Lithium Enolates in the Enantioselective Construction of Tetrasubstituted Carbon Centers with Chiral Lithium Amides as Noncovalent Stereodirecting Auxiliaries

Lithium
enolates derived from carboxylic acids are ubiquitous intermediates
in organic synthesis. Asymmetric transformations with these intermediates,
a central goal of organic synthesis, are typically carried out with
covalently attached chiral auxiliaries. An alternative approach is
to utilize chiral reagents that form discrete, well-defined aggregates
with lithium enolates, providing a chiral environment conducive of
asymmetric bond formation. These reagents effectively act as noncovalent,
or traceless, chiral auxiliaries. Lithium amides are an obvious choice
for such reagents as they are known to form mixed aggregates with
lithium enolates. We demonstrate here that mixed aggregates can effect
highly enantioselective transformations of lithium enolates in several
classes of reactions, most notably in transformations forming tetrasubstituted
and quaternary carbon centers. Easy recovery of the chiral reagent
by aqueous extraction is another practical advantage of this one-step
protocol. Crystallographic, spectroscopic, and computational studies
of the central reactive aggregate, which provide insight into the
origins of selectivity, are also reported.