Enantioselective Total Synthesis of (−)-Vallesamidine Enabled by Asymmetric Hydrogenation and Aza-Wacker Cyclization to Construct the Core Spirocyclopentane-1,2′-indoline Structure

An enantioselective total synthesis of (-)-vallesamidine is described, integrating asymmetric hydrogenation with aza-Wacker cyclization to form the chiral spirocyclopentane-1,2'-indoline. Intramolecular Stetter reaction and alkylation are employed to construct a tetracyclic framework featuring a chiral quaternary carbon center. Schmidt rearrangement and intramolecular aldol condensation facilitate the formation of the D and E rings. This synthesis achieves (-)-vallesamidine in 14 steps in an overall yield of 4.2% from an exocyclic enone ester.