Myers

Reviews: Wadsworth, W. S., Jr. Org. React. 1977, 25, 73-253. Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863-927. Boutagy, J.; Thomas, R. Chem. Rev. 1974, 74, 87-99.

Horner-Wadsworth-Emmons Olefination
Mechanism:

Chem 215

Kelly, S. E. In Comprehensive Organic Synthesis; Trost, B. M. and Fleming, I. Ed.; Pergamon: Oxford, 1991, Vol. 1, pp. 729-817. Walker, B. J. In Organophosphorus Reagents in Organic Synthesis; Cadogan, J. I. G., Ed.; Academic Press: New York, 1979, pp. 155-205. Applications in Natural Product Synthesis: Nicolaou, K. C.; Hrter, M. W.; Gunzner, J. L.; Nadin, A. Liebigs Ann./Recueil 1997, 1283-1301. Asymmetric Wittig-Type Reactions: Rein, T.; Reiser, O. Acta. Chem. Scand. 1996, 50, 369-379. R'CHO + O (RO)2P M

R' (RO)2(O)P R'' 1E

H O M W

R' H

R'' W O P(OR)2 O M 2E

R' H

R'' W

(E)-alkene

ratedetermining step W R'' R'

Direct interconversion possible if R'' = H

Development and General Aspects: Olefin synthesis employing phosphonium ylides was introduced in 1953 by Wittig and Geissler. Wittig, G.; Geissler G. Liebigs Ann. 1953, 580, 44-57. In 1958, Horner disclosed a modified Wittig reaction employing phosphonate-stabilized carbanions; the scope of the reaction was further defined by Wadsworth and Emmons. CO2Et O (EtO)2P O 1. NaH, DME, 23 C OEt 2. Cyclohexanone, 23 C, 15 min. 70% Phosphonate-stabilized carbanions are more nucleophilic (and more basic) than the corresponding phosphonium ylides. The by-product dialkylphosphate salt is readily removed by aqueous extraction. In contrast to phosphonium ylides, phosphonate-stabilized carbanions are readily alkylated: O H 3C CH2 60%, two steps CH3 OEt

W = CO2 , CO2R, CN, aryl, vinyl, SO2R, SR, OR, NR2

H O M W R'' P(O)(OR)2 1Z

R' H

W R'' O P(OR)2 O M 2Z

R' H

W R''

(Z)-alkene

Phosphonate anion addition to the carbonyl is rate determining (determined for olefination of aromatic aldehydes employing sodium ethoxide):

+ (EtO)2PO2Na

Larsen, R. O.; Aksnes, G. Phosphorus Sulfur 1983, 15, 219-218.

Carbanion-stabilizing group (W) at the phosphonate-substituted carbon is necessary for elimination to occur; nonstabilized phosphonates (W = R or H) afford stable -hydroxyphosphonates. Corey, E. J.; Kwiatkowski, G. T. J. Am. Chem. Soc. 1966, 88, 5654-5656.

O (EtO)2P

1. NaH, DME OEt 2. n-BuBr, 50 C

O (EtO)2P

1. NaH, DME OEt 2. CH2O

Direct interconversion of intermediates 1E,Z or 2E,Z is possible when R'' = H: Lefbvre, G.; Seyden-Penne, J. J. Chem Soc., Chem. Commun. 1970, 1308-1309.

The ratio of olefin isomers is dependent upon the stereochemical outcome of the initial Horner, L.; Hoffmann, H. M. R.; Wippel, H. G. Chem. Ber. 1958, 91, 61-63. Horner, L.; Hoffmann, H. M. R.; Wippel, H. G.; Klahre, G. Chem. Ber. 1959, 92, 2499-2505. Wadsworth, W. S.; Emmons, W. D. J. Org. Chem. 1961, 83, 1733-1738. addition and upon the ability of the intermediates to equilibrate. Kent Barbay

Acidity of Stabilized Phosphonates in DMSO:

Acylation of Alkylphosphonate Anions: The synthesis of -ketophosphonates from -haloketones by the Michaelis-Arbusov

O (EtO)2P

Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456-463.; Bordwell, F. G. Unpublished results. (http://daeiris.harvard.edu/DavidEvans.html)

reaction is impractical due to competing formation of dialkyl vinyl phosphates by the Perkow reaction: O CH2 (EtO)3P CH3 100 C (EtO)3P Cl O CH3 O CH3 (EtO)3P Cl EtCl

W CN CO2Et Cl Ph SiMe3

pKa 16.4 18.6 26.2 27.6 28.8

Phosphonium salts are considerably more acidic than the corresponding phosphonates:
(Ph3P+CH2CN)Cl: pKa = 6.9 (Ph3P+CH2CO2Et)Cl: pKa = 8.5

Cl

O (EtO)2P

CH2 O CH3

Bhattacharya, A. K.; Thyagarajan, G. Chem. Rev. 1981, 81, 415-430. -ketophosphonates are prepared by acylation of alkylphosphonate anions:

Bordwell, F. G.; Zhang, X.-M. J. Am. Chem. Soc. 1994, 116, 968-972.

Preparation of phosphonates: Michaelis-Arbusov Reaction: Review: Bhattacharya, A. K.; Thyagarajan, G. Chem. Rev. 1981, 81, 415-430. O Br CH3 P(OEt)3 OEt reflux (EtO)3P Br CH3 O EtBr OEt

O (EtO)2P CH3

1. n-BuLi, THF, 60 C 2. CuI 3. H3C CH3 O

O (EtO)2P 86%

O CH3 CH3

Cl

O (EtO)2P

O OEt CH3 59%

Mathey, F.; Savignac, P. Tetrahedron, 1978, 34, 649-654. Phosphonate Ester Interchange: O (MeO)2P O PCl5 OMe 0 75 C O Cl2P O F3CCH2OH OMe DIPEA, PhH 40%, two steps O (CF3CH2O)2P O OMe

Arbusov, A. E.; Durin, A. A. J. Russ. Phys. Chem. Soc. 1914, 46, 295.

Michaelis-Becker Reaction: Worms, K. H.; Schmidt-Dunker, M. In Organic Phosphorus Compounds; Kosolapoff, G. M. and Maier, L. Ed.; Wiley: New York, 1976, Vol. 7, pp. 27-28. Muller, E. (ed.) Methoden der Organishen Chemie (Houben-Weyl); George Theime Verlag: Stuttgart, 1964, Vol 12/1, p. 446. O 1. Na, hexane (EtO)2P H 2. ClCH2CO2Et 58% Kosolapoff, G. M. J. Am. Chem. Soc. 1946, 68, 1103-1105. O (EtO)2P O OEt Still, W.C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405-4408. Bodnarchuk, N. D.; Malovik, V. V.; Derkach, G. I. Zh. Obshch. Khim. 1970, 40, 1210. Ester Interchange: CH3 O (i-PrO)2P O OMe ()-menthol cat. DMAP toluene, reflux 94% O (i-PrO)2P O O H3C CH3

The use of isopropyl phosphonates minimizes alkoxy exchange at phosphorus. Hatakeyama, S.; Satoh, K.; Kuniya, S.; Seiichi, T. Tetrahedron Lett. 1987, 28, 2713-2716.

Kent Barbay

Stereoselectivity of HWE Olefination: Disubstituted Olefins: Reaction of phosphonates with aldehydes favors formation of (E)-alkenes. TESO H3C OTBS CHO CH3 CH3 O (EtO)2P O OEt NaOEt, EtOH RCHO R E Aldehyde PhCHO n-PrCHO i-PrCHO Ratio of products (E : Z) 98 : 2 95 : 5 84 : 16 O OEt + OEt Z R O

O (RO)2P

CO2Et 5

TESO H3C

OTBS

O 4 OEt

LiTMP, THF, 30 C Ratio of products (E : Z) 1 : 1.2 1.75 : 1 E only E only

CH3 CH3 68% for R = i-Pr

R Me Et i-Pr CH(Et)2

Boschelli, D.; Takemasa, T.; Nishitani, Y.; Masamune, S. Tetrahedron Lett. 1985, 26, 5239-5242. Trisubstituted Olefins: Reaction of -Branched Phosphonates with Aldehydes:

Larsen, R. O.; Aksnes, G. Phosphorus Sulfur, 1983, 16, 339-344.

In a systematic study of the synthesis of disubstituted olefins by HWE, E : Z ratio increases: (1) in DME relative to THF, (2) at higher reaction temperatures, (3) M+ = Li > Na > K, (4) with increasing -substitution of the aldehyde. In general, conditions which increase the reversibility of the reaction (i.e., increase the rate of retroaddition relative to the rate of elimination) favor the formation of E-alkenes. Thompson, S. K.; Heathcock, C. H. J. Org. Chem. 1990, 55, 3386-3388. Bulky phosphonate and ester substituents enhance (E)-selectivity in disubstituted olefin synthesis: CH3 BnO Reagent BnO CH3 CO2R + BnO CH3 CO2R

The size of the phosphonate and ester substituents plays a critical role in determining the stereochemical outcome in the synthesis of trisubstituted olefins large substituents favor (E)-alkenes. O (R1O)2P CHO CH3 O OR2 CH3 t-BuOK, THF 78 C CO2R CH3 CH3 (E)-alkene Ratio of products (E : Z) 5 : 95 10 : 90 40 : 60 90 : 10 95 : 5 + CH3 CH3 CO 2R (Z)-alkene

R1 Me Me Et i-Pr

R2 Me Et Et Et i-Pr

CHO t-BuOK, THF 78 C

Reagent O (i-PrO)2P O (MeO)2P O

Ratio of products (E : Z) 95 : 5 OEt

i-Pr

O 1:3 OMe (Z)-selective olefination with the trimethyl phosphonate (R1, R2 = CH3) is unsuccessful with aromatic aldehydes. The Still modification of the HWE olefination (see below) can be applied for (Z)-selective olefination of aromatic aldehydes. Kent Barbay Nagaoka, H.; Kishi, Y. Tetrahedron 1981, 37, 3873-3888.

Nagaoka, H.; Kishi, Y. Tetrahedron 1981, 37, 3873-3888.

Olefination of Ketones: (E)-selectivities are typically modest in condensations with ketones. In some cases, use of a bulky ester increases the selectivity: H3C H3C O O H O H O H H O O CH3 CH3 O (MeO)2P O OR H3C H3C O

P(OEt)2 O H3C CH3 O

H3C CH3 O O O CH3 OTIPS K2CO3 MeOH 76%

O O O H t-BuOK, DMF R2 H R1 A: R1 = CO2R, R2 = H B: R1= H, R2 = CO2R O H H O O CH3 CH3

O O O O

CH3 OTIPS

LiCl, Et3N CH3CN 1 mM 86%

single olefin isomer H3C CH3

R Me t-Bu

Ratio of products (A : B) 2.7 : 1 9:1

H O MeO HO O

CH3 OTIPS

The failure of this hindered ketone to react with Ph3P=CHCO2Et (benzene, reflux) provides an example of the increased reactivity of phosphonates in comparison to phosphonium ylides. Mulzer, J.; Steffin, U.; Zorn, L.; Schneider, C.; Weinhold, E.; Mnch, W.; Rudert, R.; Luger, P.; Hartl, H. J. Am. Chem. Soc. 1988, 110, 4640-4646. Tadano, K.; Idogaki, Y.; Yamada, H.; Suami, T. J. Org. Chem. 1987, 52, 1201-1210. EtO2C O MeO O O O CH3 O O (MeO)2P O Ot-Bu MeO O O 77%, 7:1 E : Z White, J. D.; Theramongkol, P.; Kuroda, C.; Engelbrecht, J. R. J. Org. Chem. 1988, 53, 5909-5921. Control of double-bond geometry in tri-substituted olefin synthesis has been accomplished by the use of a tethered HWE reagent: OEt O H3C CH3 O O CH3 OTIPS O (EtO)2P O O(CH2)5CO2H O H3C CH3 O O O O O CH3 OTIPS P(OEt)2 O Single-step two-carbon homologation of esters: O (EtO)2P O OEt O 81%, 91 : 9 E : Z Ester reduction in the presence of the phosphonate minimizes overreduction of the intermediate O O CH3 O Ot-Bu Bestmann, H. J.; Ermann, P.; Rppel, H.; Sperling, W. Liebigs. Ann. Chem. 1986, 479-498. O P(OEt)2 CH3 CH3O CH3O NaH, THF, 55 C 83% Evans, D. A.; Carreira, E. M. Tetrahedron Lett. 1990, 31, 4703-4706. Tetrasubstitued olefins can be prepared in some cases, but isomeric mixtures are obtained: O CH3 EtO2C CH3 OCH3 CH3 OCH3 E E : Z = 28 : 72 H3CO + EtO2C CH3 Z OCH3 CH3

NaH, LiBr, THF, 23 C

OEt n-BuLi, THF, 78 C; DIBAL-H, 78 23 C

DCC, DMAP, CH2Cl2 HO (1:1 mixture of diastereomers) 100%

aldehyde.
Takacs, J. M.; Helle, M. A.; Seely, F. L. Tetrahedron Lett. 1986, 27, 1257-1260.

Kent Barbay

Olefination of Base-Sensitive Substrates (Masamune-Roush Conditions): Masamune and Roush reported mild conditions (LiCl, amine base, ambient temperature) for olefinations employing base-sensitive substrates or phosphonates: O (EtO)2P O CH3 CH3

(Z)-Selective Olefination Still Modification of HWE Olefination: Disubstituted olefins: O (CF3CH2O)2P H3C CH3 aldehyde CHO H3C CO2Me CHO CO2Me CHO CO2Me CHO CH3O CH3 H3C CH3 CHO H3C CO2Me Trisubstituted olefins: O (CF3 CH2O)2P CHO O OMe CH3 KHMDS, 18-crown-6, THF, 78 C aldehyde CH3 H3C CHO CHO H3C O CHO H H H3C CH3 CO2Me CH3 CO2Me 30 : 1 >95 product CH3 CO2Me >50 : 1 80 H3C 88%, 46 : 1 Z : E Z:E >50 : 1 CH3 CO2Me CH3O CH 3 CH3 22 : 1 81 CO2Me >50 : 1 >95 4:1 74 product CHO O OMe H3C CO2Me 90%, 12 : 1 Z : E Z:E yield, %

NHCbz CHO CH3

NHCbz

KHMDS, 18-crown-6, THF, 78 C

LiCl, DIPEA CH3 CN, 23 C, 17 h 90%

This aldehyde substrate epimerizes under standard HWE conditions (NaH as base). Addition of LiCl enhances acidity of phosphonate, allows use of weak bases (DBU, i-Pr2NEt) and ambient temperature. M

H3C

>50 : 1

87

M
O OEt

solvent DMSO diglyme

pKa 19.2 12.2

>50 : 1

>95

O (EtO2)P

K Li

Application of the Masamune-Roush conditions does not alter the inherent (E)-selectivity of the HWE reaction. Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183-2186. Application of mild HWE conditions to (Z)-selective olefin synthesis (see adjacent column): O MeO O P(OCH2CF3)2 O CHO H H3C CH3 H O CH3 LiCl, DBU, CH3CN O H3C O O MeO2C H H3C CH3 80%, 3 : 1 Z : E H O

yield, % 79

Application of the normal conditions for (Z)-selective HWE (KHMDS, 18-crown-6) yielded only the internal aldol product A. Hammond, G.S.; Cox Blagg, M.; Weimer, D. F. J. Org. Chem. 1990, 55, 128.

A
H3C CH3

From: Still, W.C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405-4408. The electrophilic phosphonate and the use of strongly dissociating conditions favor rapid elimination, resulting in excellent (Z)-selectivity. Kent Barbay

(Z)-Selective Olefination (Diarylphosphono)acetates: Disubstituted olefins: O (PhO)2P CH3 CHO NaH, THF 78 10 C O OEt CH3 CO2Et 100%, 90 : 10 Z : E aldehyde CH3 CO2Et CHO CO2Et CHO CO2Et CHO CH3 CH3 TBSO CHO Me3NBuOH 93 : 7 98 NaH 91 : 9 98 product base Z:E yield, %

Trisubstituted olefins: O (ArO)2P RCHO base, THF O OEt R R' CO2Et

aldehyde

Ar

R' n-Pr

product CH3 CO2Et

base

Z:E

yield, %

CH3

CHO

Me3NBuOH

89 : 11

97

n-Pr

CHO o-MePh CHO o-i-PrPh CHO Ph

Me

Me3NBuOH

89 : 11

97

CH3 Me CO2Et n-Bu n-Bu CO2 Et NaH 96 : 4 91 t-BuOK 97 : 3 100

n-Bu CH3 CH3 CH3 CH3 TBSO CO2Et NaH 97 : 3 78 CH 3 CO2Et CH3

CHO Ph n-Bu

n-Bu CH3

n-Bu CO2Et CH3 NaH 95 : 5 85

NaH

94 : 6

100

n-C7H15CHO

Ph

i-Pr

n-C7H15

CH3 CO2Et CH3

NaHLiBr

91 : 9

75

CHO Ph i-Pr OCH2 Ph

CH3 PhCH2O

(Z)-Selectivity was further enhanced using ortho-alkyl substituted (diarylphosphono)acetates: O (ArO)2P O OEt 93 : 7 99 : 1 (Z)-selectivity, 92100% yield. Aryl, ,-unsaturated, alkyl, branched alkyl, and -oxygenated aldehydes are suitable substrates.

CH 3 CO2 Et

NaH

98 : 2

65

Ando, K. J. Org. Chem. 1998, 63, 84118416. Masamune and Roush's mild conditions have been adapted for (Z)-selective olefin synthesis using (diarylphosphono)acetates: O (PhO)2P O 1. NaI, DBU, THF, 0 C OEt 2. CH3 CH3 CHO CH3 CH3 ArSO2N

Ar = o-MePh, o-EtPh, o-i-PrPh In analogy to Still's (Z)-selective HWE reaction employing [bis(trifluoroethyl)phosphono]acetates, (Z)-selectivity is attributed to the electron-withdrawing nature of the aryloxy substituent, which accelerates elimination relative to equilibration of oxaphosphatane intermediates. Ando, K. J. Org. Chem. 1997, 62, 19341939. For (diphenylphosphono)acetate esters, (Z)-selectivity increases with increasing steric bulk of the ester moiety. Ando, K. J. Org. Chem. 1999, 64, 84068408.

CO2Et

NHSO2Ar 78 0 C

89%, 87 : 13 Z : E no racemization Ar = 2,4,6-trimethylphenyl

Ando, K.; Oishi, T.; Hirama, M.; Ohno, H.; Ibuka, T. J. Org. Chem. 2000, 65, 47454749. Kent Barbay

HWE Reaction in Macrolide Synthesis: ()-Vermiculine:

Amphotericin B:

O O O S S CHO O CH3 O O
NaH

CH3 O O S O

CH3 O O O O O H3C O

H3C TBSO H3C

OTHP CH3

O (EtO)2P

O
2 OEt

S S O O

P(OMe)2 THF, 23 C O
5.6 mM 49%

CHO LDA, THF, 78 0 C

60%

S H3C TBSO H3C OTHP CH3 O H3C O

()-Vermiculine

OEt O OTBS OCH3 O O O O O P(OMe)2 O OCH3 O O O O OH OH OH O O O

Amphotericin B

High-dilution or syringe-pump additions are frequently required to achieve highyielding macrocyclizations. Burri, K. F.; Cardone, R. A.; Chen, W. Y.; Rosen, P. J. Am. Chem. Soc. 1978, 100, 7069-7071.

()-Asperdiol:
EtO O

H3C TBSO O OEt H3C Me EEO CH3 (E) only

1. LiAlH4, 20 C, 78 %

O O CH3 O O O

OTBS OMe
DBU, CH3CN, 10 mM LiCl, 25 C, 4 h 70%

H O

P(O)(OEt)2

H
LiCl, DBU

CHO Me EEO CH3 OH H O Me HO CH3

()-Asperdiol

CH3 CH3CN, 23 C 3 mM
61%

CH3 2. PPTS, 23 C, 71% OTBS H3C TBSO H3C O O CH3 O O O

OTBS OMe

CH3 Tius, M.A.; Fauq, A. J. Am. Chem. Soc. 1986, 108, 6389-6391.

H3C HO

O O HO CH3 OH HO

OH OH

Intramolecular HWE olefinations are usually selective for (E)-alkenes, but the selectivity can vary based on ring size and substitution. For example, compare to above:

EtO H

O P(O)(OEt)2 CHO H
LiCl, DBU CH3CN, 23 C

H3C O HO

OEt

CH3 OH NH2

Me EEO CH3

Me EEO CH3
2:1E:Z

CH3
Nicolaou, K. C.; Daines, R. A.; Chakraborty, T. K.; Ogawa, Y. J. Am. Chem. Soc. 1988, 110, 4685-4696. Nicolaou, K.C.; Daines, R. A.; Ogawa, Y.; Chakraborty, T. K. J. Am. Chem. Soc. 1988, 110, 4696-4705. Kent Barbay

CH3

4 mM
30 %

Tius, M. A.; Fauq, A. H. J. Am. Chem. Soc. 1986, 108, 1035-1039.

Asymmetric HWE: Chiral Phosphonamidates: O Li H H3C O Ph O P N i-Pr O H t-BuLi, THF 70 C; R H3C O O PR' N H R

Asymmetric Olefin Synthesis Chiral Ester:

Li O (MeO)2P O Ph O CH3 CH3 CH3 H n-BuLi, THF; O O O (MeO)2P O Ph O

CH3 CH3 CH3

R' = i-Pr

H O O

H O O Attack by -face of phosphonate on convex face of ketone H

H H3C

O O P N i-Pr Ph

OH R

Ph3COTf, 2,6-lutidine CH3CN, 60 C

94-98%, 88-100% de

CPh3 H O OH H3C O P N Ph i-Pr

OTf

THF, 60 C

Ph

R t-Bu Me Ph

yield, % 65 72 71 75

ee, % >99 86 >99 95

O (MeO)2P LiO

O H Ph O

CH3 CH3 CH3 H syn-elimination H O

O Ph O

CH3 CH3 CH3 H 93%, 90% de

CO2t-Bu

O O

H O

Electrophilic attack occurs from the less hindered -face of the phosphonamidate-stabilized carbanion. Bulky nucleophiles display high selectivity for equatorial attack on cyclohexanones. Gais, H.-J.; Schmeidl, G.; Ball, W. A.; Bund, J.; Hellmann, G.; Erdelmeier, I. Tetrahedron Lett. 1988, 29, 1773-1774. 8-phenylmenthol: Corey, E. J.; Ensley, H. E. J. Am. Chem. Soc. 1975, 97, 6908-6909.

Stable -hydroxy phosphonamidates are isolated and transformed to alkenes by electrophilic activation with trityl salts. This procedure results in stereospecific syn-cycloelimination. (Attempted base-catalyzed olefin formation led to retroaddition.)

Denmark, S. E.; Chen, C.-T. J. Am. Chem. Soc. 1992, 114, 10674-10676. Denmark, S. E.; Chen, C.-T. J. Org. Chem. 1994, 59, 2922-2924.

Kent Barbay

Kinetic Resolution: O O (F3CCH2O)2P O Ph O CH3 CH3 CH3

O H 3 eq O H + CO2R 81%, 98% de 14%, 92% de O H CO2R

Discrimination of enantiotopic or diastereotopic carbonyls: CH3 H3C H3C RO2C OHC OTBS CHO CH3 CH3 KHMDS, 18-crown-6 THF, 100 C OHC CH3 H3C O H H3C CO2R O CH2 O Nu H O H major product synelimination O CO2R P(O)(OR)2 H O CO2R P(O)(OR)2 H3C H3C CH3 Ph O O O P(OMe)2 Diastereoselectivity is depend on conversion, because the minor diastereomeric products are preferentially bis-olefinated. See: Schreiber, S. L.; Schreiber, T. S.; Smith, D. B. J. Am. Chem. Soc. 1987, 109, 1525-1529. Exercise: Based on the previous example, rationalize the stereochemical outcome of these olefinations. (Note that the phosphonate used in this example is enantiomeric to that used in the previous example). Tullis, J. S.; Vares, L.; Kann, N.; Norrby, P.-O.; Rein, T. J. Org. Chem. 1998, 63, 8284-8294. 1. (CH2)2I CH3 O O O O CH3 H3C H3C Ph O O CH3 O O O P(OMe)2 t-BuOK, THF 50 C, 30 min Ph O O O P(OMe)2 CH3 CH3 53%, 90% de Ph O O O P(OCH2CF3)2

TBSO CHO CH3 CH3

1.1 eq

1 eq KHMDS, 18-crown-6 THF, 100 C

Crude Z : E = 85 : 15 E and Z products are formed from different enantiomers of the starting aldehyde. Mechanistic hypothesis:

83%, 96% de OTBS CO2R

O H H fast-reacting enantiomer

18-crown-6 O Ph O CH3 CH3 CH3

O Felkin-Anh addition (RL = OR) O

O (F3CCH2O)2P

Attack from -face of (Z)-enolate H2C O O Nu H H slow-reacting enantiomer O H O H synelimination

NaH, DMF, 23 C 2. Acetone, Amberlyst-15 (MeO)2(O)P CO R 2 LiO O P(OMe)2

CO2R H3C

CH3 Ph O

(Slow step may be addition or elimination)

minor product

Incapable of syn-elimination, therefore reverts O CH3 (MeO)2(O)P CO2R LiO CO2R

H3C

O CH3 O

For consideration of the stereochemical outcome of addition to -alkyloxy aldehydes, see: Lodge, E. P.; Heathcock, C. H. J. Am. Chem. Soc. 1987, 109, 3353-3361.

Rein, T.; Kann, N.; Kreuder, R.; Benoit, G.; Reiser, O. Angew. Chem., Int. Ed. Engl. 1994, 33, 556-558. Rein, T.; Reiser, O. Acta. Chem. Scand. 1996, 50, 369-379.

Auxiliary shields -face of (Z)-enolate

O CH3

O CH3 80%, 98% de

Attack occurs at either diastereomeric carbonyl from the face opposite the methyl group. Mandai, T.; Kaihara, Y.; Tsuji, J. J. Org. Chem. 1994, 59, 5847-5849.

Kent Barbay