SODIUM-SALT GLYCOSYLATION IN THE SYNTHESIS OF PURINE 2'-DEOXYRIBONUCLEOSIDES - STUDIES OF ISOMER DISTRIBUTION

A systematic study of 2-deoxyribonucleoside isomer distribution from the sodium salt glycosylation of substituted purines is reported. Reactions of 1-alpha-chloro-2-deoxy-3,5-di(p-toluyl)-erythro-pentofuranose with the sodium salts of purines in acetonitrile typically results in 9-beta and 7-beta regioisomers as major products in a ratio of about 4:1, results consistent with a S(N)2 reaction of base anion with the 1-alpha chlorosugar. However, the reaction with 2,6-dibromopurine (2) gave 9-beta and 9-alpha stereoisomers as major products in a 4:1 ratio. We have isolated and identified all nucleoside products from sodium salt glycosylations of several 2,6-disubstituted purines and 6-substituted purines. In addition to the major products, the 9-alpha and 7-alpha isomers were obtained in small yields in most cases. Rate studies showed that fastest glycosylations occurred with 2,6-bis(methylthio)purine (3). Glycosylations of 2,6-dichloropurine (1) and of 2 proceeded with nearly identical rates for the formation of the 9-beta isomers and with comparable rates for the formation of 7-beta and 9-alpha isomers, respectively. These observations indicate that the extent of sugar anomerization during glycosylation of 2 does not alone account for 9-alpha isomer formation, although, in a separate experiment, aging of chlorosugar solutions did increase the yield of 9-alpha product in the reaction. Studies of possible interconversion of isomers under the reaction conditions indicated that formation of the 9-alpha isomer from 2 was not the result of conversion of a kinetically favored (7-beta) isomer, nor was the 7-beta isomer from 1 derived from conversion of the 9-alpha isomer. We conclude that a combination of steric effect of the 6-bromo group and an as yet unidentified rate effect of the 2-bromo group is responsible for the significant yield of 9-alpha product from 2. The ability of substituents to enhance the rate and regioselectivity in the sodium salt glycosylation was evaluated with 2-bromo-6-(methylthio)purine (6). This base afforded the highest total nucleoside yield (86%) and the highest 9-beta isomer yield (68.3%) among all purines tested, suggesting a useful strategy to increase yield of intermediates that can be converted to biologically important purine 2'-deoxy-ribonucleosides.