Department of Chemistry and Shenzhen Grubbs Institute , Southern University of Science and Technology , Shenzhen , China.
J Am Chem Soc. 2019 Jul 24;141(29):11713-11720. doi: 10.1021/jacs.9b05641. Epub 2019 Jul 12.
The intriguing structural complexity and bioactivities of the alkaloids have long attracted much attention. Herein, we report the first and enantioselective total synthesis of alkaloid dapholdhamine B and its lactone derivative. The chemical structure of dapholdhamine B contains a unique aza-adamantane core skeleton and eight contiguous stereocenters, including three contiguous fully substituted stereocenters, which present a formidable synthetic challenge. This concise approach used to achieve the first synthesis of an aza-adamantane natural product features a vinylogous Mannich reaction, an optimized α-bromo-α,β-unsaturated ketone synthesis, a substrate-dependent intramolecular aza-Michael addition, a key annulation via amide activation, an S2'-type lactonization, and a facile Horner-Wadsworth-Emmons reaction that converts the hemiacetal moiety to the corresponding homologated carboxylic acid.
生物碱结构的复杂性和生物活性一直引起人们的广泛关注。在此，我们首次完成了 dapholdhamine B 及其内酯衍生物的对映选择性全合成。 dapholdhamine B 的化学结构含有独特的氮杂金刚烷核心骨架和八个连续的手性中心，其中包括三个连续完全取代的手性中心，这给合成带来了巨大的挑战。该简洁的方法首次实现了氮杂金刚烷天然产物的合成，其特征在于乙烯基曼尼希反应、优化的α-溴-α，β-不饱和酮合成、底物依赖性分子内氮杂迈克尔加成、通过酰胺活化的关键环化反应、S2'-型内酯化以及易于实施的 Horner-Wadsworth-Emmons 反应，该反应将半缩醛部分转化为相应的同系化羧酸。
