具有新颖骨架的木藜芦烷类毒素Mollanol A的全合成研究

Two new grayanoids, mollanol A and rhodomollein XXV , were isolated from the fruits of Rhododendron molle in 2014. Mollanol A possesses a new C-nor-D carbon skeleton and exhibited transcriptional activation effects on the xbp1 upstream promoter in IEC-6, 293T, and RAW264.7 cells, which has potential therapeutic value for inflammatory bowel disease.This project focuses on the total synthesis of Mollanol A , based upon its structural characteristics of molecular framework and relationship of the eight stereocenters，we proposed a synthesis of Mollanol A, a pentacyclic molecule, featuring tandem palladium- catalyzed dearomative cyclization/oxa-Michael addition reaction、Lithium-Halogen exchange induced epoxide ring- opening reaction as key steps. The absolute configuration of C-3 would be introduced by CBS asymmetric reduction, which could control the stereochemistry of other chiral centers. By the tandem dearomative cyclization/oxa-Michael addition reaction, the [3,2,1] bridge ring system could be installed, namely, the two quaternary carbon stereocenter could be formed in one step.

两个结构新颖的木藜芦烷类毒素Mollanol A和Rhodomollein XXV于2014年从闹羊花的果实中分离得到。Mollanol A具有新的C/D骈合的碳环结构并对IEC-6, 293T, and RAW264.7三种细胞里的xbp1上游启动子具有转录激活效应,对炎症性肠病具有潜在的治疗价值。本课题将对Mollanol A开展全合成研究，通过考察分子骨架结构特征以及8个手性中心的相互联系，提出以钯催化的去芳香化关环与氧杂-Michael加成的串联反应、卤锂交换促进的环氧开环反应作为关键步,构筑该分子的五环体系。合成特色在于通过CBS不对称还原引入C-3 位的绝对构型，进而控制其控制其它立体中心的建立；路线中采用去芳香化关环与氧杂-Michael加成的串联反应构建分子骨架的[3,2,1]桥环结构,同时一步生成两个季碳中心。

天然产物mollanol A是2014年从闹羊花的果实中分离得到的一种新的木藜芦烷类毒素，具有新颖的碳环结构和良好的生物活性。本项目主要对天然产物mollanol A开展全合成研究。我们通过设计关键的Pd催化的关环反应来快速构筑该分子的核心骨架。经过三年的努力，本项目组首先发展了一条能够以线性10步和克级规模制备关键关环前体的合成路线，然后以此为底物开发了一种新颖的Pd催化的乙烯基邻芳基化反应。利用该方法，项目组完成了对天然产物mollanol A[5/6/7]三环骨架的快速构建。同时，将新发展的催化体系经过改良成功应用到了氮杂[4.3.1]桥环骨架的构建中。以上工作为最终完成mollanol A的全合成以及类似物的合成奠定了良好的基础。