Convergent synthesis of 2′,3′-dideoxy-3′-methylthio and 2′,3′-dideoxy-3′-mercapto nucleosides and their disulfide analogues - Potential anti-HIV agents

Abstract

The iodide 4(α) or 7 synthesized in three steps from 2-deoxy-D-ribose 1, has been subjected to a number of nucleophilic substitution reactions producing the 3-benzoylthio-, 3-methylthio- and the 3-thiocyanato-2,3-dideoxy-D-erythro-pentofuranosides 8, 13 and 15, respectively, in addition to the disulfide 17 of their 3-mercapto analogue. Subjecting the thiobenzoate 8 to the Friedel-Crafts catalyzed silyl Hilbert Johnson reaction in conjunction with the silylated nucleobases of uracil, thymine and N4-isobutyrylcytosine 9a-c resulted in the isolation of the 2′,3′-dideoxy-3′-mercapto nucleosides 11 and their disulfides 12 subsequent to deprotection. The 2,3-dideoxy-3-methylthio-pentofuranoside 13 afforded both anomers of the 2′,3′-dideoxy-3′-methylthio nucleosides 19 and 20 under similar conditions. The first known example of a coupling directly on a 2,3-didehydro-2,3-dideoxyfuranose is presented. 2′,3′-Dideoxy-3′-mercaptocytidine showed protection against HIV-1 in MT-4 cells with ED50=20 μM. © 1993 Springer-Verlag.