cross-aldol reaction -
syn selectivity - axial chirality - amino sulfonamides
Significance
<P>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.</P>
Comment
<P>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.</P>
