Diverse Asymmetric Quinolizidine Synthesis: A Stereodivergent One‐Pot Approach

Abstract

Abstract A diverse stereodivergent organocatalytic one‐pot addition/cyclization/annulation sequence to optically active quinolizidine derivatives from easily available starting materials is presented. The one‐pot sequence relies on a pyrrolidine‐catalyzed enantioselective conjugate addition of electron‐deficient amide α‐carbons to α,β‐unsaturated aldehydes, spontaneous hemiaminal formation and acid‐catalyzed/mediated N ‐acyliminium ion cyclization to give the quinolizidine framework. Simple tuning of the reaction conditions in the N ‐acyliminuim ion cyclization step provides a diastereomeric switch, which gives access to both of the two bridgehead epimers through kinetic, thermodynamic or chelation control. The methodology display a broad substrate scope that is demonstrated by the stereoselective formation of indolo‐, thieno‐, benzofuro‐, furo‐ and different benzoquinolizidine derivatives with high atom efficiency, up to >99% ee and up to >95:5 dr . Due to its efficiency, synthetic diversity and operational simplicity, this protocol has the potential to find important use as a key step in natural product synthesis, biochemistry and pharmaceutical science. The stereochemical outcome of the one‐pot sequence was investigated, and the mechanism and origin of stereoselectivity of the different steps is discussed.