Enantioselective Construction of Tetrasubstituted Stereogenic Carbons through Brønsted Base Catalyzed Michael Reactions: α′-Hydroxy Enones as Key Enoate Equivalent

Catalytic
and asymmetric Michael reactions constitute very powerful
tools for the construction of new C–C bonds
in synthesis, but most of the reports claiming high selectivity are
limited to some specific combinations of nucleophile/electrophile
compound types, and only few successful methods deal with the generation
of all-carbon quaternary stereocenters. A contribution to solve this
gap is presented here based on chiral bifunctional Brønsted base
(BB) catalysis and the use of α′-oxy enones as enabling
Michael acceptors with ambivalent H-bond acceptor/donor character,
a yet unreported design element for bidentate enoate equivalents.
It is found that the Michael addition of a range of enolizable carbonyl
compounds that have previously demonstrated challenging (i.e., α-substituted
2-oxindoles, cyanoesters, oxazolones, thiazolones, and azlactones)
to α′-oxy enones can afford the corresponding tetrasubstituted
carbon stereocenters in high diastereo- and enantioselectivity in
the presence of standard BB catalysts. Experiments show that the α′-oxy
ketone moiety plays a key role in the above realizations, as parallel
reactions under identical conditions but using the parent α,β-unsaturated
ketones or esters instead proceed sluggish and/or with poor stereoselectivity.
A series of trivial chemical manipulations of the ketol moiety in
adducts can produce the corresponding carboxy, aldehyde, and ketone
compounds under very mild conditions, giving access to a variety of
enantioenriched densely functionalized building blocks containing
a fully substituted carbon stereocenter. A computational investigation
to rationalize the mode of substrate activation and the reaction stereochemistry
is also provided, and the proposed models are compared with related
systems in the literature.