syn-Selective Direct Asymmetric Cross-Aldol Reaction

Key words

cross-aldol reaction - syn selectivity - axial chirality - amino sulfonamides

Significance

A highly syn-selective asymmetric direct cross-aldol reaction between two different aldehydes has been developed. By employing 5 mol% of the axially chiral amino sulfonamide (S)-3, syn-aldol products 4 resulting from mostly electron-poor acceptor 1 and aliphatic donor aldehydes 2 are obtained in moderate to good yields along with high diastereo- (syn/anti ratio up to >20:1) and excellent enantioselectivities (er up to 99.5:0.5). The authors rationalize the stereo­chemical outcome with the help of proposed transition states A and B. In contrast to the anti-enamine B, the syn-enamine geometry in A allows for effective hydrogen bonding activation of the acceptor aldehyde by the acidic proton of the triflamide moiety. This favors the reaction to proceed via the syn-enamine intermediate and explains the observed syn selectivity.

Comment

The described method represents one of the rare examples of syn-selective direct cross-aldol reaction proceeding via an enamine intermediate (e.g., C. F. Barbas, III and co-workers J. Am. Chem. Soc. 2007, 129, 288-289). With respect to the syn/anti selectivity, the use of axially chiral amino sulfonamide (S)-3 complements the proline-catalyzed version of both the direct asymmetric cross-aldol and the Mannich reaction, recently reported by the same group (J. Am. Chem. Soc. 2005, 127, 16408-16409). The drawback of multi-step catalyst synthesis is compensated not only by low catalyst loading but also by 95% catalyst recovery after column chromatography. A more general substrate scope with regard to the acceptor aldehyde might be desirable.