New Saturated Bicyclic Pyrrolidines: The Multigram Synthesis and Orthogonal Functionalization

A practical and scalable strategy for the synthesis and functionalization of saturated pyrrolidine-based bicyclic scaffolds has been developed. Starting from commercially available cyclic β-keto esters, a two- or four-step sequence enabled efficient access to condensed 2-pyrrolidones in high yields. Seven structurally distinct bicyclic systems were prepared, each bearing a carboxyl group at the nodal 3a-position, serving as a versatile handle for downstream transformations. Strategic use of orthogonal protecting groups (Bn, Boc, and Cbz) facilitated purification and enabled selective modifications. Curtius rearrangement allowed direct conversion of the carboxylic acid into the corresponding amine, while further diversification included reduction to alcohols, Swern oxidation to aldehydes, mesylation–azidation–reduction, and thiolation–oxidation to sulfonyl chlorides. All transformations were conducted under mild, operationally simple conditions and demonstrated good functional group tolerance. The described methodology provides a robust platform for accessing medicinally relevant pyrrolidine-based bicyclic building blocks and offers practical advantages for application in drug discovery and process chemistry.