5a-Carba-β-D-, 5a-Carba-β-L- and 5-Thio-β-L-xylopyranosides as New Orally Active Venous Antithrombotic Agents

Abstract

Mitsunobu displacement of (−)-(1S,4R,5S,6S)-4,5,6-tris{[(tert-butyl)dimethylsilyl]oxy}cyclohex-2-en-1-ol ((−)-12; a (−)-conduritol-F derivative) with 4-ethyl-7-hydroxy-2H-1-benzopyran-2-one (16) provided a 5a-carba-β-D-pyranoside (+)-17 that was converted into (+)-4-ethyl-7-[(1′R,4′R,5′S,6′R)-4′,5′,6′-trihydroxycyclohex-2′-en-1′-yloxy]-2H-1-benzopyran-2-one ((+)-5) and (+)-4-ethyl-7-[(1′R,2′R,3′S,4′R)-2′,3′,4′-trihydroxycyclohexyloxy]-2H-1-benzopyran-2-one ((+)-6). The 5a-carba-β-D-xyloside (+)-6 was an orally active antithrombotic agent in the rat (venous Wessler's test), but less active than racemic carba-β-xylosides (±)-5 and (±)-6. The 5a-carba-β-L-xyloside (−)-6 was derived from the enantiomer (+)-12 and found to be at least 4 times as active as (+)-6. (+)-4-Cyanophenyl 5-thio-β-L-xylopyranoside ((+)-3) was synthesized from L-xylose and found to maintain ca. 50% of the antithrombotic activity of its D-enantiomer. Compounds (±)-5, (±)-6, and (−)-6 are in vitro substrates for galactosyltransferase 1.