enamine catalysis - proline - oxazolidinones
Significance
Mayr and co-workers have performed a kinetic analysis of the
reaction of proline carboxylate enamine 1a,
pyrrolidine enamine 1b, and proline ester
enamine 1c with electrophiles 2a-c.
The superior reactivity of the proline carboxylate 1a compared to 1b-c was interpreted as evidence
for the operation of an alternative mechanistic pathway
that includes anchimeric assistance of the carboxylate group in
the addition to the electrophile. These data were suggested to support
the formation of oxazolidinones in the stereogenic step
of proline carboxylate catalyzed reactions
(D. G. Blackmond et al. J. Am. Chem. Soc. 2010, 132, 7598),
although catalytic reactions have not actually been studied.
Comment
Recently, Seebach, Eschenmoser, and co-workers suggested Hajos’ ‘oxazolidinone mechanism’ (J. Org. Chem. 1974, 39, 1615) as an alternative to the commonly
accepted List-Houk model in proline enamine catalysis (Helv. Chim. Acta. 2007, 90, 425). Blackmond, Armstrong, and co-workers
discussed a variation of this mechanism (to account for the opposite
stereochemical outcome) for proline carboxylate catalyzed
reactions as an alternative to a simple steric argumentation (J. Am. Chem. Soc. 2010, 132, 7598). Proline and proline carboxylate catalyzed reactions seem
to consistently give the opposite stereochemistry in agreement
with the crucial role of the COOH proton in the Houk-List
model. In the current paper, the kinetics of reactions of enamines 1 with electrophiles 2 were
examined. The lower reactivity of 1c was
explained by the electron-withdrawing influence of the ester group
and higher reactivity of 1a by
anchimeric assistance of the carboxylate group. Alternatively, the
higher nucleophilicity of 1a compared to 1b could also be a consequence of the electrostatic
stabilization by the carboxylate of the positive charge generated on
the nitrogen in the transition state.
