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

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• 作者：Yuan Shi ; Jeremy T. Wilmot ; Lars Ulrik Nordstr酶m ; Derek S. Tan ; David Y. Gin
• 刊名：Journal of the American Chemical Society
• 出版年：2013
• 出版时间：September 25, 2013
• 年：2013
• 卷：135
• 期：38
• 页码：14313-14320
• 全文大小：509K
• 年卷期：v.135,no.38(September 25, 2013)
• ISSN：1520-5126

文摘

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鈥揂lder cycloaddition between two unstable components, cyclopropene 10 and cyclopentadiene 11. A second Diels鈥揂lder 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.