Department of Chemistry, University of Chicago, 5735 South Ellis Avenue, Chicago, Illinois 60637, United States.
J Am Chem Soc. 2021 Aug 11;143(31):11951-11956. doi: 10.1021/jacs.1c05942. Epub 2021 Aug 2.
The annotinolides are one of the most recent additions to the family of alkaloids, with its members possessing challenging, caged structures that include a [3.2.1]-bicyclic core bearing six contiguous stereocenters, including four that are fully substituted. Herein, we document a concise and stereoselective route that achieves the first total syntheses of three of its members: annotinolides C, D, and E. Key operations include a gold(I)-catalyzed Conia-ene reaction that fashions much of the main core in a single operation, as well as a number of other challenging and chemoselective transformations to generate the remaining elements. Moreover, efforts utilizing the natural products themselves, seeking adjustments in their oxidation states and the rearrangement of individual ring systems, shed light on their potential biogenesis with some outcomes counter to those originally proposed. Finally, formal enantioenriched syntheses of the target molecules are also presented.
annotinolides 是生物碱家族中最新的成员之一，其成员具有具有挑战性的、笼状结构，包括一个带有六个连续立体中心的[3.2.1]-双环核心，其中四个完全取代。在此，我们记录了一条简洁和立体选择性的路线，实现了其三个成员的首次全合成：annotinolides C、D 和 E。关键操作包括金（I）催化的 Conia-ene 反应，该反应在单个操作中形成了大部分主要核心，以及许多其他具有挑战性和化学选择性的转化，以生成其余元素。此外，利用天然产物本身的努力，寻求它们氧化态的调整和单个环系统的重排，揭示了它们潜在的生物发生，有些结果与最初提出的相反。最后，还提出了目标分子的正式对映体富集合成。
