Pd-Catalyzed Stereospecific Glycosyl Cross-Coupling of Reversed Anomeric Stannanes for Modular Synthesis of Nonclassical <i>C</i>-Glycosides
Guoqiang Cheng, Bo Yang, Yang Han, Wei Lin, Siyuan Tao, Yong Nian, Yingzi Li, Maciej A. Walczak, Feng Zhu
Abstract
High Resolution Image Download MS PowerPoint Slide Nonclassical C -glycosides, distinguished by their unique glycosidic bond connection mode, represent a promising avenue for the development of carbohydrate-based drugs. However, the accessibility of nonclassical C -glycosides hinders broader investigations into their structural features and modes of action. Herein, we present the first example of Pd-catalyzed stereospecific glycosylation of nonclassical anomeric stannanes with aryl or vinyl halides. This method furnishes desired nonclassical aryl and vinyl C -glycosides in good to excellent yields, while allowing for exclusive control of nonclassical anomeric configuration. Of significant note is the demonstration of the generality and practicality of this nonclassical C -glycosylation approach across more than 50 examples, encompassing various protected and unprotected saccharides, deoxy sugars, oligopeptides, and complex molecules. Furthermore, biological evaluation indicates that nonclassical C -glycosylation modifications of drug molecules can positively impact their biological activity. Additionally, extensive computational studies are conducted to elucidate the rationale behind differences in reaction reactivity, unveiling a transmetalation transition state containing silver (Ag) within a six-membered ring. Given its remarkable controllability, predictability, and consistently high chemical selectivity and stereospecificity regarding nonclassical anomeric carbon and Z/E configuration, the method outlined in this study offers a unique solution to the longstanding challenge of accessing nonclassical C -glycosides with exclusive stereocontrol.