Organocatalytic Enantioselective Construction of Conformationally Stable C(sp²)-C(sp³) Atropisomers

Nonbiaryl atropisomers are molecules defined by a stereogenic axis featuring at least one nonarene moiety. Among these, scaffolds bearing a conformationally stable C(sp²)-C(sp³) stereogenic axis have been observed in natural compounds; however, their enantioselective synthesis remains almost completely unexplored. Herein we disclose a new class of chiral C(sp²)-C(sp³) atropisomers obtained with high levels of stereoselectivity (up to 99% ee) by means of an organocatalytic asymmetric methodology. Multiple molecular motifs could be embedded in this class of C(sp²)-C(sp³) atropisomers, showing a broad and general protocol. Experimental data provide strong evidence of the conformational stability of the C(sp²)-C(sp³) stereogenic axis (up to t_1/2²⁵ >1000 y) in the obtained compounds and show kinetic control over this rare stereogenic element. This, coupled with density functional theory calculations, suggests that the observed stereoselectivity arises from a Curtin-Hammett scenario establishing an equilibrium of intermediates. Furthermore, the experimental investigation led to evidence of the operating principle of central-to-axial chirality conversions.