Orally active antithrombotic thioglycosides, part XI. Synthesis of 4-cyano- and 4-nitrophenyl 2,5-anhydro-1,6-dithio-alpha-D-gluco- and -alpha-L-guloseptanosides carrying different substituents at C-3 and C-4

Treatment of 1,6:2,5-dianhydro-3,4-di-O-methanesulfonyl-1-thio-D-glucitol i n methanol with sodium hydroxided afforded 1,6:2, 5:3,4-trianhydro-1-thio-a llitol, 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-deoxyl-thio-D-erythro -hex-3-ulose (14) in 5, 4, 28, 5.5 and 41% yield, respectively. Formation of these derivative s can be explained via a common sulfonium intermediate. Reduction of 14 wit h 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 whi ch was proved by X-ray crystallography. The 1,6:2,5-dianhydro-1-thio-D-hexi tol derivatives in which the free OH groups were protected by acetylation, methylation or mesylation were converted by a Pummerer reaction of their su lfoxides into the corresponding 1-O-acetyl hexoseptanose derivatives which were used as donors for the glycosidation of 4-cyano- and 4-nitrobenzenethi ol, respectively. The Pummerer reaction of 1,6.2, 5-dianhydro-4-deoxy-3-O-m ethyl-1-thio-D-xylo-hexitol S-oxide gave, besides 1-O-acetyl-2,5-anhydro-3- deoxy-4-O-methyl-6-thio-alpha -L- (23) and 1-O-acetyl-2,5-anhydro-4-deoxy-3 -O-methyl-6-thio-alpha -D-xylo-hexoseptanose (25), 1-O-acetyl-4-deoxy-2,6-t hioanhydro-D-lyxo-hexopyranose, formed in a rearrangement reaction. The sam e rearrangement took place, when a mixture of 23 and 25 was used as donor i n the glycosidation reaction with 4-cyanobenzenethiol, applying trimethylsi lyl triflate as promoter. The oral antithrombotic activity of the obtained a-thioglycosides was determined in rats, using Pescador's model. (C) 2000 E lsevier Science Ltd. All rights reserved.