Synthesis and biological activity of (22E,24R)- and (22E,24S)-1.ALPHA.,24-dihydroxy-22-dehydrovitamin D3.

Abstract

Chemical synthesis of (22E,24R)- and (22E,24S)-1,24-dihydroxy-.DELTA.22-vitamin D3 was achieved starting with the commercially available dinorcholenic acid acetate. Synthesis involved introduction of the 1-hydroxy group by a reduction of the 1,2-epoxide generated by epoxidation of the 1,4,6-trien-3-one. The side chain on the steroid was then constructed by means of a Wittig reaction followed by introduction of the .DELTA.7 bond by standard methods and its protection with 1-phenyl-1,2,4-triazoline-3,5-dione. Subsequent reduction of the hydroxy groups in the steroid side chain followed by reduction of the Diels-Alder addition products yielded both 24-isomers. The 5,7-dienes were irradiated and the corresponding vitamin D compounds isolated. NMR was used to identify individual isomers. The (22E,24S)-1,24-hydroxyvitamin D3 compound bound equally well to the chick intestinal cytosol receptor as 1,25-dihydroxyvitamin D3, while the 24R-isomer was approximately 10 times less active. In vivo, both isomers were less active than 1,25-dihydroxyvitamin D3; however, the 24S-isomer was considerably more active than the 24R-isomer approaching the activity of 1,25-dihydroxyvitamin D3.