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

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 Zemplén 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 gr