Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States.
Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, Georgia 30322, United States.
J Am Chem Soc. 2024 Nov 27;146(47):32276-32282. doi: 10.1021/jacs.4c12121. Epub 2024 Nov 12.
We report an efficient total synthesis of (±)-phaeocaulisin A, a guaianolide sesquiterpene natural product possessing a complex tetracyclic skeleton embedded with an oxaspirolactone and a fused bicyclic lactone, four oxygen-containing stereocenters, and an 8-oxabicyclo[3.2.1]octane core. Our synthesis features a novel palladium-catalyzed cyclopropanol ring-opening carbonylation to access a key γ-ketoester, a chemo- and stereoselective aldol cyclization to form the seven-membered carbocycle, and a cascade ketalization-lactonization to construct the desired tetracyclic skeleton. With these strategically important C-C and C-O bond formation transformations, a 10-step total synthesis of (±)-phaeocaulisin A was achieved. We further developed the cyclopropanol ring-opening carbonylation chemistry to provide an alternative approach to prepare γ-ketoesters. Biologically, the penultimate intermediate with an α-methylene γ-butyrolactone moiety was identified as a promising lead compound with anticancer proliferation activity against a panel of triple-negative or HER2+ breast cancer cell lines.
我们报告了（±）-绵马素 A 的高效全合成，（±）-绵马素 A 是一种具有复杂四环骨架的愈创木烷型倍半萜天然产物，其中包含一个氧杂螺内酯和一个稠合双环内酯、四个含氧立体中心以及一个 8-氧杂双环[3.2.1]辛烷核心。我们的合成方法具有新颖的钯催化环丙醇开环羰基化反应，可获得关键的γ-酮酯，以及立体选择性的醛醇缩合反应，形成七元碳环，以及级联缩酮化-内酯化反应，构建所需的四环骨架。通过这些具有战略重要性的 C-C 和 C-O 键形成转化，实现了（±）-绵马素 A 的 10 步全合成。我们进一步开发了环丙醇开环羰基化化学，提供了一种替代方法来制备γ-酮酯。在生物学方面，具有α-亚甲基γ-丁内酯部分的倒数第二个中间体被鉴定为一种有前途的先导化合物，对一组三阴性或 HER2+乳腺癌细胞系具有抗癌增殖活性。
