 tBuO pKa = 19 O O more favorable pKa = 10 enolate concentration H3C CH2 OEt

- Common bases: NaH, EtONa, tBuOK, NaNH2, LiNiPr2, M N(SiMe3)2, Na CH2S(O)CH3

Enolate Formation: - H+ Catalyzed (thermodynamic) O OH H+

- Base induced (thermodynamic or kinetic) O O - :B +B:H 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 O - Li+ LDA, THF, -78°C C-C BOND FORMATION 73 typical conditions: strong hindered (non-nucleophilic) base such as LDA R2NH pKa= ~30

Li N

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 O

OR' LDA, THF, -78°C N E+ R R

O O- Li+ N Li R OR' OR' R THF, -78°C

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

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 a,b -unsaturated ketones O thermodynamic kinetic site site

Trapping of Kinetic Enolates - enol acetates 1) NaH, DME 2) Ac O Ph Ph 2 Ph + O O kinetic O O O isolatable separate & purify

CH3Li, THF CH3Li, THF

Regiochemically pure enolates Ph Ph O- Li+ O- Li+ C-C BOND FORMATION 74 - silyl enolethers Synthesis 1977, 91. Acc. Chem. Res. 1985, 18, 181. 1) LDA 2) Me SiCl Ph Ph 3 Ph + OTMS O kinetic OTMS isolatable separate & purify

CH3Li, THF CH Li, THF -or- 3 Bu4NF -or- TiCl4

Geometrically Ph Ph pure enolates O- M+ O- M+

- tetraalkylammonium enolates- "naked" enolates - TMS silyl enol ethers are labile: can also use Et3Si-, iPr3Si- etc. - Silyl enol ether formation with R3SiCl+ Et3N gives thermodyanamic silyl enol ether

- From Enones 1) MeLi 1) Li, NH3 + 2) TMS-Cl 2) E

O TMSO O H H E

O OSiMe OSiMe3 3

TMS-Cl, Et3N TMS-OTf

Et3N

O OSiMe3

Li, NH3, tBuOH

TMS-Cl

- From conjugate (1,4-) additions O O- Li+ O + (CH3)2CuLi E E

Trap or use directly

- From reduction of a -halo carbonyls O O- M+ Br Zn or Mg

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 75 O O a) LDA, THF, -78°C Me b) MeI

- Rate of alkylation is increased in more polar solvents (or addition of additive) O O O O NMe2 (Me2N)3P O S CH3N CH3N NCH3 R NMe2 H3C CH3 HMPA Me2N R= H DMF DMSO R-CH3 DMA TMEDA Mechanism of Enolate Alkylation: SN2 reaction, inversion of electrophile stereochemistry X C 180 °

M+ -O

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

equitorial anchor

E H A E H tBu A favored Chair tBu R O R B O- M+ H E O Twist Boat B tBu R E 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 a,b -unsaturated carbonyls - + O M O R R E 1 2 R1 R2

O Kinetic H E H R1 R2

H H O- M+ O E R1 R2 R1 R2

H H E Thermodynamic C-C BOND FORMATION 76 Stork-Danheiser Enone Transposition: - overall g-alkylation of an a,b -unsaturated ketone

O O LDA HO CH3 CH3 PhCH OCH Cl CH Li H O+ 2 2 PhO 3 3 PhO PhO OMe OMe OMe O J. Org. Chem. 1995, 60, 7837.

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 O H N OH R 2 N O Me Ph Me Ph norephedrine O O R H2N OH N O

valinol O O O O O R LDA, THF R O O LiOH, H2O, THF R N N OH Et-I Me Ph Me Ph Complimentary Methods major product for enantiospecific alkylations (96:4) O O O O O Diastereoselectivity: 92 - 98 % R LDA, THF N O R LiOH, H2O, THF R for most alkyl halides N O OH Et-I

major product (96:4)

Enolate Oxidation Chem. Rev. 1992, 92, 919. O O O O NaN(SiMe ) , R 3 2 R N O THF, -78°C N O O OH N (88 - 98 % de) Ph SO2Ph

1) HO- O O 2) CH N LDA, THF 2 2 O R 3) TFA N O R O Boc N 4) Raney Ni OMe N OtBu NH2 tBuO N HN (94 - 98 % de) O Boc C-C BOND FORMATION 77 Bu Bu O O B O O O O NBS - R Bu2BOTf, Et3N N3 N O R R N O N O Br

Ph Ph Ph O O 1) LiOH O R 2) H2, Pd/C N O R OH N3 NH2

Ph D- amino acids

O O O O

R KN(SiMe3)2, THF R N O N O

N3 SO2N3 Ph Ph

Oppolzer Camphor based auxillaries Tetrahedron, 1987, 43, 1969. diastereoselectivities on the order of 50 : 1

SO2Ph R N Ar Ar N O R O SO2Ph R O O O N O S O SO2N(C6H11)2 O R 2

H H Et Cu•BF LDA, NBS H O 2 3 O O Br HO O O NH O 2 SO2N(C6H11)2 SO2N(C6H11)2 O SO2N(C6H11)2

Asymmetric Acetate Aldol O S O TIPSO O 1) Br H N O J. Am. Chem. Soc. 1998, 120, 591 Br NH2 J. Org. Chem. 1986, 51, 2391 Sn(OTf)2, CH2Cl2, R3N, -40°C 2) TIPS-OTf, pyridine 85 %, 19:1 de 3) NH3

Chiral lithium amide basess

CH3 CH Ph N OMe 3 MeO Li MeO

O CO2Et THF, -78°C (CH3)2C=O OMe OMe O (72% ee) C-C BOND FORMATION 78

H N Ph OTMS O But H N Ph N N O Li Li N THF, HMPA (97 % ee) TMSCl N tBu tBu Me

Lewis Acid Mediated Alkylation of Silyl Enolethers- SN1 like alkylations OTMS O tBu-Cl, TiCl4, CH3 CH2Cl2, -40°C note: alkylation with a 3° alkyl halide (79%) C(CH3)3 ACIEE1978, 17, 48 SPh TL 1979, 1427 OTMS O SPh O Raney Ni R Cl R R (95 %) TiCl4, CH2Cl2, -40°C (78%)

Enamines Gilbert Stork Tetrahedron 1982, 38, 1975, 3363. - Advantages: mono-alkylation, usually gives product from kinetic enolization O O

N N can not become coplanar

"Kinetic" "Thermodynamic"

O O O O •• + N N N O H R-I H2O R E + H , (-H2O)

enamine

-Chiral enamines

O N E

Imines Isoelectronic with ketones Me Ph O Li OMe Ph O E = -CH , -Et, Pr, N N 1) E 3 + PhCH2-, allyl- LDA, THF, -20°C 2) H3O E ee 87 - 99 % C-C BOND FORMATION 79 Hydrazones isoelectronic with ketones Comprehensive Organic Synthesis 1991, 2, 503

N N O N N N - N Me2N-NH2 LDA, THF - + H , (-H2O)

N + N O E hydrolysis E 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 MeO N N

NH2 H2N

SAMP RAMP

N N LDA O N OMe N OMe O3 H I OTBS

(95 % de) TBSO TBSO 1) LDA N 2) Ts-CH3, THF N -95 - -20 °C O OMe 3) MeI, 2N HCl CH3

(100 % ee) Me O Li •• MeO

R1 N N R1 N N E (C,C) R R2 H 2 H Z (C,N) E

E

Aldol Condensation Comprehensive Organic Synthesis 1991, 2, 133, 181. O a) LDA, THF, -78°C O OH b-hydroxyl aldehyde b R'CHO (aldol) R H H R' R

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

In the case of hindered enolates, the equillibrium favors reactants. Mg2+ and Zn2+ counterions will stabilize the intermediate b-alkoxycarbonyl and push the equillibrium towards products. (JACS 1973, 95, 3310)

O- M+ O OH

PhCHO, THF Ph M= Li 16% yield M= MgBr 93% yield

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

tBuO- Na +, tBuOH JACS 1979, 101 , 1330 O O H H O O

Enolate Geometry - two possible enolate geometries O O - Li+ O - Li+ LDA, THF, -78°C H + H E - enolate Z - enolate

- enolate geometry plays a major role in stereoselection. OM O OH Z -enolate 3 R2 R CHO erythro R1 R1 R3 (syn) H R2

E -enolate OM O OH R3CHO threo 1 H R R1 R3 (anti) R2 R2 - Zimmerman-Traxler Transition State : Ivanov condensation JACS 1957, 79 , 1920. + O MgBr H Br O - + O - Ph Mg Ph H + PHCHCO2 MgBr

Ph OMgBr H

"pericyclic" T.S. C-C BOND FORMATION 81 Analysis of Z-enolate stereoselectivity

2 2 R 2 R 3 R O O R O M 3 O O O OH R3 M R M O R1 R3 H H H H 1 1 H R R2 H R R1 erythro (syn) favored

2 2 2 R H R O M R O O O O O OH H M H M O R1 R3 H H R3 H 3 R1 3 R1 2 R R1 R R threo (anti) disfavored

Analysis of E-enolate stereoselectivity H H R3 H O M O O R3 M O OH 3 O O R M O 2 1 3 2 R R R R2 R H R1 1 H 2 R1 R R H threo (anti) favored

H H H O O O O H O M H M H M O OH O 2 2 R 1 3 R 2 1 R R 1 R 3 3 R R3 R R R R1 erthro (syn) R2 disfavored

Analysis of Boat Transition State for Z-Enolates R2 R3 O O O M O HO R3 H O M R1 R3 H R2 H R1 R2 R Favored Chair H 1 Boat H O R2 O O O HO R3 M O H M R2 R1 R3 staggered H R R 2 R R3 1 H 1 Boat: R1-R2 Disfavored Chair 1,3-interaction is gone C-C BOND FORMATION 82 Analysis of Boat Transition State for E-Enolates H R3 O O O M O HO R H 3 O M R1 R3 H R2 R H 1 R2 R R1 Favored Chair 2 Boat H H O O O O HO M R3 H O M H R1 R3 staggered R2 R2 R R1 3 R2 R1 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+ O HO Path A R2 R1 R1 R3 H Path R B 2

O- M+ O HO H R1 R1 R3 Path A R2 R2 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:

R O - R O - 1 1 R O - 1 O HO Favored R3 H H R2 H R3 H R2 R1 R3 R3 H H R2 R2 O O O Syn Aldol Favored R O - R O - 1 1 R O - 1 O HO Disfavored H R3 H R 2 H H R R1 R3 R3 2 H R3 H R2 R2 O O O Disfavored Anti Aldol C-C BOND FORMATION 83 E- Enolate:

- - O R1 O R1 - O R1 O HO favored R3 H R R H R2 R H R 1 3 R H 3 H 2 3 R2 H R2 O O O Syn Aldol favored

- - O R1 O R1 - O R1 O HO disfavored H R3 H R2 H H R R1 R3 R3 2 H R3 H R R2 O 2 O O disfavored Anti Aldol

NMR Stereochemical Assignment. Coupling constants (J) are a weighted average of various conformations. H O O HB Syn Aldol

R1 R3 JAB = 2 - 6 Hz R2 HA

60 ° 60 ° H HA HA A OH O HB HB R3 R3 H O R O 1 R R2 R2 2 R O R1 1 R3 O HB H non H-bonded

H O O HB Anti Aldol

R1 R3 JAB = 1 - 10 Hz R 2 HA 60 ° 60 ° H HA HA A OH O R3 R3 HB HB H O R O 1 R R2 R2 2 R O R1 1 HB O R3 H 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 R B-X OBR 2 2 X= OTf, I R= Bu, 9-BBN iPrEtN C-C BOND FORMATION 84

R N: 3 H _ OBL2

+ BL2OTf R2 R1 O R1 H R 2 Z-enolate

R3N: H _ OBEt2 + BL OTf 2 R R1 O 1 H R R2 2 E-enolate

O OBR2 R 3B R

OSiMe3 OBR2 R2B-X

+ Me3Si-X

O OBR'2 R'3B N2 R' Hooz Reaction R R Diastereoselective Aldol Condensation with Boron Enolates O OBEt O OBEt2 2 RCHO Ph Ph Ph R pure Z-enolate 100% Syn Aldol O OH OBEt2 R3CHO generally R2 > 95 : 5 R R1 R3 1 syn : anti R Z-enolate 2

O OH OBEt2 R3CHO generally R R ~ 75 : 25 R 1 3 1 anti : syn R R2 2 E-enolate Asymmetric Aldol Condansations with Chiral Auxilaries- D.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 Bu O O B OH O O Bu2BOTf, O - O + Me EtNiPr2, -78° RCHO N O R N O N O Me

> 99:1 erythro O O 1) Bu2BOTf, OH Me EtNiPr , -78° O N O 2 2) RCHO R X Ph Me C-C BOND FORMATION 85

L L H L L L L B_ + B B + O O R O _ O O _ O + O O

N O R RCHO N O N O

H L L L L

B B + R O _ O O _ O +

N R N O O O O preferred conformation

R R2 2 R3 O O H H L L O R O R3 3 B B N H N L L O O O O

Favored Disfavored

O O OH O O OH

O N R3 O N R3

R2 R2

Oppolzer Sultam

L2B O O O OH R CHO R2 R2 3 N N N R3

S S S R2 O2 O2 O2

1) LDA 2) Bu3SnCl

R3 Sn O OH O R3CHO R 2 R O N N 3 R S S 2 O2 O C-C BOND FORMATION 86 Chiral Boron

O BOTf OH O OH O StBu Ph + StBu Ph StBu iPrEt2N, PhCHO,-78°C when large, 1 : 33 higher E-enolate (> 99 % ee) selectivity Ph Ph

O ArO SN NSO Ar 2 B 2 OH O OH O R Br SPh + Ph SPh Ph SPh iPrEt2N, R R PhCHO,-78°C > 95 : 5 (> 95 % ee)

• 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.

RCHO, TiCl4, OH OH OSiMe3 CH Cl , -78°C 2 2 CO Et 2 + CO Et R R 2 OEt CH3 CH3 R= iPr (anti : syn) = 100 : 0 C6H11 94 : 6 Ph 75 : 25

RCHO, TiCl4, OH OSiMe OH 3 CH2Cl2, -78°C CO2Et + CO2Et R R OEt CH 3 CH3 R= iPr (anti : syn) = 52 : 48 C6H11 63 : 37 Ph 67 : 33

Asymmetric Mukiayama Aldol:

OH O Ph O RCHO, TiCl4, OH O CH Cl , -78°C 2 2 + R Rc R R OSiMe3 c H3C NMe2 (90-94% de)

syn : anti = 85 : 15 selectivity insenstivie to enolate geometry C-C BOND FORMATION 87

Ph iPrCHO, TiCl4, O HO N CH2Cl2, -78°C 96 % de SO2Ph Rc anti : syn = 93 : 7 O OSitBuMe 2 CH3

O HO RCHO, TiCl4, CH2Cl2, -78°C + Syn product O Rc CH OSitBuMe 3 SO N(C H ) 2 2 6 11 2 E-Enolate R= Ph % de= 90 anti : syn = 91 : 19 nPr 85 94 : 6 iPr 85 98 : 2

Z-Enolate R= iPr % de= 87 anti : syn = 97 : 7

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

O O

TiCl4, CHCl2, -78 °C O O

O HO O O

O OTMS

+ O O Cl4Ti O Cl4Ti O + OSiMe3

TiCl , OTMS 4 O OEt (CH3)2C(OEt)2

Ph (78 %) Ph

Fluoride promoted alkylation of silyl enol ethers Acc. Chem. Res. 1985, 18, 181 O OSiMe3

nBu4NF, THF, MeI C-C BOND FORMATION 88 Meyer's Oxazolines: 1) RCHO O (ipc)2BOtf 2) 3N H2SO4 H3C H3C O iPrEt2N, Et2O 3) CH2N2 R N + R CO2Me CO2Me N (~ 30%) OH OH (ipc)2B Ester R= nPr %ee (anti) = 77 anti : syn = 91 : 9 equiv. C6H11 84 95 : 5 tBu 79 94 : 6

Anti-Aldols by Indirect Methods: SePh O 1) (C5H7)2BOTf 1) HF OTBS 2) [O] PhSe C H R3N CO2Me 6 11 R R CO Me R 2) RCHO C6H11 3) NaIO4 2 OTBS 4) CH2N2 HO HO O HO

chiral syn auxillary aldol

1) TBS-Cl CH3 CH 2) DiBAl-H O3 3 Anti Aldol R R Product 3) TsCl CHO 4) Ba(CN)BH3 OTBS OTBS

CO2Me O OH 1) LDA, THF, 1) HIO6 2) CH N -78 °C O 2 2 MeO2C N R 2) RCHO N R CH3

CH3 Anti Aldol

MOMO O HO syn : anti N CH3 O O O O KBEt3H, Et2O, 1 : 99 MOMO -78 °C MeO 1) LDA, THF, CH3 N -78 °C N CH3 OMOM CH O 2) RCOCl 3 OMOM MOMO O HO MeO Zn(BH4)2 N CH syn : anti 3 97 : 3 CH3 OMOM

Syn Aldols by Indirect Methods:

O O 1) LDA, THF, O O O O O OH Zn(BH ) O N -78 °C 4 2 O N R O N R 2) RCOCl syn : anti = 100 : 1 CH 3 CH3 C-C BOND FORMATION 89 Aldol Strategy to Erythromycin: O 9 10 8 4 3 2 1 11 7 OH 12 6 Erythromycin 5 CO2H 15 seco acid O OH OH OH O OH OH 13 4 14 1 3 OH O 2 [O] [O] syn Erythromycin aldol 3 aglycone

CHO CO2H OH O OH OH syn syn aldol 4 aldol 1

CHO + CHO + CHO CO H O OH 2

syn aldol 2

CHO + CHO O

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

1) Zn(BH ) O O LDA, O O O TiCl , iPr EtN, O O O OH 3 2 4 2 2) (H3C)2C(OMe)2 CH3CH2COCl CH2Cl2 CSA O N O N 1 O N 5 83%, (96:4) (100%) Ph CHO Ph 90% (> 99:1) Ph

1) 9-BBN, THF O O O O O O O O 2) Swern oxid. CHO O N O N 3 5 73% (85:15)

Ph Ph

1) Na BH(OAc) 3 O OH OTBS O O O O OH 2) TBS-OTf, 2,6-lutidine O O Sn(OTf)2, 3) AlMe3, (MeO)MeNH•HCl MeO Et3N, CH2Cl2 N O N O N 9 11 13 72% (>99:1) CH3 CH3CH2CHO 84% (> 96:4) Ph Ph O OH OTBS 1) PMBC(NH)CCl3 PMBO TMSO OTBS EtMgBr TfOH 11 13 2) (PhMe Si) NLi, 86% 2 2 8 TMS-Cl 48 % C-C BOND FORMATION 90 X L X H3C H H O O O OH L O Sn CH H L 3 O Ti H L X R O O L H CH3 CH3 O Disfavored CH H 3 CH CH3 anti-syn 3 X CH3 X H L J. Am. Chem. Soc. O O OH H3C O CH3 O L 1990,112, 866 H Sn H O X R Ti L L H O CH CH O H 3 3 O L H C 3 Disfavored anti-syn H CH3 H3C CH3

PMBO O PMBO O O O O TMSO OTBS BF3•OEt2, O O O OH O OTBS CH Cl , -78 °C CHO 2 2 O N 3 + O N 11 13 5 7 11 13 83% (95:5) 3 5 7 9 8

p-MeOC H Ph 6 4 Ph O O O O OH O O OTBS 1) Zn(BH3)2 1) NaH, CS2, MeI 2) nBu SnH, AIBN 2) DDQ O N 3 95% 70%

Ph

p-MeOC6H4 p-MeOC6H4 Cl C H COCl O O O O O O OTBS 1) LiOOH O O O O O OH 3 6 2 2) TBAF iPr EtN, DMAP O N HO 2 63% 13 (86%

Ph p-MeOC6H4 O O 9 10 9 1) Pd(OH) , iPrOH 2 11 8 2) PCC 11 7 3) 1M HCl, THF OH 5 12 O 6 5 58 % 13 O OH O O 1 3 13 4 1 3 O OH O 2 O

Michael Addition - 1,4-addition of an enolate to an a,b -unsaturated carbonyl to give 1,5-dicarbonyl compounds O O O O - M+ R Ph Ph R Organometallic Reagents Grignard reagents: O Mg(0) OH R-Br R-MgBr THF R O O OH often a mixture of + R-MgBr R 1,2- and 1,4-addition THF R C-C BOND FORMATION 91 O OH

R-MgBr R 1,2-addition THF, CeCl3 O O

R-MgBr 1,4-addition CuI,THF, -78C R 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 t- butyllithium. Li(0) R-Br R-Li Et2O X Li nBu-Li X= Br, I, Bu3Sn

Et2O Organocuprates Reviews: Synthesis 1972, 63; Tetrahedron 1984, 40 , 641; Organic Reactions 1972, 19 , 1. - selective 1,4-addition to a,b -unsaturated carbonyls

CuI, THF 2 R-Li R2CuLi

O O

R2CuLi

R - curprate "wastes" one R group- use non transferable ligand _ MeO MeO Cu + Cu R Li R-Li

non-transferable ligand Other non transferable ligands _ _ _ _ + + + + Bu3P Cu R Li Me2S Cu R Li NC Cu R Li F3B Cu R Li

2-

+ Mixed Higher Order Cuprate Cu R 2Li S B. Lipshutz Tetrahedron 1984, 40 , 5005 CN Synthesis 1987, 325.

Addition to Acetals Tetrahedron Asymmtetry 1990, 1, 477. n-C H CH3 1) PCC O R (n-C H ) CuLi 6 13 6 13 2 2 NaOEt H C n-C6H13 CH3 TL 1984, 25, 3087 3 O O BF3•OEt2 OH R OH Chiral axulliary is destroyed 99 % ee LA LA O O O H R O CH3 R O R O CH H 3 H Nu: Nu C-C BOND FORMATION 92

TMS O 1) TiCl 4 JACS 1984, 106, 7588 O 2) [O] 3) TsOH OH 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 - OH M 2 - " M 1) "R 1 1 S + R S R * 2) "H " R2 L L

O OH M S M S

2 - 1 2 L R1 R R R L - 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 O S M vs. L L R2 - R2 - S M 1 R1 R

better worse - Chelation Control Model- "Anti-Cram" selectivity - When L is a group capable of chelating a counterion such as alkoxide groups + M OH O S R2 M OR' 1 1 R R * "Anti-Cram" Selectivity M OR' S

M+ OR' OR' O HO R2 2 - R M S M S R1 R1 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 O usually - + R R

Benzoin Condensation Comprehensive Organic Synthesis 1991, 1, 541.

O - KCN OH PhCHO HO O - - O OH O OH PhCHO H Ph Ph - CN Ph Ph Ph Ph Ph Ph CN CN CN Cyanohydrin anion Benzoin C-C BOND FORMATION 93 Thiamin pyrophosphate- natures acyl anion equivalent for trans ketolization reactions H NH2 NH2 _ + + N N S N N S

OPO3PO3 H3C N OPO PO H3C H3C N 3 3 H3C Thiamin pyrophosphate

H2C OH CHO H2C OH O H OH O CHO thiamin-PP HO H + H OH H OH H OH + H OH H OH H OH H2C OPO3 H OH H2C OPO3 H2C OPO3 H OH glyceraldehyde-3-P D-ribose-5-P D-ribulose-5-P (C3 aldose) H2C OPO3 (C5 aldose) (C5 ketose) sedohepulose-7-P (C7 ketose)

Trimethylsilycyanohydrins O TMSO CN TMSO CN TMS-CN LDA, THF acyl anion _ equivalent R H R H R

NC O OMs NaHMDS, OEE THF, -60°C CSA, tBuOH CN Tetrahedron Lett. 1997, 38, 7471 (72%) OEE O O O O O O

Dithianes

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

H B: N tBu N tBu N O N E+

R E R E R H H

Heteroatom Stabilized Anions (Dithiane anion is an example) Sulfones O _ R' OH R' Al(Hg) OH Ph LDA, THF Ph R' R' R' R S R' R S Ph O O O O R S R O O Sulfoxides O R' _ OH R' OH Ph Ph R' R' R' Raney Ni LDA, THF R S R S Ph R' R S O O R O C-C BOND FORMATION 94 Epoxide Opening Asymmetric Synthesis 1984, 5, 216. Basic (SN2) Condition Nu: R R Nu Steric Approach Control O HO Acid (SN1-like) Condition R R OH Nu: attachs site that best stabilizes a carbocation O + Nu H Nu

OH O OH OH + OH BnO BnO BnO TL 1983, 24, 1377 OH

Me2CuLi 6 : 1 AlMe3 1 : 5 OH Me3Al O JACS 1981, 103, 7520

S S OH S O _ JOC 1974, 3645 S

O OH S S + S S _ Ph Ph (69 %)

1) TBS-Cl O OH + 2) MeI, CaCO3, H Ph Tetrahedron Lett. 1992, 33, 931

Cyclic Sulfites and Sulfates (epoxide equivalents) Synthesis 1992, 1035. O O O OH S S SOCl2, Et3N O O RuCl3, NaIO4 O O R2 R1 R R OH R1 R2 1 2 sulfite sulfate O O O- S S H O O O Nu: O H 2 HO H R R2 R 2 R1 R2 R1 Nu 1 Nu

H2O O O O O- S O S O O Nu: H H O H Nu:

Nu2 R2 R1 R2 R2 R Nu R1 Nu 1 1 C-C BOND FORMATION 95

CO2Me MeO2C CO2Me O SO2 CO Me R 2 R 2 1 R1 R2 O NaH

SO 1) H , Rh O O 2 OTBS 2 1) (CH3)2CuLi ) HF 2 carpenter Bee CO2Me CO Me O 2 pheromone O 2) TBS-Cl CH3

OBn MeO OMe OBn OMe OMe SO H 1) Ac O O 2 N OMe 2 NCH 2) HCl H3C OMe 3 D O MeO OH MeO OBn meso OBn HO OBn OBn MeO OMe OMe NCH MeO 3 NCH3

BnO BnO OAc Irreversible Payne Rearrangement OH O OH O

O SO2

Bu4NF OH OTBS

O O Payne Rearrangement of 2,3-epoxyalcohols Aldrichimica Acta 1983, 16, 60 Sigmatropic Rearrangements Asymmetric Synthesis 1984, 3, 503. Nomenclature: 2 2 1 3 R 1 3 R D s bond s bond [3,3]-rearrangement that breaks that forms 1 3 R 1 3 R 2 2

3 3 2 4 2 4 D 1 1 5 [1,5]-Hydogen migration R H 5 R H 1 1 s bond s bond that breaks that forms

3,3-sigmatropic Rearrangements Cope Rearrangemets- requires high temperatures Organic Reaction 1975, 22, 1

D R R C-C BOND FORMATION 96 Chair transition state: CH3 CH 220 °C 3 Z H H3C H3C H E

E,Z (99.7 %) E,E (0.3 %) Z,Z (0 %)

CH3 H H H3C H H3C CH3 H

CH3 E Z H3C H3C E Z H3C

E,Z (0 %) E,E (90 %) Z,Z (10 %)

"Chirality Transfer" H R Ph E S Ph CH3 CH3 CH3 (87 %) Diastereomers Ph Ph Z H3C CH3 H3C R R E H (13 %)

CH3 R Ph E R Z Ph H CH3 CH3 Diastereomers

Ph Ph Z H C 3 H H C 3 R S Z 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 97

OMe O OH KH, DME, 110°C

OMe

KH OH O - O

Ring expansion to medium sized rings

OH O KH, D 9-membered ring

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

O OH CHO

O 220 °C Hg(OAc) JACS 1979, 101 , 1330 2 O O H O H H O O O

Chair Transition State for Claisen

E-olefin R O O R H X X

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

new stereogenic centers

R O old stereogenic O center H X R X C-C BOND FORMATION 98 - Chorismate Mutase catalyzed Claisen Rearrangement- 105 rate enhancement over non-enzymatic reaction CO2H HO2C CO2H Chorismate mutase O J. Knowles JACS 1987, 109, 5008, 5013

O CO2H OH OH

Chorismate Prephenate

- Claisen rearrangement usually proceed by a chair-like T.S. H HO2C H

H O H HO2C Chair O CO H 2 T.S

OH OH Opposite H stereochemistry H H CO2H CO2H Boat O H CO2H T.S O CO2H

OH OH

OH OH OH +

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

O R R O

H H

CH O s 3 R H O R s H CH3

CH3 O

H

OH CH OH CH3 3

CH3 O CH3 CH3

CO2R H CH OH CH3 OH 3 Tocopherol 94 - 99 % ee hydrophobically accelerated Claisen - JOC 1989, 54, 5849 C-C BOND FORMATION 99 Johnson ortho-ester Claisen: EtO OEt OEt OEt

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

Ireland ester-enolate Claisen. Aldrichimica Acta 1993, 26, 17. OTMS O OH LDA, THF O [3.3] O TMS-Cl O

O OBn LDA, THF Me O TMS-Cl CO H Me 2 JOC 1983, 48, 5221 Me Me OBn

Eschenmoser NMe R 2 EtO OEt O D O OH NMe BF3 NMe2 2 R R "Chirality Transfer" R R R aldehyde O N N N O oxidation state Ph O Ph Ph R= Et, Bn, iPr, tBu (86 - 96 % de)

[2,3]-Sigmatropic Rearrangement Comprehensive Organic Synthesis 1991, 6, 873. Z H H H H E :X X Y Y: R Y: X R :X Y R R

R1 R R R1 X Y: H Y :X

-Wittig Rearrangement Organic Reactions 1995, 46, 105 Synthesis 1991, 594.

_ base O HO

BuLi _ O SnR3 O C-C BOND FORMATION 100

TBDPSO KH, 18-C-6, TBDPSO TBDPSO Me3SnCH2I nBuLi H H H MeO O MeO O MeO O OH O O J. Am. Chem. Soc. SnMe3 Li 1997, 119, 10935 TBDPSO TBDPSO

H + H MeO O MeO O OH (58%) (42%)

CH 3 H C CH3 H C 3 3 O Ph _ (87 %) H Ph OH

CH3 CH3 CH (13 %) H _ 3 H C O Ph 3 Ph OH Sulfoxide Rearrangement R R S S (MeO)3P O- O HO

O O CO2Et CO2Et (MeO)3P

S HO Ph O- 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 R H O O H H

OH CHO JOC 1992, 57, 2766 Et2AlCl

CH2Cl2 -78°C

O O Ph Ph O OH O O 99.8 % de H SnCl4

O Ph OH O + syn isomer SnCl4 H C 3 (94 : 6) C-C BOND FORMATION 101

O TiCl O 2 OH O (97% ee) Tetrahedron Lett. + 1997, 38, 6513 H CO2Me CO2Me

OH O OH + + PhS PhS CO2Me R H CO2Me CO2Me PhS R R (9 : 1) anti (99 % ee) syn (90 % ee)

- Metallo-ene Reaction Angew. Chem. Int. Ed. Engl. 1989, 28, 38 CH3 CH3

C6H13 C6H13 H2O C H CH 6 13 (10 %) 3 H3C ClMg

C6H13 C6H13 Cl MgCl H2O H C H C H C 3 3 ClMg 3 (> 1%) intramolecular

BrMg (11 : 1) + + MgBr

BrMg

CH3 1) Mg(0), Et2) 1) Li 2) 60 °C MgCl

CHO MgCl 2) SOCl2 Cl

CH3 CH3 O Cl 1) Mg(0), Et2) SOCl2 2) 60 °C OH

CH3 CH3 MgCl O2

H H MgCl OH

H3C 1) PCC CH3 4) KOH 2) MeLi 5) H2 3) O3 CHO 6) Ph3P=CH2 H H O Capnellene C-C BOND FORMATION 102

Synthesis of Phyllanthocin A. B. Smith et al. J. Am. Chem. Soc. 1987, 109, 1269. O O O O 1) LAH (Me3Si)2NLi 2) BnBr O N O N Br Ph CH Ph CH3 3

BnO 1) O 3 BnO 2) H2, Lindlar's MeAlCl CHO

BnO 1) MEM-Cl H 2) O BnO 3 BnO CH3 O H OH CHO OMEM

O O O O 1) ZnCl2 O 1) BnO + - 2) H O O - O BnO (CH3)2S(O)CH2 2) H O+ O 3 MEMO O 3) Swern

O CH3 1) DBU O O 1) LDA, TMSCl O 2) H2, Pd/C 2) BnMe3NF, MeI O O BnO BnO 3) RuO4 O O

O O O

O CH3 O CH3 Ph O Phyllanthocin O MeO C O HO2C 2 O