An Efficient Approach to the Synthesis of Nucleosides: Gold(I)-Catalyzed N-Glycosylation of Pyrimidines and Purines with Glycosyl ortho-Alkynyl Benzoates

摘要

The synthesis of nucleosides has continuously been a topical subject in efforts to develop new therapeutic agents (e.g., antitumor and antiviral drugs), to manipulate genetic processes (e.g., antisense oligonucleotides and RNA interference), and to expand the genetic code and understand the scope and limits of Watson-Crick base pairing. However, the key technique for such syntheses, namely, the N-glycosidic coupling of sugars and nitrogen heterocycles, is rather conventional. A Vorbriiggen-type reaction involving the coupling of sugar acetates with trimethylsilylated nucleobases under the action of strong Lewis acids (mostly stoichiometric amounts of trimethylsilyl triflate and SnCl4) is still the predominant method. The coupling yields are not always high. In particular, when purines are used, low coupling yields (or even failure of the reaction to occur) and moderate N9/N7 regioselectivity have been encountered. Protecting groups and temporary substituents have thus been introduced onto purines to enhance their reactivity and hinder the reaction of nonglycosylated nitrogen atoms. However, the choice of protecting groups is limited by the harsh conditions required for Vorbriiggen-type reactions. Variation of the anomeric leaving group of the glycosyl donors could enable N-glyco-sylation under milder conditions. However, only limited success has been reported for nucleoside synthesis with privileged O-glycosylation donors, including glycosyl chlor-ides/bromides, trichloroacetimidates, phosphites, sulfoxides, thioglycosides, n-pentenyl glycosides, and sugar 1,2-anhydrides.One rationale is that nucleobases are poorly nucleophilic (and often poorly soluble) and thus compete unfavorably for glycosidation with other nucleo-philic species that occur in a glycosylation system, such as those derived from the leaving groups and promoters.