Rr. Sicinski et Hf. Deluca, SYNTHESIS, CONFORMATIONAL-ANALYSIS, AND BIOLOGICAL-ACTIVITY OF THE 1-ALPHA-25-DIHYDROXY-10,19-DIHYDROVITAMIN D-3 ISOMERS, Bioorganic chemistry, 22(2), 1994, pp. 150-171
The synthesis of the four 1 alpha,25-dihydroxy-10,19-dihydrovitamin D-
3 stereoisomers (8-11) is described starting from 25-hydroxyvitamin D-
3 (1c). Acetic acid-catalyzed cycloreversion of 1 alpha-hydroxylated 3
,5-cyclovitamin D compound 14, produced by allylic oxidation of the in
termediate cyclovitamin 13, afforded 1 alpha,25-dihydroxyvitamin D-3 3
-acetate (16) and its 5E-isomer 17. Catalytic hydrogenation of 16 prod
uced 10,18-dihydrovitamin acetates 20 and 21, whereas the same reactio
n of 17 resulted in the formation of SE-isomers 22 and 23. The analogo
us saturation of the 10,19-double bond in 14 gave 10(S), 19- and 10(R)
, 19-dihydrocyclovitamins 18 and 19 which after cycloreversion with ac
etic acid yielded different stereoisomeric pairs of 10,19-dihydrovitam
in acetates 21, 23, 20, and 22, respectively. The stereochemistry and
solution conformations of the A-ring of the 3-acetates 20-23 and their
parent alcohols 8-11 were studied using H-1 NMR data. The A-ring chai
r population ratios of these stereoisomers were determined by the meth
od of correlation of the observed coupling constants with the limiting
values derived from cyclohexanol. The obtained results were confirmed
by evaluation of interaction energies introduced by A-ring substituen
ts and calculation of the free energy differences between the respecti
ve dihydrovitamin conformers. Conformational analyses of 10,19-dihydro
vitamins were also carried out on model compounds 24-27 by using force
-field calculations. Biological activity in vivo revealed that the 1 a
lpha,25-dihydroxy-10(S), 19-dihydrovitamin D-3 (9) followed by the 1 a
lpha,25-dihydroxy-10(S), 19-dihydro-(5E)-vitamin D-3 (11) to be the mo
st active, while the 10(R)-isomers 8 and 10 possessed little or no act
ivity. In vitro, the compounds possessing the most equatorial 1-hydrox
yl, i.e., the 10(R)-isomers, were found most active, and the least equ
atorial were the least active. (C) 1994 Academic Press, Inc.