Deployment of Sulfinimines in Charge-Accelerated Sulfonium Rearrangement Enables a Surrogate Asymmetric Mannich Reaction

β-Amino acid derivatives are key structural elements
in synthetic
and biological chemistry. Despite being a hallmark method for their
preparation, the direct Mannich reaction encounters significant challenges
when carboxylic acid derivatives are employed. Indeed, not only is
chemoselective enolate formation a pitfall (particularly with carboxamides),
but most importantly the inability to reliably access α-tertiary
amines through an enolate/ketimine coupling is an unsolved problem
of this century-old reaction. Herein, we report a strategy enabling
the first direct coupling of carboxamides with ketimines for the diastereo-
and enantioselective synthesis of β-amino amides. This conceptually
novel approach hinges on the innovative deployment of enantiopure
sulfinimines in sulfonium rearrangements, and at once solves the problems
of chemoselectivity, reactivity, and (relative and absolute) stereoselectivity
of the Mannich process. In-depth computational studies explain the
observed, unexpected (dia)­stereoselectivity and showcase the key role
of intramolecular interactions, including London dispersion, for the
accurate description of the reaction mechanism.