Synthesis of 4-cyanophenyl 1,5-dithio-β-d-glucopyranoside and its 6-deoxy, as well as 6-deoxy-5-ene derivatives as oral antithrombotic agents

Condensation of 5-thio-d-glucopyranose pentaacetate with 4-cyanobenzenethiol, in the presence of trimethylsilyl triflate, gave 4-cyanophenyl 2,3,4,6-tetra-O-acetyl-1,5-dithio-α-d-glucopyranoside7 and 3,4,6-tri-O-acetyl-2,5-anhydro-5-thio-d-mannose bis(4-cyanophenyl) dithioacetal 9 in a 2:3 ratio. The latter is probably formed from the 4-cyanophenyl 2,3,4,6-tetra-O-acetyl-1,5-dithio-β-d-glucopyranoside6 via a transannular participation of the ring sulfur atom. When 2,3,4,6-tetra-O-acetyl-5-thio-α-d-glucopyranosyl bromide was used as donor and the reaction was carried out in the presence of potassium carbonate, 6, 7, 4-cyano-2-(2,3,4,6-tetra-O-acetyl-5-thio-α-d-glucopyranosyl)phenyl and 4-cyano-2-(2,3,4,6-tetra-O-acetyl-5-thio-β-d-glucopyranosyl)phenyl 1,5-dithio-β-d-glucopyranoside (14 and 16) were formed in a 23:4:2:1 ratio. The mechanism of formation of 14 and 16 is discussed. Condensation of 2,3,4-tri-O-acetyl-6-deoxy-5-thio-α-d-glucopyranosyl bromide with 4-cyanobenzenethiol in the presence of potassium carbonate gave 4-cyanophenyl 2,3,4-tri-O-acetyl-6-deoxy-1,5-dithio-α- and β-d-glucopyranoside (29 and 30) as well as 4-cyano-2-(2,3,4-tri-O-acetyl-6-deoxy-5-thio-α-d-glucopyranosyl)phenyl2,3,4-tri-O-acetyl-6-deoxy-1,5-dithio-β-d-glucopyranoside in a ratio of ∼ 1:8:1. Compound 30 could be obtained in a higher overall yield using 2 as starting material and converting it via its 4-cyanophenyl 2,3,4-tri-O-acetyl-6-O-methanesulfonyl-1,5-dithio-β-d-glucopyranoside derivative into the 4-cyanophenyl 2,3,4-tri-O-acetyl-6-deoxy-6-iodo-1,5-dithio-β-d-glucopyranoside33 which gave 30 on reduction with sodium borohydride-nickel(II) chloride. Treatment of 33 with silver acetate gave 4-cyanophenyl 2,3,4-tri-O-acetyl-6-deoxy-1,5-dithio-β-d-xylo-hex-5-enopyranoside 35. The compounds obtained on deacetylation of 6, 9, 14, 30 and 35 showed a stronger oral antithrombotic effect in rats as compared to beciparcil, used as reference.