Chen Bolin, Wu Qianwei, Xu Dongdong, Zhang Xijing, Ding Yahui, Bao Shiqi, Zhang Xuemei, Wang Liang, Chen Yue
State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, 38 Tongyan Road, Tianjin, 300353, P. R. China.
College of Chemistry, Nankai University, 94 Weijin Road, Tianjin, 300071, P. R. China.
Angew Chem Int Ed Engl. 2022 May 2;61(19):e202117476. doi: 10.1002/anie.202117476. Epub 2022 Feb 25.
Alterbrassicicene D (1) and 3(11)-epoxyhypoestenone (2) were synthesised via a two-phase approach featuring concise construction of the 5-8-5 tricyclic intermediate and a tandem base-mediated epoxide opening-transannular oxa-Michael addition cascade to forge the complex skeleton of 2. The route is scalable and we generated 15 g of the tricyclic intermediate in 8 steps from (R)-limonene and 720 mg of the penultimate bioactive intermediate in a protecting-group-free manner. Our synthesis enabled the structural determination of 2 and provided materials for preliminary anticancer evaluation. The penultimate intermediate showed therapeutic potential in terms of its ability to dramatically reduce the tumourigenic potential of PANC-1 pancreatic cancer cells according to a limiting dilution tumour-initiating assay. Our synthetic approach will facilitate unified access to naturally occurring fusicoccanes and their derivatives for anticancer evaluation.
通过一种两相方法合成了变油菜素烯D（1）和3(11)-环氧次烯酮（2），该方法的特点是简洁构建5-8-5三环中间体，并通过串联碱介导的环氧化物开环-跨环氧杂迈克尔加成级联反应来构建2的复杂骨架。该路线具有可扩展性，我们以（R）-柠檬烯为原料，经过8步反应生成了15克三环中间体，并以无保护基的方式生成了720毫克倒数第二个生物活性中间体。我们的合成方法实现了对2的结构测定，并为初步抗癌评估提供了材料。根据有限稀释肿瘤起始试验，倒数第二个中间体显示出显著降低PANC-1胰腺癌细胞致瘤潜力的治疗潜力。我们的合成方法将有助于统一获取天然存在的镰刀菌烷及其衍生物以进行抗癌评估。
