Asymmetric Synthesis and Biological Evaluation of Platensilin, Platensimycin, Platencin, and Their Analogs via a Bioinspired Skeletal Reconstruction Approach
Zong-Xu Gao, Hongliang Wang, Ai-Hong Su, Qian-Ying Li, Zhen Liang, Yueqing Zhang, Xuyuan Liu, Ming‐Zhu Zhu, Haixia Zhang, Yue-Tong Hou, Xin Li, Longru Sun, Jian Li, Zejun Xu, Hong‐Xiang Lou
Abstract
Platensilin, platensimycin, and platencin are potent inhibitors of β-ketoacyl–acyl carrier protein synthase (FabF) in the bacterial and mammalian fatty acid synthesis system, presenting promising drug leads for both antibacterial and antidiabetic therapies. Herein, a bioinspired skeleton reconstruction approach is reported, which enables the unified synthesis of these three natural FabF inhibitors and their skeletally diverse analogs, all stemming from a common ent -pimarane core. The synthesis features a diastereoselective biocatalytic reduction and an intermolecular Diels–Alder reaction to prepare the common ent -pimarane core. From this intermediate, stereoselective Mn-catalyzed hydrogen atom–transfer hydrogenation and subsequent Cu-catalyzed carbenoid C–H insertion afford platensilin. Furthermore, the intramolecular Diels–Alder reaction succeeded by regioselective ring opening of the newly formed cyclopropane enables the construction of the bicyclo[3.2.1]-octane and bicyclo[2.2.2]-octane ring systems of platensimycin and platencin, respectively. This skeletal reconstruction approach of the ent -pimarane core facilitates the preparation of analogs bearing different polycyclic scaffolds. Among these analogs, the previously unexplored cyclopropyl analog 47 exhibits improved antibacterial activity (MIC 80 = 0.0625 μg/mL) against S. aureus compared to platensimycin.