Stereocontrolled four-carbon homologation of vicinally functionalized allylic pyrrolidines to highly customized azonines bearing remote benzylic stereocenters

Abstract

Polysubstituted pyrrolidines and azonanes bearing at least two (vicinal) stereocenters constitute the core of several pharmaceuticals or advanced intermediates that directly lead to marketed drugs. Here, we leverage our recently developed 1,3-azadiene-succinic anhydride annulation protocol to produce vicinally functionalized allylic pyrrolidine methanols and explore their amenability to four-carbon homologation. The success of the aza-Cope rearrangement hinges on the use of hexafluoroisopropanol (HFIP) as the reaction medium. The method provides rapid, modular, and efficient access to highly customized azonines. The ring expansion reaction of these sterically-imposing and vicinally functionalized α-styrenyl pyrrolidine methanols proceeds with complete control of the E/Z geometries of the enamine and alkene CC double bonds resident in the 9-membered ring. Additionally, the approach furnishes sp³-rich nine-membered nitrogen heterocycles bearing at least two tetrahedral stereocenters, including a remote benzylic stereocenter.