Synthesis and evaluation of a series of 1-(3-alkyl-2,3-dideoxy-α,β- d- erythro-pentofuranosyl)thymines

Abstract

A series of 1-(3-alkyl-2,3-dideoxy-α,β- d- erythro-pentofuranosyl)thymines (3′-alkyl-3′-deoxythymidines) has been prepared from 5- O-( tert-butyldiphenylsilyl)-2,3-dideoxy- d- glycero-pent-2-enono-1,4- lactone{( S)-5-[( tert-butyldiphenylsilyl)oxymethyl]-2(5 H)-furanone} by Michael addition of the appropriate organocopper reagent, followed by reduction of the lactone, acetylation of the resulting hemiacetal, and trimethylsilyl triflate-catalyzed coupling with 2,4-di- O-(trimethylsilyl)thymine. The protected nucleosides were desilylated by using tetrabutylammonium fluoride to give anomeric mixtures of the free nucleosides. The unsubstituted 2′,3′-dideoxynucleoside analog was similarly prepared from 5- O-( tert-butyldiphenylsilyl)-2,3-dideoxy- d- glycero-pentono-1,4- lactone{( S)5-[( tert-butyldiphenylsilyl)oxymethyl]-dihydro-2(3 H)-furanone}.