Myers Stereoselective, Directed Aldol Reaction Chem 115

Reviews:

Heathcock, C. H. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon
Press: New York, 1991, Vol. 2, pp. 133-238.
Kim, B. M.; Williams, S. F.; Masamune, S. In Comprehensive Organic Synthesis, Trost, B. M.;
Fleming, I., Eds., Pergamon Press: New York, 1991, Vol. 2, pp. 239-275.
• Note: the enantiomeric transition states (not shown) are, by definition, of equal energies. The
pericyclic transition state determines syn/anti selectivity. To differentiate two syn or two anti
transition states, a chiral element must be introduced (e.g., R1, R2, or L), thereby creating
diastereomeric transition states which, by definition, are of different energies.

Paterson, I. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon
Press: New York, 1991, Vol. 2, pp. 301-319.

(E)-enolates R1 L
H O OH
M
O OH O O L
H3C R1 R2
2 O
H3C H H3C H OML2 R2 CH3
H
R1 FAVORED anti
CH3
• The aldol reaction was discovered by Aleksandr Porfir'evich Borodin in 1872 where he first + R1 L
observed the formation of "aldol", 3-hydroxybutanal, from acetaldehyde under the influence of R2 O OH
R2CHO M
catalysts such as hydrochloric acid or zinc chloride. O L
H3C R1 R2
O
H CH3
H
syn
DISFAVORED
Diastereofacial Selectivity in the Aldol Addition Reaction-
Zimmerman-Traxler Chair-Like Transition States

• Zimmerman and Traxler proposed that the aldol reaction with metal enolates proceeds via a
R1 L chair-like, pericyclic process. In practice, the stereochemistry can be highly metal dependent.
(Z)-enolates
H O OH
M Only a few metals, such as boron, reliably follow the indicated pathways.
O L
H R1 R2
O
R2 CH3 • (Z)- and (E)-enolates afford syn- and anti-aldol adducts, respectively, by minimizing
OML2 CH3 1,3-diaxial interactions between R1 and R2 in each chair-like TS‡.
syn
CH3 FAVORED
R1
+ R1 L
R2CHO R2 O OH
M
O L
H R1 R2 Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920-1923.
O
H CH3
CH3 Dubois, J. E.; Fellman, P. Tetrahedron Lett. 1975, 1225-1228.
anti
DISFAVORED
Heathcock, C. H.; Buse, C. T.; Kleschnick, W. A.; Pirrung, M. C.; Sohn, J. E.; Lampe, J. J.
Org. Chem. 1980, 45, 1066-1081.

M. Movassaghi
Myers Stereoselective, Directed Aldol Reaction Chem 115
Preparation of (Z)- and (E)-Boron Enolates (Z)-Selective Preparation of Boron Enolates from Evans' Acyl Oxazolidinones (Imides)

n-Bu n-Bu
O (n-Bu)2BOTf OB(n-Bu)2 PhCHO O OH
–OTf
CH3 CH3 B
Et iPr2NEt, Et2O Et –78 ºC Et Ph Bn O O O
(n-Bu)2BOTf
–78 ºC, 30 min CH3 CH3 CH3
77% N O N
CH2Cl2
>97% (Z) syn >99% O
O Bn

O (c-Hex)2BCl OB(c-Hex)2 PhCHO O OH

CH3 n-Bu n-Bu
Et Et3N, Et2O Et –78 ºC Et Ph H H
n-Bu n-Bu
–78 ºC, 10 min CH3 CH3 B O B O
75% O O
>99% (E) anti >97% O N O N
H3C H H H CH3 H
Bn Bn

FAVORED DISFAVORED

• Dialkylboron triflates typically afford (Z)-boron enolates, with little sensitivity toward the amine i-Pr2NEt i-Pr2NEt
used or the steric requirements of the alkyl groups on the boron reagent.

• In the case of dialkylboron chlorides the geometry of the product enolates is much more
sensitive to variations in the amine and the alkyl groups on boron. n-Bu n-Bu n-Bu n-Bu
B B
• The combination of (c-Hex)2BCl and Et3N provides the (E)-boron enolate preferentially. O O O O
CH3
O N O N
CH3
Bn Bn

Evans, D. A.; Vogel, E.; Nelson, J. V. J. Am. Chem. Soc. 1979, 101, 6120-6123.
• Observed selectivity > 100:1 Z : E.
Evans, D. A.; Takacs, J. M.; McGee, L. R.; Ennis, M. D.; Mathre, D. J.; Bartroli, J. Pure & Appl.
Chem. 1981, 53, 1109-1127.
Evans, D. A.; Takacs, J. M.; McGee, L. R.; Ennis, M. D.; Mathre, D. J.; Bartroli, J. Pure Appl.
Brown, H. C.; Dhar, R. K.; Bakshi, R. K.; Pandiarajan, P. K.; Singaram, B. J. Am. Chem. Soc. Chem. 1981, 53, 1109-1127.
1989, 111, 3441-3442.

M. Movassaghi
Myers Stereoselective, Directed Aldol Reaction Chem 115
Syn-Selective Aldol Reactions of Imide-Derived Boron (Z)-Enolates
• Chiral controller group biases enolate !-faces such that one of the two diastereomeric (syn)
transition states is greatly favored.
Open coordination site
required for pericyclic aldol rxn
• Dipole-dipole interactions within the imide are minimized in the reactive conformation (see:
n-Bu n-Bu
Li Noe, E. A.; Raban, M J. Am. Chem. Soc. 1975, 97, 5811-5820).
B O
O Bn OB(n-Bu)2 O
O
CH3 CH3
CH3 N O N
O N
O H3C CH3 H3C CH3
O Bn O 1. n-Bu2BOTf, i-Pr2NEt O OH
Bn
CH3 CH2Cl2, 0 °C
UNREACTIVE cf. reactive enolate in
N N R
RCHO Evans' asymmetric 2. RCHO
O A O CH3
alkylation O –78 " 23 °C O

CH3 O 1. n-Bu2BOTf, i-Pr2NEt CH3 O OH

CH3 CH2Cl2, 0 °C
Bn H Ph Ph N R
O O N
H Bn
n-Bu n-Bu O B 2. RCHO O CH3
N N –78 " 23 °C O
H O O
O H vs.
B B
O n-Bu n-Bu O
H H
O O
R R diastereomerica
CH3 CH3
imide aldehyde ratio yield (%)
FAVORED DISFAVORED A (CH3)2CHCHO 497:1 78
B (CH3)2CHCHO <1:500 91
A n-C4H9CHO 141:1 75
B n-C4H9CHO <1:500 95
n-Bu n-Bu n-Bu n-Bu
A C6H5CHO >500:1 88
B B
Bn O O Bn O O C6H5CHO <1:500 89
B
N R N R aRatio of major syn product to minor syn product.
O CH3 O CH3
O O
• A variety of chiral imides can be used for highly selective aldol reactions.

• Anti products are typically formed in less than 1% yield.

Bn O OH Bn O OH

N N • Often, a single crystallization affords diastereomerically pure product.

R R
O CH3 O CH3
O O
Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127-2129.

Evans, D. A.; Takacs, J. M.; McGee, L. R.; Ennis, M. D.; Mathre, D. J. Bartroli, J. Pure & Appl. Evans, D. A.; Gage, J. R. Org. Syn. 1990, 68, 83.
Chem. 1981, 53, 1109-1127.
M. Movassaghi
Myers Stereoselective, Directed Aldol Reaction Chem 115
Carboximide Hydrolysis with Lithium Hydroperoxide Other Methods for Removal of the Chiral Auxiliary

• Reductive cleavage:
O O
LiOOH O
O O
N R + N R Br LiAlH4, THF
or HO R H Br
O OH O N HO
LiOH
O CH3 CH2 –78 ! 0 °C CH3 CH2
A B Bn CH3
90%
substrate reagent yield of A (%)a yield of B (%)a
• Esterification:
Bn O H CH3
H LiOOH 76 16
N H3C
LiOH 0 100 CH3
O H H3C O
O OBOM OBn
CH3 O
H3C
O O CH3
CH3 O OH H H
CH3 CH3
LiOOH 98 <1 N O
Ph N Ph O
LiOH 43 30 CH3
O
O CH3 Ph BnOLi
THF, 0 °C
aYield of diastereomerically pure (>99:1) product. 77%
H3C
CH3
• LiOOH displays the greatest regioselectivity for attack of the exocyclic carbonyl group. H3C O
OBOM OBn
O
H3C
• This selectivity is most pronounced with sterically congested acyl imides. O CH3
H H
CH3 CH3
• This is a general solution for the hydrolysis of all classes of oxazolidinone-derived BnO O
carboximides and allows for efficient recovery of the chiral auxiliary.
• Transamination:

O Bn O O O OH
Al(CH3)3 O OH
CH3
N OH O N CH3O CH3
N
N3 O LiOOH N3 OBn CH3 CH3ONHCH3•HCl
H3CO H3CO CH2Cl2, 0 °C CH3 OBn CH3
O Bn CH3
O THF, H2O; O
NHBoc NHBoc
Na2SO3 92%
OBn OBn
0 °C
O O • A free "-hydroxyl group is required.
96%

• The selective hydrolysis of carboximides can be achieved in the presence of unactivated • Weinreb amides can be readily converted into ketones or aldehydes (see: Nahm, S.;
esters using LiOOH. Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-3818).

Evans, D. A.; Bender, S. L.; Morris, J. J. Am. Chem. Soc. 1988, 110, 2506-2526.
Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron Lett. 1987, 28, 6141-6144.
Gage, J. R.; Evans, D. A. Org. Syn. 1990, 68, 83-91.
M. Movassaghi
Myers Stereoselective, Directed Aldol Reaction Chem 115
H3C
Cytovaricin: CH3 O
O
O O CH3 CH3 O O DEIPSO CH3
H Ph N OBn
H3C H3C TBSO O + H
Ph Ph CH3 + H
H + N N + H OPMB H3C CH3 O
O N O O H O O
O O PMB = p-Methoxybenzyl H
O O H O 1. n-Bu2BOTf, Et3N
H3C Ph H CH2Cl2, –78 °C
n-Bu2BOTf, Et3N n-Bu2BOTf, Et3N OCH2OCH2CCl3
CH3 2. Al(CH3)3, THF
CH2Cl2, 0 °C; CH2Cl2, 0 °C;
CH3ONHCH3•HCl
RCHO, –78; RCHO 1. n-Bu2BOTf, Et3N
H2O2, 0 °C –78 ! 23 °C; CH2Cl2, –78 °C; 83%
H2O2, 0 °C RCHO O OH
92% 2. Al(CH3)3, THF
87% H3CO OBn
CH3ONHCH3•HCl N
OH O CH3 CH3 O OH CH3 CH3
H3C H3C 92%
N Ph Ph N OPMB
CH3 O O CH3 DEIPSO
O O H
H CH3
1. Al(CH3)3
OH H O t-Bu t-Bu
CH3ONHCH3•HCl H
THF, 0 °C TBSO O Si
2. TESCl, Im. DMF H O O
H3C CH3 OCH2OCH2CCl3 OBn
O N CH3
H3C CH3 CH3 91% OCH3 CH3 CH3
N
O O N CH3 O TESO
H3C CH3O
CH3 + N OPMB
CH3 CH3 CH3
LDA, Et2O,
CH3
THF, 0 °C; TESO CH3
H t-Bu
–45, 90 % O HO O
H3C OCH2OCH2CCl3 Si t-Bu
H3C CH3 CH3 DEIPSO HH O O O
N H CH3 H3C H
H3C CHO OCH3
O O H3C N O TESO H + TESO CH3
TBSO O O
H3C OTES
OPMB CH3
OPMB PhSO2
CH3 CH3 OTES
CH3
HF, H2O, CH3CN
H
25 °C H3C O
O
H3C HO H O O OH
H3C 92% H
H CH3
CH3 CH3
H3C O H
HO DEIPSO OH
H H HO
H CH3 H CH3 OH OCH3
OH
H O O H O OH O O CH3
H Cytovaricin OH
O H O CH3
PMBO H H
O OCH2OCH2CCl3
CH3 CH3 Evans, D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J. Am. Chem. Soc. 1990, 112,
DEIPS = diethylisopropylsilyl 7001-7031. M. Movassaghi
Myers Stereoselective, Directed Aldol Reaction Chem 115
Diastereoselective Syn-Aldol Reaction of !-Ketoimides Diastereoselective Anti-Aldol Reaction of !-Ketoimides

Xp 1. (c-Hex)2BCl
O O O EtN(CH3)2, Et2O O O O OH O O O OH
Sn(OTf)2 H3C O O O OH CH3 0 °C, 1 h
Et3N, CH2Cl2 L H O O N O N R + O N R
H O N
Sn R CH3 2. RCHO CH3 CH3 CH3 CH3
O
RCHO, –20 °C L O H CH3 CH3 Bn Bn Bn
–78 °C, 3h
R Bn anti-anti syn-anti
O O O CH3
anti-syn
CH3 ratio
O N
aldehyde yield %a anti-anti : syn-anti
CH3 Xp
Bn TiCl4 H3C
O O O OH (CH3)2CHCHO 78 84:16
i-Pr2NEt, CH2Cl2 H O Cl
H CH2=C(CH3)CHO 72 92:8
TI Cl O N R
RCHO O
H CH3 CH3
–78 " 0 °C O Cl CH3CH2CHO 70b 80:20
R Bn
CH3 syn-syn PhCH2CH2CHO 84b 88:12
CHO
enolization ratio Ph 84 97:3
conditions RCHOa yield %b anti-syn : syn-syn CH3
aIsolated yield of major diastereomer. bYield of
A H3C CHO 83 95:5 purified mixture of diastereomers.
B CH3 86 <1:99
• Enolization of the less hindered side of the ketone under Brown's conditions affords the
A H3C CHO 77c 95:5 (E)-boron enolate.
B 64c 2:98
CH2
• The C2 stereocenter is the dominant control element in these aldol reactions; "matched" vs.
A 71 79:21 "mismatched" effects of the remote auxiliary are negligible.
H3C CHO
O OH
B 86 <1:99
RCHO RL
Si face R
A CHO 85 89:11 CH3 CH3
B 81 4:96 O M syn-anti, predicted
H3C O H
A: Sn(OTf)2, Et3N; B: TiCl4, i-Pr2NEt. a1.0-1.1 equiv bIsolated yield of RL
CH3 +
major diastereomer (>99% purity). c3-5 equiv of RCHO was used. CH3 CH3 RL H
O OH
• Both enolization methods provide (Z)-enolates and (diastereomeric) syn aldol products. RCHO RL
Re face R
CH3 CH3
• The stereochemical outcome of both reactions is dominated by the C2 methyl-bearing
anti-anti, observed
stereocenter, as shown in the proposed transition states above.
• The sense of asymmetric induction observed in these reactions was unexpected
• The chirality of the oxazolidinone has little influence on the diastereoselectivity of these and opposite to a prediction based on a reactant-like transition state model minimizing
reactions. A(1,3) strain.

Evans, D. A.; Clark, J. S.; Metternich, R.; Novack, V. J.; Sheppard, G. S. J. Am. Chem. Soc. Evans, D. A.; Ng, H. P.; Clark, J. S.; Reiger, D. L. Tetrahedron 1992, 48, 2127-2142.
1990, 112, 866-868. M. Movassaghi
Myers Stereoselective, Directed Aldol Reaction Chem 115
Directed Reduction of !-Hydroxy Ketones
O O O O O Internal hydride delivery:
CH3 CH3 BzO CH3
O N BnO
H H OAc OH OH
CH3 CH3 CH3 O+ –
Bn B OAc
R1 O R1 R2
• In addition to !-ketoimides, the two chiral ethyl ketones above are known to undergo aldol H
R2 1,3-anti-diol
reactions at the unexpected Re face of the enolate, deilvering anti-anti aldol products. OH O
(CH3)4NBH(OAc)3 FAVORED
Paterson, I.; Goodman, J. M.; Isaka, M. Tet. Lett. 1989, 30, 7121-7124. R1 R2
Paterson, I.; Wallace, D. J.; Cowden, C. J. Synthesis 1998, 639-652.
H OAc OH OH
R2 –
R1 B OAc R1
O R2
Syn-Anti-Selective Aldol Reactions of Chiral Ethyl Ketones + H
H O 1,3-syn-diol
1. (c-Hex)2BCl DISFAVORED
TBSO O Et3N, Et2O TBSO O OH
H3C CH3 0 °C H3C CH3 • The reactivity of the reagent is attenuated such that the reduction of ketones proceeds
at convenient rates only intramolecularly, favoring formation of 1,3-anti-diols.
CH3 CH3 2. i-PrCHO CH3 CH3 CH3 CH3
–78 °C
90%, 88% de
External hydride delivery:

1. (c-Hex)2BCl
TBSO O Et3N, Et2O TBSO O OH BH4–
OH O L OH OH
H3C CH3 0 °C H3C CH3 H
Zn(BH4)2
R1 R2 R1 Zn R1 R2
2. i-PrCHO O L
CH3 CH3 CH3 CH3 CH3 CH3 O
–78 °C 1,3-syn-diol
75%, 92% de R2

• The C2 stereocenter is believed to be the dominant control element for both substrates.

• Chelated transition state, axial attack provides 1,3-syn-diol.

CH(i-Pr)OTBS
H
TBSO OB(c-Hex)2 CH3 c-Hex TBSO O OH • These directed reductions are applicable to #-hydroxy-!-ketoimides:
H3C H H3C
B R
O c-Hex
CH3 CH3 CH3 H3C CH3 CH3 CH3
O CH3 O O OH CH3 O OH OH
R NaBH(OAc)3
Ph CH3 Ph CH3
N N
O CH3 CH3 AcOH, CH3CN O CH3 CH3
• Minimization of A(1,3) interactions in the enolate biases the approach of the aldehyde to the 25 °C, 30 min
O O
methyl-bearing "-face of the enolate, while the (E)-enolate geometry affords anti-aldol products.
99%, >96% de

Evans, D. A.; Weber, A. E. J. Am. Chem. Soc. 1986, 108, 6757-6761.

Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc. 1988, 110, 3560-3578.
Jaron Mercer, M. Movassaghi
Myers Stereoselective, Directed Aldol Reaction Chem 115
Premonensin Anti-Aldols with Magnesium Enolates
O O O O O O 1. MgCl2 (10-20 mol%), O O OH
O Et3N, TMSCl
CH3 CH3 CH3 +
O N + H O N O N R
H R EtOAc, 23 ºC
CH3 CH3 CH3 CH3
Bn Sn(OTf)2 Bn 2. TFA; CH3OH Bn
N-ethylpiperidine
CH2Cl2, –78 °C aldehyde dr yield (%)

94%, 94% de
CHO X = CH3 24:1 -
O O O OH
X = OCH3 32:1 91
CH3
O N X
X = NO2 7:1 71
CH3 CH3 CH3 CH3
Bn
NaBH(OAc)3
AcOH X = Ph, Y = H 21:1 92
Y
X X = Ph, Y = CH3 28:1 92
91%, >94 de CHO
O O OH OH X = H, Y = CH3 16:1 77
CH3
O N
CH3 CH3 CH3 CH3 "-napthaldehyde 14:1 91
Bn
furfural 6:1 80

H3C CH3
• Silylation of the magnesium alkoxide in the aldol product turns over the magnesium.
NO2 O O O O O H3CO OCH3
• The aldehyde component is limited to non-enolizable aromatic and ",#-unsaturated aldehydes.
O H + H3C CH3
CH3 CH3 CH3 CH3 CH3 CH3 CH3
H3C Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am. Chem. Soc. 2002, 124, 392-393.
2, LDA, THF
1 –78 °C; 1 2

57% (+19% undesired diastereomer) • Use of the analogous N-acylthiazolidinethione chiral auxiliary affords products of the opposite
H3C CH3
anti-stereochemistry in comparable yields and with high selectivities.
NO2 O O O OH O H3CO OCH3
O CH3
S O 1. MgBr2•Et2O, (10 mol%), S O OH
CH3 CH3 CH3 CH3 CH3 CH3 CH3 O Et3N, TMSCl,
H3C CH3 +
S N S N R
h!, THF, 0 °C; H R EtOAc, 23 ºC
H2O, HCl, 25 °C CH3
Bn 2. 5:1 THF/1 N HCl Bn

O OH OH OH O 58% O
• Both reactions are proposed to proceed through boat transition states. See: Evans, D. A.;
HO CH3
Downey, W. C.; Shaw, J. T.; Tedrow, J. S. Org. Lett. 2002, 4, 1127-1130.
CH3 CH3 CH3 CH3 CH3 CH3 CH3
H3C
Premonensin
Evans, D. A.; DiMare, M. J. Am. Chem. Soc. 1986, 108, 2476-2478.
M. Movassaghi Chris Coletta, Jaron Mercer
Myers Stereoselective, Directed Aldol Reaction Chem 115
Open Transition State Aldol Reactions Synthesis of Oxazolidinethione and Thiazolidinethione Chiral Auxiliaries

• Heathcock and coworkers reported that complexation of the aldehyde with an added Lewis
acid allows access to non-Evans syn and anti aldol products via open transition states. S
Cl2CS, Et3N
O NH
Bu Bu CH2Cl2
B O 95% Bn
O O Bu2BOTf, i-Pr2NEt, O O H O O OH NH2 NaBH4, I2 NH2
CH3 CH2Cl2; CH3 HO HO
O N O N LA O N R Bn THF Bn
Lewis acid, RCHO R H O CH3 95%
S
t-Bu t-Bu t-Bu CS2, KOH
S NH
1, favored for small non-Evans syn
Lewis acids H2O
80% Bn

aldehyde Lewis acid anti:syn* yield (%)*

Crimmins, M. T; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org. Chem. 2001, 66, 894-902.
SnCl4 10:90 66
H3C CHO
TiCl4 12:88 72
Asymmetric Aldol Reactions with Titanium Enolates of N-Acylthiazolidinethiones

Ph CHO TiCl4 8:92 65

1. TiCl4 (1.1 equiv) S O OH S O OH
S O
(–)-sparteine
CH3 CH2Cl2, 0 °C S N R +
S N S N R
CH3 CH3
Bu Bu 2. RCHO, 0 °C Bn
B Bn Bn
O O Bu2BOTf, i-Pr2NEt, O O R O O OH A B
CH3 CH2Cl2; CH3
O N O N O N R
Lewis acid, RCHO H H O RCHO (–)-sparteine (equiv) yield (%) A:B
CH3
i-Pr i-Pr LA i-Pr
CH2=CHCHO 1.0 49 >99:1
2, favored for large anti
Lewis acids
i-PrCHO 1.0 60 98:2

aldehyde Lewis acid anti:syn* yield (%)* CH2=CHCHO 2.0 77 <1:99

H3C CHO Et2AlCl 88:12 81 i-PrCHO 2.0 75 3:97

• Selectivities are generally >95:5 for syn:anti products.

PhCHO Et2AlCl 74:26 62
• Both the yield and diastereoselectivities are high and synthetically useful, although they are
*Determined by 1H NMR. Yield given is the total yield of diastereomeric aldol mixture.
typically lower than the corresponding oxazolidine aldol reactions.

• Gauche interactions around the forming C-C bond dictate which face of the aldehyde reacts. For • An advantage of this method is that a single acyloxazolidinethione can provide either syn
small Lewis acids, transition state 1 is favored. For large Lewis acids, transition state 2 is aldol product by changing the amount of sparteine in the reaction mixture.
favored.

Walker, M. A.; Heathcock, C. H. J. Org. Chem. 1991, 56, 5747-5750.

Jaron Mercer, M. Movassaghi
Myers Stereoselective, Directed Aldol Reaction Chem 115
• Proposed transition states provide a rationale for the selectivity dependence on amine equivalents: Anti-Selective Aldol Reactions with Titanium Enolates of N-Glycolyloxazolidinethiones
S O
CH3 S O S O OH S O OH
S N 1. TiCl4, (–)-sparteine
TiCl4 OR O N R' +
TiCl4 O N O N R'
(–)-sparteine (1 equiv) Bn 2. TiCl4, R'CHO OR
(–)-sparteine (2 equiv) OR
RCHO Bn
RCHO Bn Bn
A B
S Bn yield (%)
S R aldehyde A : B : syn
H S H
H N Cl N
S H allyl H3CCHO 94 : 6 : 0 84
Bn TI Cl
O TiLx
HR O Cl
O
H allyl Ph CHO 65 : 24 : 11 56
O
CH3 R
CH3 CHO
allyl CH3 94 : 6 : 0 74

allyl CHO 95 : 5 : 0 58
S O OH S O OH
Bn CHO 88 : 12 : 0 64
S N R S N R CH3
CH3 CH3 CHO
Bn 74 : 26 : 0 48
Bn Bn

CH3 CHO 84 : 11 : 5 63
• The thiazolidinethione auxiliary is easily removed under mild conditions: CH3

OH O OH CH3 CHO 88 : 12 : 0 59

HO BnHN i-Pr
Ph
CH3 NaBH4 PhCH2NH2 CH3
• Complexation of the aldehyde with excess titanium occurs in situ to give anti products with high
83% 79%
selectivity.
i-Bu O OH

N • The proposed transition state is analogous to that of the anti-selective Heathcock aldol.
R
S CH3 CH3ONHCH3•HCl
DIBAL-H imidazole
69% S L4
77%
CH3OH Ti
O OH O OH S O R' R
imidazole
CH3O i-Pr O
H i-Pr 79% N O N TiL4
CH3 CH3 CH3 H H O
O OH
t-Bu
CH3O i-Pr
CH3

• The thiazolidinethione auxiliary is recovered by basic extraction (1 M NaOH) of the product Crimmins, M. T.; McDougall, P. J. Org. Lett. 2003, 5, 591-594.
mixture.

Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am. Chem. Soc. 1997, 119, 7883-7884.
Crimmins, M. T.; Chaudhary, K. Org. Lett. 2000, 2, 775-777.
M. Movassaghi, Jaron Mercer
Myers Stereoselective, Directed Aldol Reaction Chem 115
Asymmetric Synthesis of Syn-!-Hydroxy-"-Amino Acids Asymmetric Synthesis of Anti-!-Hydroxy-"-Amino Acids

• The isothiocyanate below serves as a chiral glycine equivalent. Stannous triflate-mediated aldol • 2-Chloro- and 2-Bromoacetyl imides undergo aldol addition with high diastereoselectivity.
reactions give cyclized aldol adducts in high yield and diastereoselectivity.

O O Bu2BOTf, Et3N, O O OH
O O Sn(OTf)2, O O OSnL O O R Cl Et2O;
NCS N-ethylpiperidine; O N O N R
O N O N R O N O Cl
RCHO
RCHO N HN Ph CH3 Ph CH3
C Bn
Bn Bn S S 1

O O O O OH
Bu2BOTf, Et3N,
Br
aldehyde ratio* yield (%) O N Et2O; O N R
Br
RCHO
H3CCHO 91:9 75 Bn Bn
2
PhCHO 99:1 91

H3C CHO imide aldehyde ratio* yield (%)

99:1 92
CH3 1 H3CCHO 95:5 67
CHO 94:6 1 PhCHO 97:3 79
CH3 73
CH3
1 H3C CHO 96:4 75
CHO
CH3 97:3 71 2 98:2 63
CH3
CH3
2 CHO 94:6 63
*Ratio of desired (illustrated) stereoisomer to the sum of all other stereoisomers. H3C
CH3
• The N-methyl amino acid can be reached in 4 steps. *Ratio of desired (illustrated) stereoisomer to the sum of all other stereoisomers.

H3C
O O CH3 O R
Mg(OCH3)2 • Halide displacement with NaN3 occurs with inversion of stereochemistry. Hydrolytic removal of
O N O H3CO O the auxiliary followed by hydrogenation of the azide delivers the amino acid.
HN HOCH3 HN
Bn S S OH O OH
O O 1. NaN3
2. LiOH/H2O
(H3C)3OBF4 O N CH3 HO CH3
Cl 3. H2, Pd/C, TFA NH2
O R O R Ph CH3
O OH 76%, ≥99% de
1. KOH H2O
H3CO H3CO O
HO R O
2. H3O+ N N Evans, D. A.; Sjogren, E. B.; Weber, A. E.; Conn, R. E. Tetrahedron Lett. 1987, 28, 39-42.
NHCH3 H3C H3C SCH3
O

Evans, D. A.; Weber, A. E. J. Am. Chem. Soc. 1986, 108, 6757-6761.

Jaron Mercer
Myers Stereoselective, Directed Aldol Reaction Chem 115
Vancomycin Aglycon: Direct Aldolization of Pseudoephenamine Glycinamide

O O
NCS 1. LiHMDS, LiCl, THF
O N O HO RS
O
NH2 2. O X!+ RL
Bn N
O O NH2
Sn(OTf)2, N-ethylpiperidine; OH CH3 RS RL –78 to 0 ºC
Br
O N
OHC Cl
95:5 dr
Bn O OH O OH
F
CH3 89% 72%
NO2 Bu2BOTf, Et3N; X!+ CH3 X!+ CH3
76%, 94 : 6 dr 83 : 17 dr
95:5 dr OHC NO2 NH2 CH3 NH2
F
O2N O OH O OH
Cl
F 80% 75%
X!+ X!+
O O 85 : 15 dr 83 : 17 dr
NH2 NH2 TIPS
O N O O OH
O
NO2 O HO CH3 O HO CH3
HN O N
Bn 98% CH3 82%
S Br X!+ CH3 X!+
F 98 : 2 dr 94 : 6 dr
Bn NH2 OTBDPS NH2 CH3
1. Boc2O, DMAP;
HCO2H, H2O2 1. TMGA, CH2Cl2 Isolated yields of stereoisomerically pure products. Diastereomeric ratios reported as
2. LiOOH 2. LiOOH major isomer : sum of all other diastereomers.

Cl
• Pseudoephenamine glycinamide undergoes a direct aldol addition with both aldehyde and
F O OH
ketone substrates.
NO2
O HO
O2N
O N3 • The corresponding N-Boc-protected or methyl ester hydrochloride derivatives can be prepared
F
HO2C N in two steps from the aldol products.
Boc O OH
Boc2O, NaHCO3 CH3
OH HO CH3
Cl 1:1 H2O:dioxane
O O BocHN CH3
79%
HO Cl OH
O O O
N H H O OH O OH
H N N NHCH3 NaOH CH3
N N CH3
O H H H H N NaO CH3
O O CH2CH(CH3)2 CH3 THF, CH3OH
NH O OH CH3 NH2 CH3 23 ºC NH2 CH3
HO2C 95%
NH2
O OH
OH SOCl2 CH3
OH vancomycin aglycon H3CO
BnO CH3
CH3OH
HCl• NH2 CH3
91%
Evans, D. A.; Wood, R. W.; Trotter, B. W.; Richardson, T. I.; Barrow, J. C.; Katz, J. L. Angew.
Chem. Int. Ed. 1998, 37, 2700-2704. Seiple, I. B.; Mercer, J. A. M.; Sussman, R. J.; Myers, A. G. Unpublished.
Evans, D. A.; Watson, P. S. Tet. Lett. 1996, 37, 3251-3254. Jaron Mercer
Myers Stereoselective, Directed Aldol Reaction Chem 115
Paterson Aldol Proposed Origin of Selectivity:

Reviews:
OB(–)-Ipc2
Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1. H3C
R1 + R2CHO
Franklin, A. S.; Paterson, I. Contemp. Org. Synth. 1994, 1, 317.

Syn-Aldol Adducts via Enol Diisopinocampheylborinates

O (–)-Ipc2BOTf OBIpc2 OH O
H3C i-Pr2NEt H3C R2CHO, –15 °C;
R1 R1 R2 R1
CH2Cl2,–78 °C H2O2 CH3 H3C H3C

H3C H3C
H H
H H
ketone aldehyde syn:anti ee (%) yield (%) H CH3 R1 CH3
R1 CH3 H H CH3 H
CH3 B B
O O CH3 CH3
98:2 91 78 HR2 O H3C H
O
O H3C
H3C CH3
CHO R2
CH3 H CH3 H
O CH3
96:4 66 45
H3C CH3 H3C CHO DISFAVORED FAVORED
O O CHO 96:4 80 84
H3C CH3
O
CH3
H3C CH3 95:5 88 99
CHO
CH3 OH O OH O
O CH3 CH3
97:3 86 79 R2 R1 R2 R1
H3C
CH3 CHO CH3 CH3

• Enolization occurs selectively on the less hindered side of the ketone and with (Z)-selectivity.

• Diastereofacial selectivity is believed to be due to a favored transition state wherein

• The (E)-Enolate, generated in low yield using (–)-Ipc2BCl, does not lead to a selective
steric interactions between the (–)-Ipc ligand on boron and the R1 substituent on the ketone
anti-aldol reaction.
are minimized.

• Highest enantioselectivities are obtained with unhindered aldehydes.

Paterson, I.; Goodman, J. M.; Lister, M. A.; Scumann, R. C.; McClure, C. K.; Norcross, R. D.
• Aldol additions of methyl ketones are not highly enantioselective (53–73% ee).
Tetrahedron 1990, 46, 4663-4684.

Paterson, I.; Goodman, J. M.; Lister, M. A.; Scumann, R. C.; McClure, C. K.; Norcross, R. D.
Tetrahedron 1990, 46, 4663-4684.

M. Movassaghi
Myers Stereoselective, Directed Aldol Reaction Chem 115
Anti-Aldol Reactions of Lactate-Derived Ketones • The origin of the diastereoselectivity is proposed to be due to a formyl hydrogen bond in the
favored transition state.
O 1. (c-Hex)2BCl OB(c-Hex)2 1. RCHO, 14 h O OH
BzO CH3 (CH3)2NEt BzO –78 ! –26 BzO OBL2
R BzO + RCHO
CH3 Et2O, 0 °C CH3 CH3 2. H2O2, pH 7 CH3 CH3
2h CH3OH, 0 °C CH3 CH3

L = c-Hex
aldehyde de (%) yield (%)a

CH3
94 95
H3C CHO
H3C CHO 99 82 Ph
O
H CH3 L Ph
H3C 90 97 L O
CHO O H H
H3C H vs. B O
CH3 R O
96 97 B L
L O R H3C
CHO CH3 O
O
PhCHO 99 85 H
H
aIsolated yield for 3 steps.
FAVORED DISFAVORED
• Diastereofacial selectivity is very high; "-chiral aldehydes afford anti-aldol adducts with high
diastereoselectivity regardless of their stereochemistry.

OB(c-Hex)2 O MATCHED O OH
BzO + BzO O OH O OH
H OBn OBn BzO BzO
CH3 CH3 CH3 CH3 CH3 CH3 R R
CH3 CH3 CH3 CH3
80%, >94% de

OB(c-Hex)2 O MISMATCHED O OH 1. TBSOTf

BzO + BzO 2,6-Lutidine
H OBn OBn O OH CH2Cl2, 78 °C OH OTBS 3. NaIO4 O OTBS
CH3 CH3 CH3 CH3 CH3 CH3 BzO HO
R 2. LiBH4, THF R H R
61%, 84% de CH3OH/H2O
CH3 CH3 –78 ! 20 °C CH3 CH3 CH3
• Other examples:
R = i-Pr, 74%, >99% de
O O OH R = Ph, 85%, >99% de
(c-Hex)2BCl
BzO (CH3)2NEt BzO 95%, 86% de O OTBS SmI2, THF O OTBS
CH3 i-Pr
CH3OH H3C
CH3 CH3 BzO
i-PrCHO R R
CH3
CH3 CH3 0 °C, 10 min CH3
R = i-Pr, 81%
O (c-Hex)2BCl O OH R = Ph, 96%
BzO OBn (CH3)2NEt BzO
i-Pr 77%, 98% de
CH3 i-PrCHO CH3 OBn • Paterson, I.; Wallace, D. J.; Cowden, C. J. Synthesis 1998, 639-652.
M. Movassaghi
Myers Stereoselective, Directed Aldol Reaction Chem 115
Oleandolide: CH3 Acetate Aldol
OBn Addition of a Chiral !-Sulphinylester Enolate to Aldehydes
H3C
O
(c-Hex)2BCl (+)-(Ipc)2BOTf
CH3
Et3N, Et2O, –78 °C; i-Pr2NEt, CH2Cl2, 20 °C;
(E)-CH3CH=CHCHO, 0 °C CH2=CHCHO, 0 °C O CH3CO2t-Bu O O
S S
93%, 94% de 74%, 80% de Ar O Ar Ot-Bu
i-Pr2NMgBr
H3C CH3 t-BuMgBr
CH3 CH3 CH3 CH3 CH3 THF, –78 °C;
H3C OBn OBn Ar = 4-CH3C6H4 RCHO
H2C
OH O OH O
OH O Al, Hg OH O

R Ot-Bu R Ot-Bu
SOAr
SOPh
CH3 CH3
CH3 O O H3C • The "-hydroxy ester products are isolated in 50-85% yield and 80-91% ee.
O + O
PMBO CH3
CH3 CH3 H BnO O
CH3
CH3 Proposed Transition State

CH3

CH3 O O L
O
HO
Mg O
CH3 CH3 CH3
O
O
H3C
O O S Ot-Bu
Ar
CH3 R
HO O H
CH3
CH3 H

O • Approach of the aldehyde is proposed to occur from the side of the non-bonding
O
H3C electron pair of the sulfur atom with the R-group of the aldehyde anti to the sulfinyl
H3C CH3 substituent. A chelated enolate is proposed.
OH
H3C
H3C O OH
Mioskowski, C.; Solladie, G. J. Chem. Soc., Chem. Commun. 1977, 162-163.
O OH
oleandolide
CH3

Paterson, I.; Norcross, R. D.; Ward, R. A.; Romea, P.; Lister, M. A. J. Am. Chem. Soc. 1994, 116,
11287-11314. M. Movassaghi
Myers Stereoselective, Directed Aldol Reaction Chem 115
Addition of a Chiral Acetate Enolate to Aldehydes An Approach to the Acetate Aldol Problem
H3C CH3 H3C CH3
Ph Ph
HO HO O 1. n-Bu2BOTf, i-Pr2NEt O OH
H CO2CH3 PhMgBr Ph AcCl O Ph
SCH3 CH2Cl2, 0 °C
HO Ph H H N N R
77% HO Pyridine H3C O Ph
Ph O 2. PhCHO O SCH3
(R)-mandelic acid 82% O –78 ! 23 °C O
LDA; MgX2 3. Ra-Ni, 60 °C
THF, (CH3)2O acetone
86-99% de
4. 2N KOH
CH3OH, 0 °C
Ph Ph
NaOH HO MO O OH
OH O OH O Ph RCHO MO Ph
H –135 °C H • A temporary substituent is used to afford acetate HO R
R OH R O Ph H2C O Ph aldol products selectively. Simple N-acetyl imides
do not react selectively. R = Ph, CH3,
76-85% (2 steps) M = Li, MgX n-C3H7, i-C3H7
84-96% ee
80-90% (4 steps)
86-99% ee

• Both (R)- and (S)-mandelic acids are commercially available. Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127-2129.

An Enantioselective Mukaiyama Aldol Reaction Catalyzed by a Tryptophan-Derived

Oxazaborolidine
CH3 Ph CH3 O
H3C HO H3C H
O O Ph O O
O Ph MATCHED O OH N B
CHO + H3C O n-Bu
H
>94% de Ts
OH O
N 3
H
Ph
CH3 HO 3 (20 mol%), 14 h
O Ph CH3 O OSi(CH3)3 OH O
H3C H3C C2H5CN, – 78 °C;
O H O +
O + H3C O Ph MISMATCHED O R1 H R2 R1 R2
CHO OH 1N HCl/THF
40% de
OH O R1 R2 yield (%) ee (%)

Ph C6H5 82 89
• Low diastereoselectivities are obtained with mismatched chiral aldehydes.
c-C6H11 C6H5 67 93
• A mechanistic rationale has not been proposed.
2-furyl C6H5 100 92

c-C6H11 n-C4H9 56 86
Braun, M. Angew. Chem., Int. Ed. Engl. 1987, 26, 24-37.
• The Lewis-acid catalyzed addition of silyl enol ethers to aldehydes is known as the Mukaiyama
Aldol reaction: Kobayashi, S.; Uchiro, H.; Shina, I.; Mukaiyama, T. Tetrahedron 1993, 49,
1761-1772.
M. Movassaghi
Myers Stereoselective, Directed Aldol Reaction Chem 115
• Use of terminal trimethylsilyl enol ethers provide the highest level of enantioselectivities. Catalytic, Enantioselective Acetate Aldol Additions with Silyl Ketene Acetals

CH3 Review: Carreira, E. M.; Singer, R. A. Drug Discovery Today 1996, 1, 145-150.
CH3
Nu

O B t-Bu
H
O N S
O
R O O N
HN H
O Br
O Ti
O
O O

• A transition state is proposed in which the si face of the aldehyde is blocked by the indole ring. t-Bu

(–)-1 t-Bu
Corey, E. J.; Cywin, C. L; Roper, T. D. Tetrahedron Lett. 1992, 33, 6907-6910.

Catalytic, Enantioselective Mukaiyama Aldol Condensation of Silyl Thioketene Acetals O OSi(CH3)3 1. (–)-1 (0.5-5 mol %); OH O
Et2O, 4 h, –10 °C
R1 H + OR2 R1 OR2
1. (S)-BINOL, Ti(Oi-Pr)4 2. Bu4NF, THF
(20 mol%), 4Å-MS
O OSi(CH3)3 Et2O, –20 °C OH O
+
R H St-Bu 2. Silyl thioketene acetal R St-Bu
3. 10% HCl, CH3OH Aldehyde %ee: R2 = Et %ee: R2 = CH3 %ee: R2 = Bn

CHO 92 97 -
CH3

CHO 88 95 -
aldehyde yield (%) ee (%) CH3

PhCHO 90 97 CHO 93 97 96
Ph
PhCH2CH2CHO 80 97
CHO 89 94 91
furylCHO 88 >98 Ph
CHO
c-C6H11CHO 70 89
94 95 -
PhCH2OCH2CHO 82 >98
CHO
93 96 96

• This reaction is highly sensitive to the solvent and to reactant concentrations. Yields for two steps (addition and desilylation) range from 72-98%.

Keck, G. E.; Krishnamurthy, D. J. Am. Chem. Soc. 1995, 117, 2363-2364.

M. Movassaghi
Myers Stereoselective, Directed Aldol Reaction Chem 115
Catalytic, Enantioselective Aldol Additions of an Acetone Enolate Equivalent

• Catalyst 1 is formed by condensation of the chiral amino alcohol with 3-bromo-5-tert- t-Bu
butylsalicylaldehyde followed by complexation with Ti(Oi-Pr)4 and 3,5-di-tert-butylsalicylic
acid. Both enantiomeric forms are available.
N
• Complete removal of i-PrOH during catalyst preparation is key to achieving high yields O Br
and selectivities. This may be done by azeotropic removal of i-PrOH with toluene or by O Ti
Oi-Pr
its silylation in an in situ catalyst preparation (TMSCl, Et3N). Oi-Pr
(–)-2
• The reaction can be carried out in a variety of solvents, such as toluene, benzene,
chloroform, diethyl ether, and tert-butyl methyl ether.

• Alkenyl and alkynyl aldehydes are particularly good substrates for this catalytic
process. O OCH3 1. (–)-2 (2-10 mol %); OH O
0 ! 23 °C
R H + CH3 R CH3
2. Et2O, 2N HCl

O OSi(CH3)3 1. (–)-1 (3 mol %) OH O

Et2O, 0 °C
R H + OCH3 R OCH3
2. n-Bu4NF aldehdye temp. (°C) yield %ee

Ph(CH2)3 CHO 0 99 98

TBSOCH2 CHO 0 85 93

aldehyde yield (%) %ee Ph CHO 0 99 91

CHO 0 ! 23 98 90
TBSOCH2 CHO 88 96 Ph
PhCHO 0 ! 23 83 66
Ph CHO 96 94
c-C6H11CHO 0 ! 23 79 75

TIPS CHO 88 97

TBSO
• 2-methoxypropene is used as the reaction solvent.
H3C CHO 88 96
H3C
• Unhindered aldehydes afford products with the highest enantioselectivities.

• 2,6-di-tert-butyl-4-methylpyridine (0.4 equiv) is used in the reaction to prevent decomposition

of the product by adventitious acid.
Carreira, E. M.; Singer, R. A.; Lee, W. J. Am. Chem. Soc. 1994, 116, 8837-8838.
Singer, R. A.; Carreira, E. M. Tetrahedron Lett. 1997, 38, 927-930.
Singer, R. A.; Shepard, M. S.; Carreira, E. M. Tetrahedron 1998, 54, 7025-7032. Carreira, E. M; Lee, W.; Singer, R. A. J. Am. Chem. Soc. 1995, 117, 3649-3650.

M. Movassaghi
Myers Stereoselective, Directed Aldol Reaction Chem 115
• The vinyl ether products can be isolated, or transformed into other useful products: • The silyl dienolate is easily prepared, purified by distillation, and is stable to storage.
• The absolute sense of induction parallels that of acetate-derived silyl enol ether and
O3, CH2Cl2; OH O
2-methoxypropene addition reactions.
Ph3P
Ph OCH3 • The protected acetoacetate adducts are versatile precursors for the preparation of optically
active !-hydroxy-"-keto esters, amides, and lactones.
OH OCH3

Ph CH2 OH O O
LiAl(NHBn)4 X = NHBn, 73%
84% isolated yield OsO4, NMO OH O H3C CH3 Ph X X = On-Bu, 81%
acetone, H2O OH or
Ph OH O O O
n-BuOH
Ph O O
Carreira, E. M; Lee, W.; Singer, R. A. J. Am. Chem. Soc. 1995, 117, 3649-3650. K2CO3, Zn(NO3)2
Ph O
CH3OH
Catalytic, Enantioselective Dienolate Additions to Aldehydes
79%
t-Bu

Singer, R. A.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 12360-12361.

N
O Br Catalytic, Enantioselective Dienolate Additions to Aldehydes Using a Nucleophilic Catalyst.
O Ti
O
O O
H3C CH3 H3C CH3
(S)-Tol-BINAP•CuF2
t-Bu O O O (2 mol %) OH O O
(–)-1 t-Bu R H + OSi(CH3)3 THF, –78 °C; R O
acidic work-up
1. (–)-1 (1-3 mol %)
H3C CH3 H3C CH3
2,6-lutidine
O O O (0.4 equiv) OH O O
Et2O, 0 °C, 4 h aldehyde yield (%) %ee
R H + OSi(CH3)3 R O
2. 10% TFA, THF PhCHO 92 94

yield (%) %ee CHO 98 95

aldehyde S
CHO
TIPS CHO 86 91 82 90
OCH3
TBSO CHO 97 94
CHO 48 91
Ph
CHO 88 92
CH3 CH3
CHO 81 83
CHO 79 92 Ph
n-Bu3Sn
CHO
CHO 97 80 Ph 74 65
Ph
CH3
PhCHO 83 84 (96)a
aafter recrystallization. M. Movassaghi
Myers Stereoselective, Directed Aldol Reaction Chem 115
• (S)-Tol-BINAP-CuF2 is readily prepared in situ by mixing (S)-Tol-BINAP, Cu(OTf)2, and Catalytic, Enantioselective Aldol Additions of Silyl Thioketene Acetals and Silyl Enol Ethers
(n-Bu4N)Ph3SiF2 in THF.
• This process is efficient for non-enolizable (!,"-unsaturated, aromatic, and heteroaromatic)
aldehydes. 2+ H3C CH3 2+
–
• Enolizable, aliphatic aldehydes give products with high enantioselectivity, but in poor yield O N O 2 SbF6 O O
2 TfO–
(<40%). N Cu N N N
• Spectroscopic evidence supports a catalytic process involving a chiral transition metal Cu
Ph Ph C(CH3)3 C(CH3)3
dienolate as an intermediate.
1 2

Krüger, J.; Carreira, E. M. J. Am. Chem. Soc. 1998, 120, 837-838.

Pagenkopt, B. L.; Krüger, J.; Stojanovic, A.; Carreira, E. M. Angew. Chem., Int. Engl. Ed.
1998, 37, 3124-3126.
1. 1 (10 mol%)
O OTMS CH2Cl2, –78 °C OH O
BnO + BnO
Enantioselective Acetate Aldol Addition Using a Chiral Controller Group H SR2 SR2
2. 1 N HCl, THF
R1 R1

H3C CH3
Ph Ph
enol silane
R1 R2 geometry time (h) T (°C) syn:anti %ee yield (%)
S N B N S
O O O
Br O –
H t-Bu 24 –78 – 99 99
3
CH3 Et (Z) 4 –78 97:3 97 90

BX2 CH3 Et (E) 1d –50 86:14 85 48

O 3 O OH O
RCHO
SPh R SPh i-Bu Et (Z) 2d –50 95:5 95 85
H3C SPh
CH2Cl2 –90 °C, 2h
Et3N
–78 # 23 °C

2+
aldehdye yield (%) ee (%) O
N N H
C6H5CHO 84 91 Cu
O N O Ph
i-PrCHO 82 83 Ph
O H
Bn
H
• Bromide 3 is produced from the corresponding (R,R)-bissulfonamide by reaction with
BBr3 in CH2Cl2. Nu (si face)

• Upon completion of the reaction, the (R,R)-bis-sulfonamide can be recovered and reused.

Corey, E. J.; Imwinkelried, R.; Pikul, S.; Xiang, Y. B. J. Am. Chem. Soc. 1989, 111, 5493-5495. Evans, D. A.; Kozlowski, M. C.; Murry, J. A.; Burgey, C.; Campos, K. R.; Connell, B. T.; Staples, R.
J. J. Am. Chem. Soc. 1999, 121, 669-685.
M. Movassaghi
Myers Stereoselective, Directed Aldol Reaction Chem 115
Proline-Catalyzed Asymmetric Aldol Reaction of Acetone
O
1. 1 (2 mol%) H
O TMSO OTMS OH O O
CH2Cl2, –78 °C OH
BnO BnO
H + Ot-Bu Ot-Bu NH (30 mol%)
2. PPTS, CH3OH O O O OH
+
85%, 99% ee H3C CH3 H R DMSO H3C R

aldehyde yield %ee

Evans, D. A.; Kozlowski, M. C.; Murry, J. A.; Burgey, C.; Campos, K. R.; Connell, B. T.; Staples, R. 68 (60) 76 (86)
p-NO2C6H4CHO
J. J. Am. Chem. Soc. 1999, 121, 669-685.
C6H5CHO 62 (60) 60 (89)
p-BrC6H4CHO 74 (85) 65 (67)
o-CCl6H4CHO 94 (71) 69 (74)
2 (10 mol%)
O OTMS THF H3C OH O !-napthaldehyde 54 (60) 77 (88)
H3CO + H3CO 97 (65) 96 (96)
CH3 St-Bu St-Bu i-PrCHO
–78 °C
O R O R c-C6H11CHO 63 (45) 84 (83) H3C CH3 O
1 N HCl
t-BuCHO 81 >99 S OH
R = H, CH3, Et, i-Bu H
85 >99 NH
77-97% CHO
≥96% ee DMTC
H3C CH3
≥94:6 syn:anti
• Typically a 20–30 equivalent excess of acetone is used in relation to the aldehyde.
• Based on structural data acquired with catalyst 1, a bidentate coordination of methyl
pyruvate to the copper complex 2 has been proposed. • Tertiary and !-branched aldehydes result in the highest yields and enantioselectivities, while
unbranched aliphatic aldehydes give poor yields and enantioselectivities.
Evans, D. A.; Kozlowski, M. C.; Burgey, C. S.; MacMillan, D. W. C. J. Am. Chem. Soc. 1997,
119, 7893-7894. • 5,5-Dimethyl thiazolidinium-4-carboxylate (DMTC) has also been found to be an efficient
amino acid catalyst for the acetone aldol reaction. Results with DMTC are in parentheses.

List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122, 2395-2396.
O OTMS 1 (10 mol%) H3C OH O
CH2Cl2
H3CO + H3CO Kandasamy, S.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am. Chem. Soc. 2001, 123, 5260-5267.
CH3 St-Bu St-Bu
O R –78 °C O R
Proposed transition state:
R = CH3, Et, i-Bu O
81-94% H
≥96% ee OH
O O NH N O OH
≥98:2 anti:syn R H
+ O
H3C CH3 H R H O H3C R
H H3C O
Evans, D. A.; MacMillan, D. W. C.; Campos, K. R. J. Am. Chem. Soc. 1997, 119, 10859-
10860.
Rankin, K. N.; Gauld, J. W.; Boyd, R. J. J. Phys. Chem. A. 2002, 106, 5155-5159.
Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325-335.
Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List, B. J. Am. Chem. Soc. 2003, 125, 2475-2479.
For a discussion on the involvement of oxazolidinones in the mechanism, see: Seebach, D.; Beck,
A. K.; Badine, M.; Limbach, M.; Eschenmoser, A.; Treasurywala, A. M.; Hobi, R.; Prikoszovich, W.;
Linder, B. Helv. Chim. Acta 2007, 90, 425–471.
M. Movassaghi, Chris Coletta
Myers Stereoselective, Directed Aldol Reaction Chem 115
Proline-Catalyzed Asymmetric Aldol Reaction of Hydroxyacetone Proline-Catalyzed Asymmetric Aldol Reaction of Acetonide Protected Dihydroxyacetone
O O O OH
H
O 30 mol% proline
OH R
+
O NH (30 mol%) O OH O O H R DMF, 2 ºC O O
O
+
H3C CH3 H3C CH3
H3C H R DMSO H3C R
OH OH
aldehyde catalyst yield anti/syn %ee
aldehyde yield (%) anti:syn %ee
i-PrCHO (S)-proline 97 >98:2 94
c-C6H11CHO 60 >20:1 >99 (S)-proline 86 >98:2 90
c-C6H11CHO
i-PrCHO 62 >20:1 >99 (S)-proline 40 >98:2 97
BnOCH2CHO
o-ClC6H4CHO 95 1.5:1 67 (CH3O)2CHCHO (S)-proline 69 94:6 93
t-BuCH2CHO 38 1.7:1 >97
CHO
O (R)-proline 76 >98:2 >98
CHO O
O 40 2:1 >97 H3C
O CH3
H3C
CH3 CHO
O (S)-proline 80 >98:2 >96
Ph CHO NBoc (R)-proline 31 >96
51 >20:1 >95 H3C
CH3
CH3
CHO
O
NCbz (S)-proline 80 >98:2 >96
• The anti-diol product formed is not readily accessible via asymmetric dihydroxylation, making
this reaction complementary to the Sharpless asymmetric dihydroxylation. H3C
CH3
• The reaction is highly regioselective, and with suitable substrates (!-branched aliphatic
aldehydes) the anti:syn ratio (dr) and enantioselectivity are excellent. In the case of !-
unbranched aldehydes and aromatic aldehydes, the poor anti:syn selectivity is thought to result • The use of linear aldehydes in this reaction leads to poor yields, likely due to self
from a decrease in an eclipsing interaction between the alcohol and the aldehyde in the condensation.
disfavored boat transition state shown below.

Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386-7387. • Aromatic aldehydes form products with low diastereoselectivity (e.g., a 4:1 anti:syn ratio was
reported for ortho-chlorobenzaldehyde).
Proposed origin of selectivity:
• With the !-chiral !-aminoaldehyde shown above, the mismatched case results in a poor
H O OH yield,
O R HO N H
O O H3C R but excellent dr and ee.
H H O
H3C H H3C O OH
OH • Certain hexoses have been synthesized by this method.
OH NH FAVORED
+ O OH
Dowex, H2O O OH HO OH
O H O O
H O OH
O O O HO CH2OH CH2OH
H R HO N H CH3
R H3C R OH OH D-psicose OH OH
O H O H3C CH3 H3C
H3C OH
O
eclipsing DISFAVORED Enders, D.; Grondal, C. Angew. Chem. Int. Ed. 2005, 44, 1210-1212.
interaction Chris Coletta
Myers Stereoselective, Directed Aldol Reaction Chem 115
Proline-Catalyzed Enantioselective Cross-Aldol Reaction of Aldehydes • The aldol products from !-oxyaldehydes can be further elaborated as part of a two-step
synthesis of carbohydrates.
O O 10 mol% L-proline O OH
+ O O OH
H H R2 H R2 10 mol% L-proline
DMF, 4 ºC
R1 R1 H H OAc
DMSO
TIPSO 92%, 4:1 (anti:syn) TIPSO OTIPS TMSO
R1 R2 yield (%) anti:syn %ee
95% ee
Me Et 80 4:1 99
MgBr2•Et2O MgBr2•Et2O TiCL4
Me i-Bu 88 3:1 97 Et2O CH2Cl2 CH2Cl2
–20 4 ºC –20 4 ºC –20 4 ºC
Me c-C6H11 87 14:1 99

Me Ph 81 3:1 99 O OH O OH O OH
TIPSO TIPSO TIPSO
Me i-Pr 82 24:1 >99 TIPSO OAc TIPSO OAc TIPSO OAc
n-Bu i-Pr 80 24:1 98 OH OH OH
Glucose Mannose Allose
Bn i-Pr 76 19:1 91
79% yield 87% yield 97% yield
10:1 dr, 95% ee >19:1 dr, 95% ee >19:1 dr, 95% ee
• Slow addition via syringe pump of the donor aldehyde to a solution of the acceptor aldehyde
and proline is required in order to avoid dimerization of the donor aldehyde. Northrup, A. B.; MacMillan, D. W.C. Science 2004, 305, 1752-1755.
Littoralisone: TBDPSO
• Either non-enolizable aldehydes or aldehydes containg !- or "-branching are suitable O
O O OH
acceptor aldehydes for this reaction. D-proline
OBn H
H H
98% ee O
Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798-6799. OBn 78% OBn H3C
H
Proline-Catalyzed Direct and Enantioselective Aldol Reaction of !-Oxyaldehydes OR MgBr2•Et2O L-proline,
intramolecular
TMSO 65%, 10:1 dr DMSO
O OH Michael reaction
O 10 mol% L-proline 98% ee O 91%
OR HO
OR H O O H
H solvent, rt, 24–48h OH H
OR
O OBn +
HO O O
OBn O
R solvent yield (%) anti:syn %ee BnO H3C H
H3C H OH
OAc
Bn DMF 73 4:1 98
BnO
PMB DMF 64 4:1 97 OH

MOM DMF 42 4:1 96 h# = 350 nm;

O O
9:1 O H2, Pd/C O
TBDPS DMF/dioxane 61 96 H H H
O OBn 84% O OH
TIPS DMSO 92 4:1 95 OBn OH
O O O OBn O O O OH
TBS dioxane 62 4:1 88 H O H O
H3C H3C
littoralisone
Northrup, A. B.; Mangion, I. K.; Hettche, F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124,
Mangion, I. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 3696-3697.
6798-6799.
Chris Coletta, Jaron Mercer
Myers Stereoselective, Directed Aldol Reaction Chem 115
Catalytic, Enantioselective Thioester Aldol Reactions • The thioester group of the aldol products can be transformed by Pd-catalyzed cross coupling
to give ketones.
H3C CH3
OH
O O
O O OH O CH3
N N
+ O O CH3
Ph Ph H3C PhS
4 OH
1 CH3 O

O O O Cu(OTf)2 (10 mol%),

O OH Pd(dppf)Cl2, trifurylphosphine
1 (13 mol%)
+ Cu(I), i-Pr2NEt
PhS OH H R PhS R
9:1 PhCH3:acetone
CH3 CH3 DMF, 50 ºC, 6 h
23 ºC, 0.17 M, 24 h
76%

aldehyde yield (%) syn:anti %ee OH

O OH O CH3
CH3(CH2)6CHO 80 9:1 92 (R)
O CH3
O
H3C 4 OH
CH3O2C(CH3)4CHO 83 10:1 94 CH3 O
O
HO CHO
83 9:1 93 (S)
O2N
OH Magdziak, D.; Lalic, G.; Lee, H. M.; Fortner, K. C.; Aloise, A. D.; Shair, M. D. J. Am. Chem. Soc.
CHO 79 8:1 91 2005, 127, 7284-3695.
H3C
8
• A recent example of proline-catalyzed aldol reaction in the synthesis of prostaglandin PGF2":
CH3(CH2)5 CHO 59 2.2:1 96 (S)
OH OCH3
H3C H
amberlyst 15
73 7.5:1 89 O (S)-proline; O O
O MeOH, MgSO4
H3C CHO H H H H
H [Bn2NH2][OCOCF3] 14% (two steps)
c-C6H11CHO 48 (71a) 36:1 93 (109.5 g) 99% ee
O H O H O
OH H N
HO H (15.0 g)
O(CH2)4CHO H O
O H O
O 70 5.5:1 92 H O 4 steps
O
O
H3C HO
CH3 atwo equiv of aldehyde was used. CO2H

• This method is compatible with aldehyde substrates containing unprotected hydroxyl groups, CH3
including phenols. (1.9 g) HO
HO

• Aromatic aldehydes and !-branched aldehydes are generally poor substrates.

Coulthard, G; Erb, W.; Aggarwal, V. K. Nature 2012, 489, 278-281.
Chris Coletta, Fan Liu