Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, 35053, Taiwan.
Department of Chemistry, National Tsing Hua University, Hsinchu, 30013, Taiwan.
Angew Chem Int Ed Engl. 2018 Nov 19;57(47):15572-15576. doi: 10.1002/anie.201809130. Epub 2018 Oct 30.
The first total synthesis of isopalhinine A, as well as unified syntheses of palhinine A and palhinine D, were successfully accomplished by means of a biomimetic strategy that proceeds through a bioinspired 5/6/6/9 tetracyclic intermediate, which mimics the amino ketone form of palhinine D. An early-stage direct S 2 cyclization to construct the nine-membered azonane ring minimized the transannular strain that would otherwise be increased by the twisted nature of the isotwistane skeleton. Then, a diastereoselective Diels-Alder reaction of a masked ortho-benzoquinone using the nine-membered ring as a steric shielding group furnished a functionalized 6/6/9 tricyclic skeleton and established the desired stereochemistry at the C3, C7, C12, and C15 positions in one step. A thiol-mediated acyl radical cyclization gave the bioinspired intermediate bearing three differentiated oxygen-containing functional groups, from which all three total syntheses could be completed in either two or three additional steps.
成功地通过仿生 5/6/6/9 四环中间体的生物模拟策略，实现了异紫堇灵 A 的首次全合成，以及紫堇灵 A 和 D 的统一合成。该中间体模拟了紫堇灵 D 的氨基酮形式。早期的直接 S 2 环化反应构建了九元氮杂烷环，最大限度地减少了 otherwise 会因 isotwistane 骨架的扭曲性质而增加的跨环应变。然后，使用九元环作为空间位阻屏蔽基团的掩蔽邻苯醌进行非对映选择性 Diels-Alder 反应，提供了功能化的 6/6/9 三环骨架，并在一步中确定了 C3、C7、C12 和 C15 位置的所需立体化学。硫醇介导的酰基自由基环化反应得到了带有三个不同含氧官能团的仿生中间体，从该中间体出发，可以通过另外两步或三步完成所有三种全合成。
