Nucleic acid related compounds. 67. Synthesis of 5′-amino and 5′-methylthio chain-extended nucleosides from uridine

Abstract

Treatment of 2′,3′-O-isopropylideneuridine-5′-aldehyde with the stabilized Wittig reagent, (p-toluenesulfonylmethylene)triphenylphosphorane, gave high yields of 1-[5,6-dideoxy-2,3-O-isopropylidene-6-(p-toluenesulfonyl)-β-D-ribo-hex-5(E)-enofuranosyl]uracil (2). This vinylsulfone (2) underwent isomerization readily in base to give the allylic sulfone, 1-[5,6-dideoxy-2,3-O-isopropylidene-6-(p-toluenesulfonyl)-β-D-erythro-hex-4(Z)-enofuranosyl]uracil (3). Treatment of 2 or 3 with aqueous trifluoroacetic acid gave the corresponding deprotected vinyl (5) or allylic (6) sulfones, and 5 was converted to 6 readily in basic solutions. Treatment of 2 with sodium borohydride, sodium thiomethoxide, or ammonia resulted in conjugate addition (at C5′ of the vinyl sulfone) to give the 5′-hydro, 5′-methylthio, or 5′-amino-5′,6′-dideoxy-6′-(p-toluenesulfonyl) nucleosides. The 5′-substituted diastereomers were deprotected, separated, and the configuration of a 5′-amino derivative was established by X-ray crystallography.Key words: allylic sulfones, amino-nucleosides, 5′,6′-dideoxynucleosides, nucleosides, uridine, vinyl sulfones.