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

Abstract

Abstract A simple and high‐yield synthesis of biologically significant 2′‐deoxy‐6‐thioguanosine ( 11 ), ara ‐6‐thioguanine ( 16 ) and ara G ( 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 ( ara G, 17 ), which on subsequent phosphorylation with phosphorus oxychloride in trimethyl phosphate afforded ara G 5′‐monophosphate ( 18 ).