Myers Stereoselective, Directed Aldol Reaction Chem 115 Reviews: Heathcock, C. H. In Comprehensive Organic Synthesis, 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)-enolates 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 acetaldehyde under the influence of R2 O OH M catalysts such as hydrochloric acid or zinc chloride. R2CHO O L H C R1 R 3 O 2 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 L (Z)-enolates R1 chair-like, pericyclic process. In practice, the stereochemistry can be highly metal dependent. H O OH M Only a few metals, such as boron, 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 (Imides) 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 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 O O O O • The combination of (c-Hex)2BCl and Et3N provides the (E)-boron enolate 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 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 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 alkylation 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 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 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 crystallization 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 Lithium Hydroperoxide Other Methods for Removal of the Chiral Auxiliary • 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 regioselectivity for attack of the exocyclic carbonyl group. 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 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 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 O 1. n-Bu2BOTf, Et3N H H H3C Ph CH Cl , –78 °C n-Bu BOTf, Et N n-Bu BOTf, Et N 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.