Second-Generation Enantioselective Synthesis of the Tricyclic ABC Core of Daphnicyclidin A

Studies have led to a preparative-scale synthesis of the tricyclic ABC ring system of daphnicyclidin A (1). The stereoselective pathway, affording non-racemic 5, demonstrates a number of efficient reactions that are broadly applicable for the synthesis of related heterocyclic systems. Highlights include the asymmetric nickel hydride reduction of conjugated enone 11, enantiocontrolled reactions of chiral alkenylzinc reagents, a direct formation of 4-hydroxy-2-cycloheptene-1-ones via ring-closing metathesis, and the intramolecular cyclization of allylsilanes and amines to directly afford piperidines. In addition, pyrrolidinone hydrotribromide has proven to be a mild reagent for the selective α-bromination of cycloheptanones 36 and 37. These processes are robust and have considerable utility for the enantioselective synthesis of novel alkaloids.