Polyfunctional Imidazolium Aryloxide Betaine/Lewis Acid Catalysts as Tools for the Asymmetric Synthesis of Disfavored Diastereomers

Enzymes
are Nature’s polyfunctional catalysts tailor-made
for specific biochemical synthetic transformations, which often proceed
with almost perfect stereocontrol. From a synthetic point of view,
artificial catalysts usually offer the advantage of much broader substrate
scopes, but stereocontrol is often inferior to that possible with
natural enzymes. A particularly difficult synthetic task in asymmetric
catalysis is to overwrite a pronounced preference for the formation
of an inherently favored diastereomer; this requires a high level
of stereocontrol. In this Article, the development of a novel artificial
polyfunctional catalyst type is described, in which an imidazolium–aryloxide
betaine moiety cooperates with a Lewis acidic metal center (here Cu­(II))
within a chiral catalyst framework. This strategy permits for the
first time a general, highly enantio­selective access to the
otherwise rare diastereomer in the direct 1,4-addition of various
1,3-dicarbonyl substrates to β-substituted nitro­olefins.
The unique stereocontrol by the polyfunctional catalyst system is
also demonstrated with the highly stereo­selective formation
of a third contiguous stereocenter making use of a diastereo­selective
nitronate protonation employing α,β-disubstituted nitro­olefin
substrates. Asymmetric 1,4-additions of β-ketoesters to α,β-disubstituted
nitro­olefins have never been reported before in literature.
Combined mechanistic investigations including detailed spectroscopic
and density functional theory (DFT) studies suggest that the aryloxide
acts as a base to form a Cu­(II)-bound enolate, whereas the nitro­olefin
is activated by H-bonds to the imidazolium unit and the phenolic OH
generated during the proton transfer. Detailed kinetic analyses (RPKA,
VTNA) suggest that (a) the catalyst is stable during the catalytic
reaction, (b) not inhibited by product and (c) the rate-limiting step
is most likely the C–C bond formation in agreement with the
DFT calculations of the catalytic cycle. The robust catalyst is readily
synthesized and recyclable and could also be applied to a cascade
cyclization.