10 stereoselective directed aldol reaction

Myers Chem 115 Stereoselective, Directed Aldol Reaction 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 O H3C OH O H OML2 H R1 • The aldol reaction was discovered by Aleksandr Porfir'evich Borodin in 1872 where he first observed the formation of "aldol", 3-hydroxybutanal, from acetaldehyde under the influence of catalysts such as hydrochloric acid or zinc chloride + M O H3C H H3C L R1 H R2 O L O R1 R2 CH3 anti FAVORED CH3 L R1 R2 O R2CHO H3C H OH M O L O OH R1 H DISFAVORED R2 CH3 syn Diastereofacial Selectivity in the Aldol Addition ReactionZimmerman-Traxler Chair-Like Transition States L R1 H (Z)-enolates H R1 R2 CH3 OML2 CH3 M O O L O R1 R2 + H syn L R1 R2 O H CH3 • (Z)- and (E)-enolates afford syn- and anti-aldol adducts, respectively, by minimizing 1,3-diaxial interactions between R1 and R2 in each chair-like TS‡ CH3 FAVORED R2CHO OH • Zimmerman and Traxler proposed that the aldol reaction with metal enolates proceeds via a chair-like, pericyclic process In practice, the stereochemistry can be highly metal dependent Only a few metals, such as boron, reliably follow the indicated pathways M O DISFAVORED O L OH R1 R2 CH3 Zimmerman, H E.; Traxler, M D J Am Chem Soc 1957, 79, 1920-1923 Dubois, J E.; Fellman, P Tetrahedron Lett 1975, 1225-1228 anti 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 (Z)-Selective Preparation of Boron Enolates from Evans' Acyl Oxazolidinones (Imides) Preparation of (Z)- and (E)-Boron Enolates O (n-Bu)2BOTf CH3 Et iPr2NEt, Et2O –78 ºC, 30 Et OB(n-Bu)2 CH3 O –78 ºC OB(c-Hex)2 Et3N, Et2O –78 ºC, 10 CH3 >99% (E) O (n-Bu)2BOTf CH2Cl2 O O O O B –OTf O CH3 N Bn OH Et Ph CH3 75% CH3 N syn >99% –78 ºC Et Bn O Ph CH3 PhCHO n-Bu n-Bu OH Et 77% (c-Hex)2BCl CH3 O PhCHO >97% (Z) Et Chem 115 Stereoselective, Directed Aldol Reaction anti >97% n-Bu H B n-Bu n-Bu O O N O H3C H H Bn • 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 i-Pr2NEt n-Bu n-Bu O • The combination of (c-Hex)2BCl and Et3N provides the (E)-boron enolate preferentially O B O H Bn i-Pr2NEt n-Bu n-Bu O N O N CH3 O H DISFAVORED FAVORED • Dialkylboron triflates typically afford (Z)-boron enolates, with little sensitivity toward the amine used or the steric requirements of the alkyl groups on the boron reagent n-Bu H B O CH3 O B 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 Brown, H C.; Dhar, R K.; Bakshi, R K.; Pandiarajan, P K.; Singaram, B J Am Chem Soc 1989, 111, 3441-3442 Evans, D A.; Takacs, J M.; McGee, L R.; Ennis, M D.; Mathre, D J.; Bartroli, J Pure Appl Chem 1981, 53, 1109-1127 M Movassaghi Myers Chem 115 Stereoselective, Directed Aldol Reaction 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 Li B CH3 N O Bn OB(n-Bu)2 CH3 N O O O • Dipole-dipole interactions within the imide are minimized in the reactive conformation (see: Noe, E A.; Raban, M J Am Chem Soc 1975, 97, 5811-5820) n-Bu n-Bu N O O CH3 Bn O Bn UNREACTIVE O cf reactive enolate in Evans' asymmetric alkylation RCHO CH3 O H3C CH3 N O O Bn H O N O H n-Bu B O H n-Bu vs n-Bu n-Bu N O n-Bu Bn O B O Bn O O N O n-Bu O N R O CH3 n-Bu B O CH3 CH3 O Ph OH N O O R CH3 H DISFAVORED n-Bu O R O RCHO –78 " 23 °C B OH N O n-Bu2BOTf, i-Pr2NEt CH2Cl2, °C R CH3 FAVORED CH3 N O O O O R CH3 O H B Ph CH3 O H3C RCHO –78 " 23 °C A CH3 O H Bn n-Bu2BOTf, i-Pr2NEt CH2Cl2, °C R CH3 imide aldehyde A (CH3)2CHCHO B (CH3)2CHCHO A n-C4H9CHO B n-C4H9CHO A C6H5CHO B C6H5CHO aRatio diastereomerica ratio yield (%) 497:1