First Total Synthesis of Potent α-glycosidase and Protein Tyrosine Phosphatase 1B (PTP1B) Inhibitor Polyflavanostilbene B

2018-10-30

 Recently, Prof. Zhang Peicheng and his colleagues of Institute of Materia Medica (IMM), Chinese Academy of Medical Sciences, published a research article titled Iron-Catalyzed Synthesis of the Hexahydrocyclopenta[c]furan Core and Concise Total Synthesis of Polyflavanostilbene B in Angewandte Chemie International Edition (Angew. Chem. Int. Ed. 2018, 57,10127-10131). The research was conducted based on the polyflavanostilbene A (org. lett. 2013,15, 674-677), a polyphenolic potent α-glucosidase inhibitor derived from roots of Fallopia japonica (Houtt.) Ronse Decr, a common traditional Chinese medicine. The researchers realized total synthesis of polyflavanostilbene B, the hydrolysate of polyflavanostilbene A, from abundant polymeric (−)-epicatechin-3-gallate (ECG) on a gram scale in three steps without the use of protecting groups the first time. This research shows that polyflavanostilbene B is more potent than polyflavanostilbene A in inhibiting α-glucosidase (IC50=1.54μm) and protein tyrosine phosphatase 1B (PTP1B) (IC50=5.05μm). It lays a solid foundation for further development of antidiabetic drugs.

 

The synthesized polyflavanostilbene B is of complex tetracyclospiroenone structure and contains eight phenolic hydroxyl groups. It has seven contiguous stereocenters including two quaternary carbon centers, which challenges the synthesis. Researchers leverage a regioselective and stereoselective substitution of resveratrol to give the 4-derivative of ECG and an iron-catalyzed cyclization reaction to obtain the compound. The research group also discusses the cyclization mechanism in the formation of the hexahydrocyclopenta[c]furan core. This strategy may also apply to the synthesis of other hexahydrocyclopenta[c]furan analogs.

 

Zhang Peicheng’s research group has been devoted to discovery and structure transformation of novel compounds from common traditional Chinese medicines. They have made some progress. The research was funded by the CAMS Innovation Fund for Medical Sciences (CIFMS-2016-I2M-1-010).

 

 

 

 

 

(Institute of Materia Medica)