title: Total synthesis, relay synthesis, and structural confirmation of the C18-norditerpenoid alkaloid neofinaconitine.
abstract: 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 siloxydiene component 36 with a sterically demanding bromine substituent. Subsequent Mannich-type N-acyliminium and radical cyclizations provide complete hexacyclic skeleton 33 of the aconitine alkaloids. Key endgame transformations include the 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 side chain 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.
authors.affiliation: Tri-Institutional PhD Program in Chemical Biology, ‡Molecular Pharmacology & Chemistry Program, and Tri-Institutional Research Program, Memorial Sloan-Kettering Cancer Center , 1275 York Avenue, Box 422, New York, New York 10065, United States.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Shi
authors.forename: Jeremy T
authors.initials: JT
authors.lastname: Wilmot
authors.forename: Lars Ulrik
authors.initials: LU
authors.lastname: Nordstrøm
authors.forename: Derek S
authors.initials: DS
authors.lastname: Tan
authors.forename: David Y
authors.initials: DY
authors.lastname: Gin
mesh_terms: D000157:Aconitine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D018360:Crystallography, X-Ray; D061565:Cycloaddition Reaction; D004224:Diterpenes / Q000138:chemical synthesis* / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure
chemical_list: D004224:Diterpenes; C000588873:neofinaconitine; D000157:Aconitine
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