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.
J Am Chem Soc. 2013 Sep 25;135(38):14313-20. doi: 10.1021/ja4064958. Epub 2013 Sep 16.
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.
首次全合成了 C18-降二萜类乌头碱生物碱新福乌头碱，并从康德菲林出发进行了新福乌头碱和 9-去氧拉帕碱的接力合成。一种模块化、会聚的合成方法涉及两个不稳定组分环丙烯 10 和环戊二烯 11 之间的初始 Diels-Alder 环加成。第二个 Diels-Alder 反应的特点是首次使用了氮杂环庚酮二烯亲二烯体（8），通过具有空间位阻的溴取代基的硅氧二烯组分 36 的合理设计，实现了高非对映选择性。随后的 Mannich 型 N-酰亚胺基和自由基环化提供了乌头碱生物碱的完整六环骨架 33。关键的最终转化包括通过水对假定的桥头烯酮中间体 45 进行共轭加成安装 C8-羟基，以及通过 C4 侧链的一碳氧化截断得到外消旋新福乌头碱。通过从康德菲林出发的 (+)-新福乌头碱和 (+)-9-去氧拉帕碱的简明接力合成提供了完整的结构确证，并对前者进行了 X 射线晶体学分析，澄清了新福乌头碱和 delphicrispuline 之间的 NMR 光谱差异，此前它们被分配了相同的结构。
