C−H Glycosylation of Native Carboxylic Acids: Discovery of Antidiabetic SGLT‑2 Inhibitors
C−H Glycosylation of Native Carboxylic Acids: Discovery of Antidiabetic SGLT‑2 Inhibitors，
Sanshan Wang, Kaiqi Chen, Fusheng Guo, Wenneng Zhu, Chendi Liu, Haoran Dong, Jin-Quan Yu,*and Xiaoguang Lei*
https://doi.org/10.1021/acscentsci.3c00201
Publication Date:June 9, 2023
C-Glycosides are critical motifs embedded in many bioactive natural products. The inert C-glycosides are privileged structures for developing therapeutic agents owing to their high chemical and metabolic stability. Despite the comprehensive strategies and tactics established in the past few decades, highly efficient C-glycoside syntheses via C−C coupling with excellent regio-, chemo-, and stereoselectivity are still needed. Here, we report the efficient Pd-catalyzed glycosylation of C−H bonds promoted by weak coordination with native carboxylic acids without external directing groups to install various glycals to the structurally diverse aglycon parts. Mechanistic evidence points to the participation of a glycal radical donor in the C−H coupling reaction. The method has been applied to a wide range of substrates (over 60 examples), including many marketed drug molecules. Natural product- or drug-like scaffolds with compelling bioactivities have been constructed using a late-stage diversification strategy. Remarkably, a new potent sodium-glucose cotransporter-2 inhibitor with antidiabetic potential has been discovered, and the pharmacokinetic/ pharmacodynamic profiles of drug molecules have been changed using our C−H glycosylation approach. The method developed here provides a powerful tool for efficiently synthesizing C-glycosides to facilitate drug discovery.
C−H Glycosylation of Native Carboxylic Acids: Discovery of Antidiabetic SGLT‑2 Inhibitors，
Sanshan Wang, Kaiqi Chen, Fusheng Guo, Wenneng Zhu, Chendi Liu, Haoran Dong, Jin-Quan Yu,*and Xiaoguang Lei*
https://doi.org/10.1021/acscentsci.3c00201
Publication Date:June 9, 2023
C-Glycosides are critical motifs embedded in many bioactive natural products. The inert C-glycosides are privileged structures for developing therapeutic agents owing to their high chemical and metabolic stability. Despite the comprehensive strategies and tactics established in the past few decades, highly efficient C-glycoside syntheses via C−C coupling with excellent regio-, chemo-, and stereoselectivity are still needed. Here, we report the efficient Pd-catalyzed glycosylation of C−H bonds promoted by weak coordination with native carboxylic acids without external directing groups to install various glycals to the structurally diverse aglycon parts. Mechanistic evidence points to the participation of a glycal radical donor in the C−H coupling reaction. The method has been applied to a wide range of substrates (over 60 examples), including many marketed drug molecules. Natural product- or drug-like scaffolds with compelling bioactivities have been constructed using a late-stage diversification strategy. Remarkably, a new potent sodium-glucose cotransporter-2 inhibitor with antidiabetic potential has been discovered, and the pharmacokinetic/ pharmacodynamic profiles of drug molecules have been changed using our C−H glycosylation approach. The method developed here provides a powerful tool for efficiently synthesizing C-glycosides to facilitate drug discovery.
