Francois Bellamy

Radical-mediated bromination of peracetylated 5-thio-d-xylopyranosyl bromides: an easy access to the corresponding anomeric orthothiolactones

Abstract On treatment with N -bromosuccinimide in refluxing carbon tetrachloride under irradiation with visible light, both α and β anomers of 2,3,4-tri- O -acetyl-5-thio-d-xylopyranosyl bromide were converted mainly to 2,3,4-tri- O -acetyl-5-thio-d-xylopyranosylidene dibromide ( 5 ) and to 2,3,4-tri- O -acetyl-5( S )-5-bromo-5-thio-d-xylopyranosylidene dibromide ( 6 ). Whereas the more reactive β anomer could be transformed cleanly into the dibromide 5 after heating for 2 h, complete conversion of the α-bromide required a prolonged treatment (∼ 5 h) leading to a mixture of di-, tri- and tetra-bromides. Similarly, an anomeric mixture of 2,3,4,6-tetra- O -acetyl-5-thio-d-glucopyranosyl bromide yielded mainly tribromide 11 after prolonged heating. The reaction rates and the structure of the products showed again the higher reactivity of axial CH bonds at either C-1 or C-5 in pyranosyl rings towards S H 2 processes. However, activation by the sulfur atom allowed attack of equatorial bonds as well and polybromination at both C-1 and C-5. Treatment of the C-1 dibromide 5 by silver triflate in the presence of either alcohols or thiols yielded the corresponding 5-thiosugar ortholactones 12–15 . Methyl 1-methoxy-5-thio-d-xylopyranoside ( 18 ), obtained from 12 on deacetylation, showed no venous antithrombotic activity in rats according to a Wessler test.

Synthesis of the 2- and 4-monomethyl ethers and the 4-deoxy-4-fluoro derivative of 4-cyanophenyl 1,5-dithio-β-d-xylopyranoside as potential antithrombotic agents

Abstract The title glycoside undergoes acetonation with 2-methoxypropene to give a 2:1 mixture of the crystalline 2,3- and 3,4-isopropylidene acetals in 94% yield, which upon methylation under controlled conditions followed by deacetonation afforded the respective 4- and 2-monomethyl ethers. The 2,3-acetal underwent reaction with diethylaminosulfur trifluoride to introduce fluorine at C-4 with net retention of stereochemistry, but the 3,4-acetal under comparable conditions underwent migration of the arylthio group to C-2 and fluorination at C-1, with stereochemical retention at both positions.

Synthesis of the 3-methyl ether and 4-deoxy derivatives of 4-cyanophenyl 1,5-dithio-β-d-xylopyranoside (Beciparcil)

Treatment of the 2,3-isopropylidene acetal of the title dithioxyloside with 2,4,5-triiodoimidazole-PPh3 caused replacement of the 4-hydroxyl group by iodine to afford 82% of the 4-axial iodide 6, converted by base into 4-cyanophenyl 2,3-O-isopropylidene-1,5-dithio-beta-D-glycero-pent-3-enopyranoside++ + (8). Acid treatment of 8 gave 87% of the deacetonated glycos-3-ulose, borohydride reduction of which afforded 63% of 4-cyanophenyl 4-deoxy-1,5-dithio-alpha-L-threo-pentopyranoside (3), together with 27% of the 3-axial epimer. The 3-methyl ether of the title dithioxyloside was satisfactorily prepared via 2,4-protection as the cyclic phenylboronate, methylation, and deprotection; alternative strategy via the 2,4-bis(triisopropylsilyl) ether was complicated because of silyl-group migration under methylation conditions.

Chemical interconversions of 4-cyanophenyl 1,5-dithio-β-d-xylopyranoside (Beciparcil®): structural modification at the C-4 position

Abstract The title dithioxyloside 1 , an orally active antithrombotic agent, as its 2,3-isopropylidene acetal, was converted into the corresponding glycos-4-ulose, which served as precursor via reduction to the 4-epimer of 1 and via oximation–reduction to the 4-acetamido-4-deoxy 4-epimer of 1 .