Max-Planck-Institut für Kohlenforschung, 45470, Mülheim/Ruhr, Germany.
Angew Chem Int Ed Engl. 2021 Jan 4;60(1):446-454. doi: 10.1002/anie.202011472. Epub 2020 Nov 3.
Total synthesis allowed the constitution of the cytotoxic marine macrolides of the formosalide family to be confirmed and their previously unknown stereostructure to be assigned with confidence. The underlying blueprint was inherently modular to ensure that each conceivable isomer could be reached. This flexibility derived from the use of strictly catalyst controlled transformations to set the stereocenters, except for the anomeric position, which is under thermodynamic control; as an extra safety measure, all stereogenic centers were set prior to ring closure to preclude any interference of the conformation adopted by the macrolactone rings of the different diastereomers. Late-stage macrocyclization by ring-closing alkyne metathesis was followed by a platinum-catalyzed transannular 6-exo-dig hydroalkoxylation/ketalization to craft the polycyclic frame. The side chain featuring a very labile unsaturation pattern was finally attached to the core by Stille coupling.
全合成工作允许确认 formosalide 家族的细胞毒性海洋大环内酯的结构，并自信地分配其先前未知的立体结构。基础蓝图具有固有模块性，以确保可以达到每种想象的异构体。这种灵活性源于使用严格受催化剂控制的转化来设置立体中心，除了端基碳原子的构型是热力学控制的；作为额外的安全措施，所有的手性中心都是在环闭合之前建立的，以排除不同非对映异构体的大环内酯环所采用的构象的任何干扰。通过炔烃复分解的环封闭反应进行晚期大环化反应，然后进行铂催化的反式 6-endo-立体选择性氢烷氧基化/缩酮化反应，以构建多环骨架。最后，通过 Stille 偶联将带有非常不稳定的不饱和模式的侧链连接到核心上。
