Laboratory of Synthesis and Natural Products, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, EPFL-SB-ISIC-LSPN, BCH5304, 1015, Lausanne, Switzerland.
Nat Commun. 2021 Jan 4;12(1):36. doi: 10.1038/s41467-020-20274-1.
Elegant asymmetric synthesis of hasubanan alkaloids have been developed over the past decades. However, a divergent approach leading to all three sub-classes of this family of natural products remains unknown. We report herein the realization of such an endeavor by accomplishing enantioselective total syntheses of four representative members. The synthesis is characterized by catalytic enantioselective construction of the tricyclic compounds from which three different intramolecular C-N bond forming processes leading to three topologically different hasubanan alkaloids are developed. An aza-Michael addition is used for the construction of the aza-[4.4.3]-propellane structure of (-)-cepharamine, whereas an oxidation/double deprotection/intramolecular hemiaminal forming sequence is developed to forge the bridged 6/6/6/6 tetracycle of (-)-cepharatines A and C and a domino bromination/double deprotection/cyclization sequence allows the build-up of the 6/6/5/5 fused tetracyclic structure of (-)-sinoracutine.
在过去的几十年中，人们已经开发出了优雅的非对映选择性合成hasubanan 生物碱的方法。然而，一种导致该家族所有三种天然产物亚类的发散方法仍然未知。我们在此报告了通过完成四个代表性成员的对映选择性全合成来实现这一目标的情况。该合成的特点是通过催化对映选择性构建三环化合物，从而开发出三种不同的分子内 C-N 键形成过程，从而得到三种拓扑结构不同的 hasubanan 生物碱。氮杂-[4.4.3]-丙烷结构的 (-)-cephalamine 是通过氮杂迈克尔加成构建的，而桥连的 6/6/6/6 四环 (-)-cephalatines A 和 C 的形成则是通过氧化/双重脱保护/分子内半亚胺形成序列来实现的，并且一个串联的溴化/双重脱保护/环化序列允许构建 (-)-sinoracutine 的 6/6/5/5 稠合四环结构。
