Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an 710054, China.
School of Chemistry and Chemical Engineering/Key Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan, Shihezi University, Shihezi 832003, China.
J Org Chem. 2020 Apr 3;85(7):4813-4837. doi: 10.1021/acs.joc.0c00022. Epub 2020 Mar 24.
Tiglianes such as prostratin and related diterpenoids are biologically significant natural molecules and long-standing targets for organic synthesis community. Due to the complex polycyclic scaffolds, high oxygenation level, and dense functional groups and stereocenters, their de novo chemical syntheses still face formidable challenges despite extensive efforts in the past 40 years. This account details the development of a modular and concise synthesis of prostratin, a potent anti-HIV and anticancer agent. The key approach in this synthesis involved a sequence of oxidative dearomatization and sequential stereoselective installation of peripheral groups to rapidly build the contiguously substituted cyclohexane C-ring. Inspired by Wender's work, an acid- and solvent-controlled stereodivergent formation of cyclopropane D-ring was developed. Mechanistic investigations by computational methods revealed that the competition between intra- and intermolecular hydrogen bonding led to different conformations, thus favoring different protonation processes. The designed and unexpected chemistry along this campaign reflected the uniqueness of the natural structures and should be amenable to future chemical syntheses of related complex polycyclic molecules.
标题：天然产物紫杉烷类化合物的全合成研究进展
紫杉烷类如 Prostratin 及其相关二萜类化合物是具有重要生物学意义的天然分子，也是有机合成领域长期以来的研究目标。尽管过去 40 年来人们进行了广泛的研究，但由于其复杂的多环骨架、高氧化水平以及丰富的功能基团和立体中心，其从头合成仍然面临着巨大的挑战。本研究详细介绍了一种 Prostratin （一种有效的抗 HIV 和抗癌药物）的模块化、简洁合成方法。该合成方法的关键步骤包括一系列氧化去芳构化和外围基团的立体选择性分步安装，以快速构建连续取代的环己烷 C 环。受 Wender 工作的启发，开发了一种酸和溶剂控制的环丙烷 D 环立体发散形成方法。通过计算方法进行的机理研究表明，分子内和分子间氢键之间的竞争导致了不同的构象，从而有利于不同的质子化过程。在这一过程中，设计和意想不到的化学反应反映了天然结构的独特性，并且应该适用于未来相关复杂多环分子的化学合成。
