Synthesis of 4-substituted phenyl 3,6-anhydro-1,3-dithio-D-glucofuranosides and -pyranosides as well as 2,6-anhydro-1,2-dithio-alpha-D-altrofuranosides possessing antithrombotic activity.
1,2,5-Tri-O-acetyl-3,6-anhydro-3-thio-D-glucofuranose was synthesised starting from D-glucose and was used as a donor for the glycosidation of 4-cyano- and 4-nitrobenzenethiol. In the latter reaction, besides an anomeric mixture of the 4-nitrophenyl 2,5-di-O-acetyl-3,6-anhydro-1,3-dithio-D-glucofuranosides, the corresponding 2,6-anhydro-1,2-dithio-D-altrofuranosides were also obtained, formed via a rearrangement of the sugar moiety. A similar rearrangement could be observed during the hydrolysis of the glycosidic bond of methyl 3,6-anhydro-2,4-di-O-(4-nitrobenzoyl)-3-thio-alpha-D-glucopyranoside with aqueous trifluoroacetic acid, affording after acetylation besides 1-O-acetyl-3,6-anhydro-2,4-di-O-(4-nitrobenzoyl)-3-thio-alpha-D-glucopyranose (32alpha), 1,1,5-tri-O-acetyl-3,6-anhydro-2,4-di-O-(4-nitrobenzoyl)-3-thio-D-glucose, methyl 3,6-anhydro-2,4-di-O-(4-nitrobenzoyl)-3-thio-beta-D-glucopyranoside and 1,5-di-O-acetyl-2,6-anhydro-3-O-(4-nitrobenzoyl)-2-thio-alpha-D-altrofuranose (40). Glycosidation of 4-cyanobenzethiol with 32alpha in the presence of trimethylsilyl triflate as promoter afforded 4-cyanophenyl 3,6-anhydro-2,4-di-O-(4-nitrobenzoyl)-1,3-dithio-beta-D-glucopyranoside as a minor component only, besides 4-cyanophenyl 3,6-anhydro-2-S-(4-cyanophenyl)-4-O-(4-nitrobenzoyl)-1,2,3-trithio-beta-D-glucopyranoside. When boron trifluoride etherate was used as promoter in the reaction of 32alpha with 4-cyano- and 4-nitrobenzenethiol, the corresponding beta-thioglycosides were obtained, while 40 gave under identical conditions the alpha anomers exclusively. All thioglycosides obtained after deacylation were submitted to biological evaluation. Among these glycosides, the 4-cyanophenyl 3,6-thioanhydro-1,3-dithio-D-glucofuranoside possessed the strongest oral antithrombotic effect.
Bozó
E
E
Gedeon Richter Chemical Works Ltd., Budapest, Hungary.
Boros
S
S
Kuszmann
J
J
D000818:Animals; D004353:Drug Evaluation, Preclinical; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005960:Glucosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010429:Pentoses / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats
D005343:Fibrinolytic Agents; D005960:Glucosides; D010429:Pentoses