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Myers Stereoselective, Directed Chem 115

Reviews:

Heathcock, C. H. In Comprehensive , Trost, B. M.; Fleming, I., Eds., Pergamon • Note: the enantiomeric transition states (not shown) are, by definition, of equal energies. The Press: New York, 1991, Vol. 2, pp. 133-238. 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 Kim, B. M.; Williams, S. F.; Masamune, S. In Comprehensive Organic Synthesis, Trost, B. M.; diastereomeric transition states which, by definition, are of different energies. Fleming, I., Eds., Pergamon Press: New York, 1991, Vol. 2, pp. 239-275.

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

L (E)- R1 H O OH M O OH O O L H C R R 2 3 O 1 2 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 L + R1 observed the formation of "aldol", 3-hydroxybutanal, from under the influence of R2 O OH M catalysts such as hydrochloric or zinc chloride. R2CHO O L H C R1 R 3 O 2 H CH3 H syn DISFAVORED Diastereofacial Selectivity in the Aldol - Zimmerman-Traxler Chair-Like Transition States

• Zimmerman and Traxler proposed that the aldol reaction with metal enolates proceeds via a L (Z)-enolates R1 chair-like, pericyclic process. In practice, the can be highly metal dependent. H O OH M Only a few metals, such as , reliably follow the indicated pathways. O L H R R O 1 2 • (Z)- and (E)-enolates afford syn- and anti-aldol adducts, respectively, by minimizing R2 CH3 ‡ OML2 CH3 1,3-diaxial interactions between R1 and R2 in each chair-like TS . syn CH3 FAVORED R1 + L R1 R CHO R2 O OH 2 M O L H Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920-1923. O R1 R2 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 ()

n-Bu n-Bu O (n-Bu) BOTf OB(n-Bu)2 PhCHO O OH 2 –OTf CH CH B 3 3 Bn O O O Et iPr2NEt, Et2O Et –78 ºC Et Ph (n-Bu)2BOTf –78 ºC, 30 min CH CH3 CH3 77% 3 N O N CH Cl >97% (Z) syn >99% O 2 2 O Bn

O (c-Hex)2BCl OB(c-Hex)2 PhCHO O OH n-Bu n-Bu CH3 Et Et3N, Et2O Et –78 ºC Et Ph n-Bu H n-Bu H –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 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 O O O O • The combination of (c-Hex)2BCl and Et3N provides the (E)-boron preferentially. CH O N 3 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 -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 O O Bn OB(n-Bu)2 CH CH CH3 O N 3 O N 3 N O H3C CH3 H3C CH3 Bn O 1. n-Bu BOTf, i-Pr NEt O OH Bn O 2 2 CH Cl , 0 °C cf. reactive enolate in CH3 2 2 UNREACTIVE N N R Evans' asymmetric RCHO O A 2. RCHO O CH3 O –78 " 23 °C O

CH3 O 1. n-Bu2BOTf, i-Pr2NEt CH3 O OH CH Cl , 0 °C Bn H Ph CH3 2 2 Ph O O N N R Bn H O 2. RCHO O CH n-Bu n-Bu N B 3 N O –78 " 23 °C O O H vs. H O B B O n-Bu n-Bu O H H O O R R diastereomerica CH CH3 3 imide 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 C H CHO >500:1 88 B B A 6 5 Bn O O Bn O O B C6H5CHO <1:500 89

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 • Often, a single affords diastereomerically pure product. N R N 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 Hydroperoxide Other Methods for Removal of the

• Reductive cleavage: O O O LiOOH O O N R + N R HO R Br LiAlH4, THF Br or H O N O LiOH OH HO O CH3 CH2 –78 ! 0 °C A B CH3 CH2 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 OBOMOBn CH3 O H3C O O CH CH H H 3 3 O OH CH CH LiOOH 98 <1 N O 3 3 Ph N Ph O LiOH 43 30 O CH3 O CH3 Ph BnOLi THF, 0 °C a Yield of diastereomerically pure (>99:1) product. 77% H3C CH • LiOOH displays the greatest for attack of the exocyclic . H C O 3 3 OBOMOBn O H3C • This selectivity is most pronounced with sterically congested acyl imides. O CH H H 3 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:

Bn O OH O O O O OH Al(CH3)3 CH3 OH O N CH3O CH3 N N N CH ONHCH •HCl N3 O LiOOH 3 OBn CH3 3 3 H CO H3CO CH Cl , 0 °C CH3 OBn CH3 3 O Bn CH3 2 2 O THF, H O; O NHBoc 2 NHBoc Na SO 92% 2 3 OBn OBn 0 °C O O 96% • A free "-hydroxyl group is required.

• The selective hydrolysis of carboximides can be achieved in the presence of unactivated • Weinreb can be readily converted into or (see: Nahm, S.; 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

H C Cytovaricin: 3 CH O 3 O CH CH O O 3 3 O O DEIPSO Ph CH3 TBSO O H N + OBn H C H C CH + H 3 + 3 N Ph Ph 3 + H H CH H N OPMB H3C 3 O O N O O H O O O PMB = p-Methoxybenzyl H O O O H O 1. n-Bu2BOTf, Et3N H C Ph H CH Cl , –78 °C n-Bu BOTf, Et N n-Bu BOTf, Et N 3 2 2 2 3 2 3 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 H C 92% H3C Ph Ph 3 N N OPMB O O CH3 CH3 DEIPSO O O H H 1. Al(CH ) CH3 3 3 OH H O t-Bu t-Bu CH3ONHCH3•HCl H THF, 0 °C TBSO O Si 2. TESCl, Im. DMF H O O H C CH OCH OCH CCl 3 O N 3 CH 2 2 3 OBn CH 3 H3C CH3 3 91% OCH3 N CH3 CH3 O O N CH3 O TESO H3C CH3O CH3 + N OPMB CH3 CH3 CH3 LDA, Et2O, CH3 THF, 0 °C; TESO CH H 3 t-Bu –45, 90 % O HO O H3C Si t-Bu OCH2OCH2CCl3 CH H3C CH3 3 DEIPSO HH O O O N H CH3 H3C H H3C CHO OCH3 O O H3C N O TESO H + TESO CH TBSO O O 3 H3C OTES OPMB OPMB CH3 PhSO2 CH3 CH3 OTES CH3 HF, H O, CH CN 2 3 H 25 °C O H3C O HO H OH H C 92% H3C O O 3 H H CH CH CH 3 O H 3 3 HO DEIPSO H3C OH H H HO H H CH3 CH3 OH OH OCH3 H O O H O OHO O CH3 H Cytovaricin OH O O CH3 PMBO H 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

1. (c-Hex) BCl Xp 2 O O O EtN(CH ) Et O O O O OH O O O OH Sn(OTf) H3C O O O OH 3 2, 2 2 CH 0 °C, 1 h Et N, CH Cl L H O O N 3 O N R + O N R 3 2 2 H Sn O N R O CH3 2. RCHO CH3 CH3 CH3 CH3 RCHO, –20 °C CH CH Bn Bn Bn L O H 3 3 –78 °C, 3h R Bn anti-anti syn-anti O O O CH 3 anti-syn CH O N 3 ratio aldehyde yield %a anti-anti : syn-anti CH3 Xp Bn H3C TiCl4 O O O OH (CH3)2CHCHO 78 84:16 i-Pr NEt, CH Cl H O Cl 2 2 2 H TI Cl O N CH2=C(CH3)CHO 72 92:8 O R RCHO H CH CH O Cl 3 3 CH CH CHO 70b 80:20 –78 " 0 °C R Bn 3 2 CH3 b syn-syn PhCH2CH2CHO 84 88:12 CHO enolization ratio Ph 84 97:3 conditions a b anti-syn : syn-syn RCHO yield % CH3 aIsolated yield of major . bYield of H C CHO A 3 83 95:5 purified mixture of .

B CH3 86 <1:99 • Enolization of the less hindered side of the under Brown's conditions affords the c A H3C CHO 77 95:5 (E)-boron enolate.

64c 2:98 B CH2 • The C2 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 R Si face L R A CHO 85 89:11 CH3 CH3 B 81 4:96 O M syn-anti, predicted H C O H a b RL 3 A: Sn(OTf)2, Et3N; B: TiCl4, i-Pr2NEt. 1.0-1.1 equiv Isolated yield of + c CH3 major diastereomer (>99% purity). 3-5 equiv of RCHO was used. CH CH R H 3 3 L 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 observed in these reactions was unexpected • The 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 CH BzO CH O N BnO 3 3 H OAc CH3 H OH OH CH3 CH3 O + – Bn B R1 O OAc 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 R Paterson, I.; Goodman, J. M.; Isaka, M. Tet. Lett. 1989, 30, 7121-7124. 1 R2 Paterson, I.; Wallace, D. J.; Cowden, C. J. Synthesis 1998, 639-652. H OAc OH OH R2 – R B OAc 1 O R1 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 0 °C H3C CH3 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 0 °C OH O H L OH OH H3C CH3 H3C CH3 Zn(BH4)2 R R Zn R R 2. i-PrCHO 1 R2 1 O L 1 2 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: H C H H C 3 B 3 R O c-Hex CH3 CH3 CH3 H3C CH3 CH3 CH3 O CH3 O O OH CH3 O OH OH NaBH(OAc) R CH 3 CH Ph N 3 Ph N 3 AcOH, CH3CN • Minimization of A interactions in the enolate biases the approach of the aldehyde to the O CH3 CH3 O CH3 CH3 (1,3) O 25 °C, 30 min 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 Enolates O O O O O O 1. MgCl (10-20 mol%), O O OH O 2 CH CH CH Et3N, TMSCl O N 3 + H 3 O N 3 + O N R H R EtOAc, 23 ºC CH3 CH3 CH3 CH3 Bn Bn Bn Sn(OTf)2 2. TFA; CH3OH N-ethylpiperidine CH2Cl2, –78 °C aldehyde dr yield (%) 94%, 94% de 24:1 - CHO X = CH3 O O O OH X = OCH 32:1 CH 3 91 O N 3 X X = NO2 7:1 71 CH3 CH3 CH3 CH3 Bn NaBH(OAc)3 X = Ph, Y = H 21:1 92 AcOH Y X X = Ph, Y = CH 28:1 91%, >94 de CHO 3 92

O O OH OH X = H, Y = CH3 16:1 77 CH O N 3 14:1 91 CH3 CH3 CH3 CH3 "-napthaldehyde Bn furfural 6:1 80

H C CH 3 3 • Silylation of the magnesium in the aldol product turns over the magnesium. NO O O O O O H CO 2 3 OCH3 • The aldehyde component is limited to non-enolizable aromatic and ",#-unsaturated aldehydes. O H + H3C CH3 CH CH CH CH CH CH CH 3 3 3 3 H C 3 3 3 Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am. Chem. Soc. 2002, 124, 392-393. 2, LDA, THF 3 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 H CO 3 OCH3

O CH3 S O 1. MgBr2•Et2O, (10 mol%), S O OH CH3 CH3 CH3 CH3 CH3 CH3 CH3 O Et N, TMSCl, H C CH3 3 3 S N + S N R h!, THF, 0 °C; H R EtOAc, 23 ºC H O, HCl, 25 °C CH3 2 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 CH 3 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 Cl CS, Et N 2 3 O NH

Bu Bu CH2Cl2 B O 95% Bn O O Bu BOTf, i-Pr NEt, O O O O OH NaBH4, I2 2 2 H NH2 NH2 CH Cl ; HO HO CH3 2 2 CH3 O N O N LA O N R Bn THF Bn Lewis acid, RCHO R O 95% H CH3 S t-Bu t-Bu t-Bu CS , KOH 2 S NH 1, favored for small non-Evans syn Lewis 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 TiCl 12:88 72 4 Asymmetric Aldol Reactions with Titanium Enolates of N-Acylthiazolidinethiones

TiCl 8:92 65 Ph CHO 4 1. TiCl (1.1 equiv) S O 4 S O OH S O OH (–)-sparteine CH3 + S N CH2Cl2, 0 °C S N R S N R CH3 CH Bu Bu 2. RCHO, 0 °C Bn 3 B Bn Bn OH A B O O Bu2BOTf, i-Pr2NEt, O O R O O CH CH2Cl2; CH O N 3 O N 3 O N R Lewis acid, RCHO H O RCHO (–)-sparteine (equiv) yield (%) A : B H CH3 i-Pr i-Pr LA i-Pr CH =CHCHO 1.0 49 >99:1 2, favored for large anti 2 Lewis acids i-PrCHO 1.0 60 98:2

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

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

• 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 S O OH CH3 S O S O OH S N 1. TiCl4, (–)-sparteine TiCl OR + 4 TiCl O N O N R' O N R' (–)-sparteine (1 equiv) 4 2. TiCl , R'CHO Bn (–)-sparteine (2 equiv) 4 OR RCHO OR RCHO Bn Bn Bn A B S Bn S R aldehyde A : B : syn yield (%) H S H H Cl N N allyl H CCHO 94 : 6 : 0 84 Bn TI Cl S H 3 O TiL HR O x O Cl H O allyl Ph CHO 65 : 24 : 11 56 CH3 R CH 3 allyl CHO 94 : 6 : 0 74 CH3

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 CH CH3 3 Bn CHO 74 : 26 : 0 48 Bn Bn CHO CH3 84 : 11 : 5 63 • The thiazolidinethione auxiliary is easily removed under mild conditions: CH3 CHO OH O OH CH3 88 : 12 : 0 59 i-Pr HO Ph BnHN CH NaBH PhCH NH CH 3 4 2 2 3 • Complexation of the aldehyde with excess titanium occurs in situ to give anti products with high 83% 79% selectivity. i-Bu O OH • The proposed transition state is analogous to that of the anti-selective Heathcock aldol. N R S CH CH3ONHCH3•HCl DIBAL-H 3 imidazole 69% S L 77% 4 CH OH Ti O OH 3 O OH S O R imidazole R' CH3O i-Pr O H i-Pr 79% N O N TiL4 H O CH3 O OH CH3 CH3 H t-Bu i-Pr CH3O 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 O O OH Bu2BOTf, Et3N, O O Sn(OTf) , O O OSnL O O R 2 Cl Et2O; NCS N-ethylpiperidine; O N O N R O N O N O N R O RCHO Cl RCHO N HN Ph CH Ph CH C 3 3 Bn Bn S Bn S 1

O O O O OH Bu BOTf, Et N, Br 2 3 aldehyde ratio* yield (%) O N Et2O; O N R Br RCHO H3CCHO 91:9 75 Bn Bn 2 PhCHO 99:1 91 imide aldehyde ratio* yield (%) H3C CHO 99:1 92 CH3 1 H3CCHO 95:5 67

CHO 94:6 1 PhCHO 97:3 79 CH3 73 CH3 1 96:4 75 H3C CHO CHO CH3 97:3 2 98:2 63 71 CH3 CH3 2 CHO 94:6 63 *Ratio of desired (illustrated) stereoisomer to the sum of all other stereoisomers. H3C CH3 • The N-methyl 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 of the azide delivers the amino acid. HN HOCH3 HN Bn S S O O OH 1. NaN3 O OH 2. LiOH/H2O (H3C)3OBF4 O N CH3 HO CH3 3. H , Pd/C, TFA Cl 2 NH2 O R O R Ph CH3 O OH 76%, ≥99% de H O 1. KOH 2 H CO H3CO O 3 O HO R + 2. H3O N N Evans, D. A.; Sjogren, E. B.; Weber, A. E.; Conn, R. E. Tetrahedron Lett. 1987, 28, 39-42. NHCH H C 3 H3C O 3 SCH3

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 2. O X R Bn NH2 !+ L O O N NH2 Sn(OTf)2, N-ethylpiperidine; RS RL –78 to 0 ºC Br OH CH3 O N OHC Cl 95:5 dr Bn O OH O OH F CH3 89% 72% NO2 X X CH 76%, Bu2BOTf, Et3N; !+ CH3 94 : 6 dr !+ 3 83 : 17 dr OHC NO NH2 CH3 NH2 F 95:5 dr 2 O N 2 Cl O OH O OH F 80% 75% X X O O !+ 85 : 15 dr !+ 83 : 17 dr NH2 NH2 TIPS O O OH O N O NO O HO CH O HO CH HN O N 2 3 3 98% CH 82% Bn S X X 3 Br !+ CH3 98 : 2 dr !+ 94 : 6 dr Bn F 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 : sum of all other diastereomers.

Cl • Pseudoephenamine glycinamide undergoes a direct aldol addition with both aldehyde and F O OH ketone substrates. NO HO 2 O N O 2 O N • The corresponding N-Boc-protected or methyl hydrochloride derivatives can be prepared 3 F N in two steps from the aldol products. HO2C Boc O OH Boc2O, NaHCO3 CH3 OH HO CH 1:1 H O:dioxane 3 Cl 2 BocHN CH O O 79% 3 HO Cl OH O O O H H O OH N O OH NaOH H N N NHCH3 CH N N CH3 3 O H H H H N NaO CH O O CH CH(CH ) CH3 THF, CH3OH 3 NH O 2 3 2 NH CH OH CH3 NH2 CH3 23 ºC 2 3 95% HO C NH 2 2 O OH OH SOCl2 CH OH vancomycin aglycon 3 BnO H3CO CH CH OH 3 3 HCl•NH CH 91% 2 3 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 Diisopinocampheylborinates

(–)-Ipc BOTf O 2 OBIpc2 OH O i-Pr2NEt R2CHO, –15 °C; H3C H3C R1 R1 R2 R1 CH Cl ,–78 °C H2O2 H C H C 2 2 CH3 3 3

H3C H3C H H H H ketone aldehyde syn:anti ee (%) yield (%) H CH3 R1 CH3 R CH3 H H CH3 H 1 B B CH O CH O 3 HR2 3 O CH3 98:2 91 78 O H3C H O H3C H3C CH3 CHO R2 CH3 H CH H O CH3 3 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 (–)-Ipc BCl, does not lead to a selective 2 steric interactions between the (–)-Ipc ligand on boron and the R on the ketone anti-aldol reaction. 1 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 in the favored transition state. O 1. (c-Hex)2BCl OB(c-Hex)2 1. RCHO, 14 h O OH OBL BzO CH3 (CH3)2NEt BzO –78 ! –26 BzO 2 R BzO + RCHO CH3 Et2O, 0 °C CH3 CH3 2. H2O2, pH 7 CH3 CH3 2 h CH3OH, 0 °C CH3 CH3

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

CH3 94 95 H3C CHO H C CHO 99 82 Ph 3 O H CH L H C 3 Ph 3 CHO 90 97 L O H H O H C H vs. B O CH3 3 R O 96 97 B L L O R H3C CHO CH O O 3 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 R R CH3 CH3 CH3 CH3 CH3 CH3 CH CH CH CH 80%, >94% de 3 3 3 3

OB(c-Hex)2 O MISMATCHED O OH 1. TBSOTf BzO + BzO 2,6-Lutidine H OBn OBn O OH OH OTBS O OTBS CH2Cl2, 78 °C 3. NaIO4 CH3 CH3 CH3 CH3 CH3 CH3 BzO HO R 2. LiBH , THF R H R 61%, 84% de 4 CH3OH/H2O CH3 CH3 –78 ! 20 °C CH3 CH3 CH3 • Other examples: R = i-Pr, 74%, >99% de O OH R = Ph, 85%, >99% de O (c-Hex)2BCl BzO (CH3)2NEt BzO O OTBS SmI2, THF O OTBS CH i-Pr 95%, 86% de 3 CH3OH BzO H3C CH i-PrCHO CH3 3 CH R R 3 0 °C, 10 min CH3 CH3 CH3 R = i-Pr, 81% O O OH (c-Hex)2BCl R = Ph, 96% BzO OBn (CH ) NEt BzO 3 2 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 O Ar Ot-Bu Ar 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 CH O O 3 H3C • The "-hydroxy ester products are isolated in 50-85% yield and 80-91% ee. O + O PMBO CH BnO O 3 CH3 CH3 H 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 CH HO O 3 R CH3 H CH3 H

O • Approach of the aldehyde is proposed to occur from the side of the non-bonding O H3C pair of the sulfur atom with the R-group of the aldehyde anti to the sulfinyl H C CH substituent. A chelated enolate is proposed. 3 OH 3

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 H C CH H C CH Ph Ph 3 3 3 3 HO HO O 1. n-Bu2BOTf, i-Pr2NEt O OH H CO2CH3 PhMgBr Ph AcCl O Ph SCH CH2Cl2, 0 °C H H N 3 N R HO Ph 77% HO Pyridine Ph H3C O Ph O 2. PhCHO O SCH3 (R)-mandelic acid 82% O –78 ! 23 °C O LDA; MgX2 3. Ra-Ni, 60 °C THF, (CH ) O 3 2 86-99% de 4. 2N KOH CH3OH, 0 °C Ph HO Ph OH O NaOH RCHO MO O OH OH O Ph MO Ph H R OH –135 °C H • A temporary substituent is used to afford acetate HO R R O Ph H C O 2 Ph aldol products selectively. Simple N-acetyl imides R = Ph, CH3, 76-85% (2 steps) do not react selectively. 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 CH O 3 Ph CH3 H3C HO H3C H O O Ph O O O Ph MATCHED O OH CHO H C O N B + 3 H n-Bu Ts >94% de OH O N 3 H Ph HO 3 (20 mol%), 14 h CH3 CH H C O Ph 3 O OSi(CH3)3 OH O 3 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 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 enol ethers provide the highest level of enantioselectivities. Catalytic, Enantioselective Acetate Aldol Additions with Silyl

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 of Silyl Thioketene Acetals 1. (–)-1 (0.5-5 mol %); O OSi(CH3)3 OH O Et2O, 4 h, –10 °C + R1 H OR2 R1 OR2 2. Bu4NF, THF 1. (S)-BINOL, Ti(Oi-Pr)4 (20 mol%), 4Å-MS Et O, –20 °C O OSi(CH3)3 2 OH O + R H St-Bu 2. Silyl thioketene 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 Ph 93 97 96 PhCH2CH2CHO 80 97 CHO furylCHO 88 >98 Ph 89 94 91 CHO c-C H CHO 70 89 6 11 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 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 O Ti and selectivities. This may be done by azeotropic removal of i-PrOH with toluene or by 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, , chloroform, diethyl , and tert-butyl methyl ether.

• Alkenyl and alkynyl aldehydes are particularly good substrates for this catalytic 1. (–)-2 (2-10 mol %); process. O OCH3 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 Ph 0 ! 23 98 90 TBSOCH2 CHO 88 96 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 H C 3 • 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 and O , CH Cl OH O 3 2 2; 2-methoxypropene addition reactions. Ph P 3 • The protected acetoacetate adducts are versatile precursors for the preparation of optically Ph OCH3 active !-hydroxy-"-keto esters, amides, and . OH OCH3 OH O O Ph CH2 LiAl(NHBn)4 X = NHBn, 73% 84% isolated yield OsO4, NMO OH O H C CH 3 3 Ph X X = On-Bu, 81% acetone, H2O OH Ph OH O O or 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 CH OH Catalytic, Enantioselective Dienolate Additions to Aldehydes 3 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 %) H C CH H C CH 3 3 2,6-lutidine 3 3 O O O (0.4 equiv) OH O O Et O, 0 °C, 4 h aldehyde yield (%) %ee + 2 R H OSi(CH3)3 R O 2. 10% TFA, THF PhCHO 92 94

CHO 98 95 aldehyde yield (%) %ee S CHO TIPS CHO 86 91 82 90 OCH3 TBSO CHO 97 94 CHO Ph 48 91 CHO CH 88 92 3 CH3 CHO 81 83 CHO 79 92 Ph n-Bu3Sn CHO CHO Ph Ph 97 80 74 65 CH3 a PhCHO 83 84 (96) a after 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+ – 2 SbF6 O O • Enolizable, aliphatic aldehydes give products with high enantioselectivity, but in poor yield O N O 2 TfO– (<40%). N Cu N N N • Spectroscopic evidence supports a catalytic process involving a chiral transition metal Cu Ph C(CH ) C(CH3)3 dienolate as an intermediate. Ph 3 3 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 OH O CH2Cl2, –78 °C BnO + BnO Enantioselective Acetate Aldol Addition Using a Chiral Controller Group SR H SR2 2. 1 N HCl, THF 2 R1 R1

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

BX2 CH Et (E) 1d –50 86:14 85 48 O 3 O OH O 3 RCHO (Z) H C SPh SPh R SPh i-Bu Et 2d –50 95:5 95 85 3 –90 °C, 2h CH2Cl2 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- 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 O NH (30 mol%) O OH 2. PPTS, CH3OH O + 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. p-NO C H CHO 68 (60) 76 (86) J. J. Am. Chem. Soc. 1999, 121, 669-685. 2 6 4 62 (60) 60 (89) C6H5CHO 74 (85) 65 (67) p-BrC6H4CHO o-CCl H CHO 94 (71) 69 (74) 2 (10 mol%) 6 4 O OTMS O THF H3C OH !-napthaldehyde 54 (60) 77 (88) H3CO + H3CO CH St-Bu St-Bu i-PrCHO 97 (65) 96 (96) 3 –78 °C R O R 63 (45) 84 (83) H C CH3 O O 1 N HCl c-C6H11CHO 3 t-BuCHO 81 >99 S OH R = H, CH3, Et, i-Bu H 85 >99 NH 77-97% CHO ≥96% ee DMTC H C CH3 ≥94:6 syn:anti 3 • 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. 1 (10 mol%) O OTMS 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 N O OH ≥98:2 anti:syn NH R H + O H O H3C CH3 H R 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 O O O OH H 30 mol% proline OH O R + NH (30 mol%) O O O OH O O H R DMF, 2 ºC 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 60 >20:1 >99 c-C6H11CHO (S)-proline 86 >98:2 90 c-C6H11CHO i-PrCHO 62 >20:1 >99 (S)-proline 40 >98:2 97 BnOCH2CHO o-ClC H CHO 95 1.5:1 67 (S)-proline 69 94:6 93 6 4 (CH3O)2CHCHO 38 1.7:1 >97 t-BuCH2CHO 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 NBoc Ph CHO 51 >20:1 >95 (R)-proline 31 >96 H3C CH3 CH3 CHO O >98:2 • The anti-diol product formed is not readily accessible via asymmetric dihydroxylation, making NCbz (S)-proline 80 >96 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 H C R but excellent dr and ee. H H O 3 H3C H C O OH OH H 3 • Certain have been synthesized by this method. OH NH FAVORED + O OH Dowex, H O O OH HO OH O H O 2 O H O OH CH OH N O O O HO 2 CH2OH H R HO H CH3 R H3C R OH OH D-psicose OH OH O H O H C CH H3C OH 3 3 H3C 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 . O O 10 mol% L-proline O OH + H H R H R O O OH 2 DMF, 4 ºC 2 10 mol% L-proline R1 R1 H H DMSO OAc TIPSO 92%, 4:1 (anti:syn) TIPSO OTIPS TMSO R R yield (%) anti:syn %ee 1 2 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 3:1 O OH O OH O OH Me Ph 81 99 TIPSO TIPSO TIPSO 24:1 Me i-Pr 82 >99 TIPSO OAc TIPSO OAc TIPSO OAc n-Bu i-Pr 80 24:1 98 OH OH OH 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 O • Either non-enolizable aldehydes or aldehydes containg !- or "-branching are suitable O O OH D-proline acceptor aldehydes for this reaction. OBn H H H 98% ee O Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798-6799. OBn OBn H C 78% 3 H Proline-Catalyzed Direct and Enantioselective Aldol Reaction of -Oxyaldehydes MgBr •Et O L-proline, ! OR 2 2 intramolecular TMSO 65%, 10:1 dr DMSO O OH O 10 mol% L-proline 98% ee O 91% OR HO OR H O O H H solvent, rt, 24–48h H OR OH O OBn + HO O O OBn O R solvent yield (%) anti:syn %ee BnO H H H3C OH H3C OAc 73 4:1 Bn DMF 98 BnO PMB DMF 64 4:1 97 OH

MOM DMF 42 4:1 96 O h# = 350 nm; O O H , Pd/C O TBDPS DMF/dioxane 61 9:1 96 H 2 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 C H O H C H O 3 3 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. H C CH 3 3 OH O O O O O OH CH3 N N O CH H C + PhS O 3 Ph Ph 3 4 OH 1 CH3 O

Cu(OTf) (10 mol%), O O O 2 O OH 1 (13 mol%) Pd(dppf)Cl2, trifurylphosphine + PhS OH H R PhS R Cu(I), i-Pr2NEt 9:1 PhCH3:acetone CH DMF, 50 ºC, 6 h 3 23 ºC, 0.17 M, 24 h CH3 76%

aldehyde yield (%) syn:anti %ee OH O O OH CH3 CH3(CH2)6CHO 80 9:1 92 (R) O O CH3 H C 4 OH 83 10:1 94 3 CH3O2C(CH3)4CHO 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. H C 3 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 H H3C 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) a (109.5 g) 99% ee c-C6H11CHO 48 (71 ) 36:1 93 O H O H O OH H HO N H (15.0 g) O(CH ) CHO H O 2 4 O H O 5.5:1 H O 4 steps O O 70 92 O H C HO 3 CH 3 atwo equiv of aldehyde was used. CO2H

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