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

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.

本研究首次报道了C18-去二萜类乌头生物碱（aconitine alkaloid）新乌头原碱（neofinaconitine）的全合成，以及从牛扁碱（condelphine）出发完成新乌头原碱与9-脱氧高乌甲素（9-deoxylappaconitine）的接力合成。该研究采用模块化汇聚式合成策略，首先利用两个不稳定底物——环丙烯10与环戊二烯11——发生狄尔斯-阿尔德（Diels–Alder）环加成反应。第二次狄尔斯-阿尔德反应则首次使用了氮杂卓酮亲双烯体（azepinone dienophile）8，并通过对带有位阻较大溴取代基的硅氧二烯底物36进行合理设计，实现了优异的非对映面选择性。后续通过曼尼希型（Mannich-type）N-酰基亚胺环化与自由基环化反应，构建出乌头生物碱类化合物完整的六环骨架33。关键的终末阶段转化包括：通过水对假定的张力型桥头烯酮中间体45的共轭加成，引入C8位羟基；以及对C4侧链进行单碳氧化截断，最终得到外消旋新乌头原碱。本研究通过从牛扁碱出发完成(+)-新乌头原碱与(+)-9-脱氧高乌甲素的简洁接力合成，并对前者进行X射线晶体衍射分析，完成了完整的结构确证；该工作澄清了此前被认定为相同结构的新乌头原碱与delphicrispuline之间的核磁共振（NMR）谱图差异。