Diversity-oriented chiral phosphoric acid catalyzed alkylation of indolizines with aminals

Abstract

Innovations in the pharmaceutical industry and materials science are driving the need for creating enantiomerically pure heterocyclic molecules with greater complexity and diversity. This study presents a methodology to control the enantioselective alkylation of indolizines with aminals catalysed by chiral phosphoric acids (CPAs), leading to protected indolizinylamines achieved via three distinct processes by precise adjustment of the reaction conditions. This approach delivers excellent enantioselectivity and good yields at both the C1 and C3 positions of indolizine. These transformations are scalable and exhibit good functional group tolerance. A linear free-energy relationship between the property of the catalysts (% buried volume) and alkylation selectivity is demonstrated and a stereoselection model is proposed.