One-Flow, Multistep Synthesis of Nucleosides by Bronsted Acid-Catalyzed Glycosylation

摘要

Nucleosides and their structural variants are a well-established and important class of antiviral and anticancer agents. More recently, they have become the chemical centerpiece of the development of genetic therapies, biological probes, and modern DNA sequencing technologies, as well as investigations into the molecular mechanisms of chemical carcinogenesis and DNA repair. Due to this broad utility, the development of more efficient methods for the synthesis of nucleoside analogues remains a high priority. Currently the most widely used method of ribonucleoside synthesis is the Vorbrtiggen modification of the silyl-Hilbert-Johnson reaction. This approach assembles the important nucleosidic bond by joining a glycosyl donor with a silylated nucleobase, under Lewis acid promotion. A high-throughput two-step glycosylation/deprotection sequence for the synthesis of nucleoside libraries is a notable recent improvement. Nevertheless, despite these advances the stoichiometric use of Lewis acids, e.g., trimethylsilyl triflate (TMSOTf), remains the state of the art. The limitations of this requirement are not insignificant and include the functional group compatibility of the Lewis acid and the quenching, separation, and disposal thereof, particularly on preparative scale.