5a-carba-beta-D-, 5a-carba-beta-L- and 5-thio-beta-L-xylopyranosides as new orally active venous antithrombotic agents

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-beta-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'-yl oxy]-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-beta-D-xyloside (+)-6 was an orally active antithrombotic agent in the rat (venous Wessler's test),but less active than racemic carba-beta-xylosides (+/-)-5 and (+/-)-6. The 5a-carba-beta-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-beta-L-xylopyranoside ((+)-3) was synthesized from L-xylose and found to maintain ca. 50% of the antithrombotic activity of its D-enanriomer. Compounds (+/-)-5, (+/-)-6, and (-)-6 are in vitro substrates for galactosyltransferase 1.