Lithiation-Based Silylation and Stannylation for Nucleoside Synthesis

Abstract

This chapter focuses on a series of study that extend lithiation chemistry to nucleosides other than 2',3'-O-isopropylideneuridine. It discusses lithiation reactions in which silicon and tin reagents are used as electrophiles to show that it is applicable to nucleosides in general and that it is an efficient alternative to the existing nucleophilic (addition-elimination) reactions, especially for the introduction of carbon functionalities. The first study involves C8-lithiation of 6-chloro-9-(2,3-O-isopropylidene-β-D-ribofuranosyl)purine for the synthesis of 8-carbon-substituted adenosines, 6-thioinosines, and nebularines, using Me3SiCl was used as an electrophile. An alternative lithiation-based C2-substitution of 6-chloropurine riboside has become feasible by introducing a triisopropylsilyl group to the 8-position of 9-(2,3-O-isopropylidene-5-O-trityl-β-D-ribofuranosyl)-6-chloropurine. Lithiation of this substrate constitutes the first evident generation of C2-lithiated species of purine nucleosides. Addition of various types of electrophiles to the lithiated species of 6-chloro-8-(triisopropylsilyl)purine riboside has provided a more general entry to 2-substituted derivatives. Removal of the 8-triisopropylsilyl group can be effected either with NH3 in MeOH, which gives the corresponding adenosine derivative, or with Bu4NF. An anionic migration of silyl and stannyl groups was also observed in the lithiation of 1-[3,5-bis-O-(tert-butyldimethylsilyl)-2-deoxy-D-erythro-pent-1-enofuranosyl]uracil, from the 6-position of the base to the 2'-position of its glycal portion. The focus will be lithiation reactions in which silicon and tin reagents were used as electrophiles.