Innovative Strategies for the Construction of Diverse 1'-Modified C-Nucleoside Derivatives.

Abstract

Modified C-nucleosides have proven to be enormously successful as chemical probes to understand fundamental biological processes and as small-molecule drugs for cancer and infectious diseases. Historically, the modification of the glycosyl unit has focused on the 2'-, 3'-, and 4'-positions as well as the ribofuranosyl ring oxygen. By contrast, the 1'-position has rarely been studied due to the labile nature of the anomeric position. However, the improved chemical stability of C-nucleosides allows the modification of the 1'-position with substituents not found in conventional N-nucleosides. Herein, we disclose new chemistry for the installation of diverse substituents at the 1'-position of C-nucleosides, including alkyl, alkenyl, difluoromethyl, and fluoromethyl substituents, using the 4-amino-7-(1'-hydroxy-d-ribofuranosyl)pyrrolo[2,1-f][1,2,4]triazine scaffold as a representative purine nucleoside mimetic.