Scalable AnnulationApproach to Functionalized 1-Azabicycloalkanes

Abstract

Abstract A unified, scalable annulation strategy toward functionalized 1-azabicycloalkanes is presented, enabling the efficient preparation of 1-azabicyclo[3.2.0]heptane, pyrrolizidine, indolizidine, and quinolizidine cores. The approach relies on a reproducible and scalable α-alkylation of cyclic α-amino esters enabled by TMEDA-assisted lithium amide control, followed by intramolecular cyclization. Some key structure–reactivity relationships governing annulation efficiency are identified, and the resulting bicyclic amines are shown to be compatible with standard medicinal chemistry workflows, providing practical access to underrepresented three-dimensional chemical space.