A Mechanistic Rationale for the 9‑Amino(9-deoxy)<i>epi</i> Cinchona Alkaloids Catalyzed Asymmetric Reactions via
Iminium Ion Activation of Enones
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Abstract
The 9-amino(9-deoxy)<i>epi</i> cinchona alkaloids have
expanded the synthetic potential of asymmetric aminocatalysis, enabling
the highly stereoselective functionalization of a variety of sterically
hindered carbonyl compounds. However, there is a lack of basic understanding
of the mechanisms of cinchona-based primary aminocatalysis. Herein,
we describe how a combination of experimental and theoretical mechanistic
studies has revealed the origin of the stereoselectivity of the Friedel–Crafts
alkylation of indoles with α,β-unsaturated ketones catalyzed
by 9-amino(9-deoxy)<i>epi</i> quinine. An essential role
for the achiral acid cocatalyst is uncovered: upon condensation of
the cinchona catalyst with the enone, the resulting covalent imine
intermediate and the acid interact to build-up a well-structured ion-pair
supramolecular catalytic assembly, which is stabilized by multiple
attractive noncovalent interactions. All the components of the assembly
cooperatively participate in the stereocontrolling event, with the
anion of the achiral acid being the structural element responsible
for the π-facial discrimination of the iminium ion intermediate