Total Synthesis Relay Synthesis and Structural Confirmation of the C18-Norditerpenoid Alkaloid Neofinaconitine

摘要

The first total synthesis of the C18-norditerpenoid aconitine alkaloid neofinaconitine and relay syntheses of neofinaconitine and 9-deoxylappaconitine from condelphine are reported. A modular, convergent synthetic approach involves initial Diels–Alder cycloaddition between two unstable components, cyclopropene >10 and cyclopentadiene >11. A second Diels–Alder reaction features the first use of an azepinone dienophile >8, with high diastereofacial selectivity achieved via rational design of the siloxydiene component >36 with a sterically-demanding bromine substituent. Subsequent Mannich-type N-acyliminium and radical cyclizations provide the complete hexacyclic skeleton >33 of the aconitine alkaloids. Key endgame transformations include installation of the C8-hydroxyl group via conjugate addition of water to a putative strained bridghead enone intermediate >45, and one-carbon oxidative truncation of the C4 sidechain to afford racemic neofinaconitine. Complete structural confirmation was provided by a concise relay synthesis of (+)-neofinaconitine and (+)-9-deoxylappaconitine from condelphine, with X-ray crystallographic analysis of the former clarifying the NMR spectral discrepancy between neofinaconitine and delphicrispuline, which were previously assigned identical structures.