Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine, Irvine, CA, 92697, USA.
Angew Chem Int Ed Engl. 2019 Nov 4;58(45):16193-16197. doi: 10.1002/anie.201910129. Epub 2019 Sep 25.
(-)-Himeradine A is a complex lycopodium alkaloid with seven rings and ten stereogenic centers that shows anticancer activity against lymphoma L1210 cells. A total synthesis has been developed that builds off prior work on (+)-fastigiatine. A 2,4,6-trisubstitited piperidine ring forms the core of the quinolizidine segment, and was prepared by diastereoselective reduction of a pyridine and classic resolution of an intermediate. The remaining secondary amine was introduced with a catalyst-controlled Overman rearrangement. The piperidine segment was coupled in a B-alkyl Suzuki reaction with a bicyclic bromoenone, which was a key intermediate for the synthesis of (+)-fastigiatine. The final transformation featured a transannular Mannich reaction and cyclization to complete the quinolizidine. Five bonds and four new rings were generated in this one-pot procedure. (-)-Himeradine A was prepared in 17 steps in the longest linear sequence.
(-)-海麦灵 A 是一种具有七个环和十个手性中心的复杂石松生物碱,对淋巴瘤 L1210 细胞具有抗癌活性。我们开发了一种全合成方法,该方法是基于 (+)-千金藤碱的前期工作。一个 2,4,6-三取代的哌啶环形成喹诺里定部分的核心,通过吡啶的非对映选择性还原和中间产物的经典拆分来制备。其余的仲胺是通过催化剂控制的 Overman 重排引入的。哌啶部分在 B-烷基 Suzuki 反应中与双环溴烯酮偶联,这是合成 (+)-千金藤碱的关键中间体。最后一步是通过反环 Mannich 反应和环化完成喹诺里定的合成。在这个一锅法反应中生成了五个键和四个新环。(-)-海麦灵 A 通过最长线性序列的 17 步反应制备。