A convenient synthesis of 2′‐deoxy‐6‐thioguanosine, ara‐guanine, ara‐6‐thioguanine and certain related purine nucleosides by the stereospecific sodium salt glycosylation procedure

Abstract

AbstractA simple and high‐yield synthesis of biologically significant 2′‐deoxy‐6‐thioguanosine (11), ara‐6‐thioguanine (16) and araG (17) has been accomplished employing the Stereospecific sodium salt glycosylation method. Glycosylation of the sodium salt of 6‐chloro‐ and 2‐amino‐6‐chloropurine (1 and 2, respectively) with 1‐chloro‐2‐deoxy‐3,5‐di‐O‐(p‐toluoyl)‐α‐D‐erythro‐pentofuranose (3) gave the corresponding N‐9 substituted nucleosides as major products with the β‐anomeric configuration (4 and 5, respectively) along with a minor amount of the N‐7 positional isomers (6 and 7). Treatment of 4 with hydrogen sulfide in methanol containing sodium methoxide gave 2′‐deoxy‐6‐thioinosine (10) in 93% yield. Similarly, 5 was transformed into 2′‐deoxy‐6‐thioguanosine (β‐TGdR, 11) in 71 % yield. Reaction of the sodium salt of 2 with 1‐chloro‐2,3,5‐tri‐O‐benzyl‐α‐D‐arabinofuranose (8) gave N‐7 and N‐9 glycosylated products 13 and 9, respectively. Debenzylation of 9 with boron trichloride at −78° gave the versatile intermediate 2‐amino‐6‐chloro‐9‐β‐D‐arabinofuranosyl‐purine (14) in 62% yield. Direct treatment of 14 with sodium hydrosulfide furnished ara‐6‐thioguanine (16). Alkaline hydrolysis of 14 readily gave 9‐β‐D‐arabinofuranosylguanine (araG, 17), which on subsequent phosphorylation with phosphorus oxychloride in trimethyl phosphate afforded araG 5′‐monophosphate (18).