Sándor Boros

Synthesis of 4-substituted phenyl 2,5-anhydro-1,6-dithio-α-d-gluco- and -α-l-guloseptanosides possessing antithrombotic activity ☆

Abstract Two independent approaches were investigated for the synthesis of 3,4-di-O-acetyl-1,6:2,5-dianhydro-1-thio- d -glucitol (18), a key intermediate in the synthesis of 1,3,4-tri-O-acetyl-2,5-anhydro-6-thio-α- d -glucoseptanose (13), needed as glycosyl donor. In the first approach 1,6-dibromo-1,6-dideoxy- d -mannitol was used as starting material and was converted via 2,5-anhydro-1,6-dibromo-1,6-dideoxy-4-O-methanesulfonyl-3-O-tetrahydropyranyl- d -glucitol into 18. The second approach started from 1,2:5,6-di-O-isopropylidene- d -mannitol and the allyl, 4-methoxybenzyl as well as the methoxyethoxymethyl groups were used, respectively, for the protection of the 3,4-OH groups. The resulting intermediates were converted via their 1,2:5,6-dianhydro derivatives into the corresponding 3,4-O-protected 2,5-anhydro-6-bromo-6-deoxy- d -glucitol derivatives. The 1,6-thioanhydro bridge was introduced into these compounds by exchanging the bromine with thioacetate, activating OH-1 by mesylation and treating these esters with sodium methoxide. Among these approaches, the 4-methoxybenzyl protection proved to be the most suitable for a large scale preparation of 18. Pummerer rearrangement of the sulfoxide, obtained via oxidation of 18 gave a 1:9 mixture of 1,3,4-tri-O-acetyl-2,5-anhydro-6-thio-α- l -gulo- (12) and - d -glucoseptanose 13. When 12 or 13 were used as donors and trimethylsilyl triflate as promoter for the glycosylation of 4-cyanobenzenethiol, a mixture of 4-cyanophenyl 3,4-di-O-acetyl-2,5-anhydro-1,6-dithio-α- l -gulo- (58) and -α- d -glucoseptanoside (61) was formed suggesting an isomerisation of the heteroallylic system of the intermediate. A similar mixture of 58 and 61 resulted when 18 was treated with N-chloro succinimide and the mixture of chlorides was used in the presence of zinc oxide for the condensation with 4-cyanobenzenethiol. When 4-nitrobenzenethiol was applied as aglycon and boron trifluoride etherate as promoter, a mixture of 4-nitrophenyl 3,4-di-O-acetyl-2,5-anhydro-1,6-dithio-α- l -gulo- (60) and -α- d -glucoseptanoside (62) was obtained. Deacetylation of 58, 61 and 62 according to Zemplen afforded 4-cyanophenyl 2,5-anhydro-1,6-dithio-α- l -guloseptanoside (59), 4-cyanophenyl 2,5-anhydro-1,6-dithio-α- d -glucoseptanoside (63) and 4-nitrophenyl 2,5-anhydro-1,6-dithio-α- d -glucoseptanoside (66), respectively. The 4-cyano group of 63 was transformed into the 4-aminothiocarbonyl, and the 4-(methylthio)(imino)methyl derivative and the 4-nitro group of 66 into the acetamido derivative. All of these thioglycosides displayed a stronger oral antithrombotic effect in rats compared with beciparcil, used as reference.

Synthesis of 4-cyano- and 4-nitrophenyl 2,5-anhydro-1,6-dithio-α-d-gluco- and -α-L-guloseptanosides carrying different substituents at C-3 and C-4

Abstract Treatment of 1,6:2,5-dianhydro-3,4-di- O -methanesulfonyl-1-thio- d -glucitol in methanol with sodium hydroxide afforded 1,6:2,5:3,4-trianhydro-1-thio-allitol, 1,4:2,5-dianhydro-6-methoxy-1-thio- d -galactitol, 1,6:2,5-dianhydro-4- O -methyl-1-thio- d -glucitol, 1,6:2,5-dianhydro-3- O -methanesulfonyl-1-thio- d -glucitol and 1,6:2,5-dianhydro-4-deoxy-1-thio- d - erythro -hex-3-ulose ( 14 ) in 5, 4, 28, 5.5 and 41% yield, respectively. Formation of these derivatives can be explained via a common sulfonium intermediate. Reduction of 14 with sodium borohydride and subsequent acetylation afforded 3- O -acetyl-1,6:2,5-dianhydro-4-deoxy-1-thio- d - xylo -hexitol, the absolute configuration of which was proved by X-ray crystallography. The 1,6:2,5-dianhydro-1-thio- d -hexitol derivatives in which the free OH groups were protected by acetylation, methylation or mesylation were converted by a Pummerer reaction of their sulfoxides into the corresponding 1- O -acetyl hexoseptanose derivatives which were used as donors for the glycosidation of 4-cyano- and 4-nitrobenzenethiol, respectively. The Pummerer reaction of 1,6:2,5-dianhydro-4-deoxy-3- O -methyl-1-thio- d - xylo -hexitol S -oxide gave, besides 1- O -acetyl-2,5-anhydro-3-deoxy-4- O -methyl-6-thio-α- l - ( 23 ) and 1- O -acetyl-2,5-anhydro-4-deoxy-3- O -methyl-6-thio-α- d - xylo -hexoseptanose ( 25 ), 1- O -acetyl-4-deoxy-2,6-thioanhydro- d - lyxo -hexopyranose, formed in a rearrangement reaction. The same rearrangement took place, when a mixture of 23 and 25 was used as donor in the glycosidation reaction with 4-cyanobenzenethiol, applying trimethylsilyl triflate as promoter. The oral antithrombotic activity of the obtained α-thioglycosides was determined in rats, using Pescadors model.

Conversion of 2,6-anhydro-d-altrose and -mannose derivatives with 4-substituted phenyl thiols to prepare compounds with potential antithrombotic activity ☆

Acetolysis of methyl 3,4-di-O-acetyl-2,6-anhydro-D-altropyranoside afforded a mixture containing, besides 1,3,4-tri-O-acetyl-2,6-anhydro-D-altropyranose, the (1R) and (1S) diastereomers of methyl 2,6-anhydro-D-altrose-tetraacetate. Treatment of this mixture with 4-cyanobenzenethiol in the presence of trimethylsilyl triflate resulted in a mixture containing the 3,4,5-tri-O-acetyl-2,6-anhydro-D-altrose bis(4-cyanophenyl) dithioacetal, the corresponding O-methyl S-aryl monothiohemiacetal diastereomers and the beta-thiopyranoside, respectively. Acetolysis of methyl 3,4-di-O-acetyl-2,6-anhydro-D-mannopyranoside led to a mixture of the (1R) and (1S) diastereomers of methyl 2,6-anhydro-D-mannosetetraacetate, which was converted into the corresponding O-methyl S-aryl monothiohemiacetals. Treatment of 1,1,3,4,5-penta-O-acetyl-2,6-anhydro-aldehydo-D-altrose and -D-mannose with 4-cyano- and 4-nitrobenzenethiol, respectively, in the presence of trimethylsilyl triflate afforded the corresponding dithioacetal derivatives. All arylthio derivatives obtained after deacetylation were tested for their oral antithrombotic activity.

Synthesis of 4-substituted phenyl 3,6-anhydro-1,3-dithio-d-glucofuranosides and -pyranosides as well as 2,6-anhydro-1,2-dithio-α-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.

The fate of the methanesulfonyloxy group on reduction with LAH

Abstract Reduction of 1,6:2,5-dianhydro-3,4-di-O-methanesulfonyl-1-thio-D-glucitol with LAH afforded the corresponding 3,4-dihydroxy compound in a yield of 51% and six by-products were isolated after acetylation. Three differed from the original molecule only in the substituents, which were AcO at C-3 and H, CH 3 S and CH 3 SCH 2 S at C-4, respectively. The other compounds had a rearranged skeleton and were 1,4:2,5-dianhydro-1-thio-D-galactitol derivatives, containing the AcO group at C-3 and the aforementioned three substituents attached to C-6. A mechanism is suggested for the rearrangement, and for the formation of the substituent including the fate of the methanesulfonyloxy groups on reduction with LAH which is generally applicable to any mesyloxy derivative.