In a search for novel vitamin D compounds of potential therapeutic value, E- and Z-isomers of 1alpha,25-dihydroxy-2-(3'-hydroxypropylidene)-19-norvitamin D(3), as well as a derivative of the former compound possessing a 3'-(methoxymethoxy)propylidene substituent at C-2, were efficiently prepared. All vitamins were obtained in convergent syntheses, starting with (-)-quinic acid and the protected 25-hydroxy Grundmann ketones. Quinic acid was converted into keto lactone 11, and a substituted hydroxypropylidene group was attached by Wittig reaction yielding pairs of isomeric compounds 12, 13 and 14, 15. These olefinic products were then transformed into phosphine oxides 32-34 which were subjected to Lythgoe type Wittig-Horner coupling with C,D-fragments 35a and 35b. An alternative route was also elaborated that comprised Julia coupling of sulfones 39a and 39b with the cyclohexanone derivative 23. The binding of all synthesized vitamins to the full-length rat recombinant vitamin D receptor (VDR) is either similar to or within one log of 1alpha,25(OH)(2)D(3). The in vivo tests have revealed that the calcemic activity of all analogues in the E-series (5a, 6a, 6b) is considerably higher than that of the native hormone.

To establish the conformation of vitamin D compounds responsible for biological activity, a 1alpha,25-dihydroxy-19-norvitamin D analogue 4 possessing a 1alpha-hydroxy group fixed in the axial orientation (beta-chair form) was synthesized. The starting compounds were bicyclic lactones 6, 7a, and 7b, derived from the quinic acid lactone, which were converted to the bicyclic ketone 13. Julia coupling of this compound with sulfone 15 produced the 19-norvitamin D analogue 4, possessing an additional ring connecting the 3beta-oxygen and C-2, and the isomeric 3beta-hydroxy compound 5. In vitro, both analogues 4 and 5 exhibit reduced activity compared to the natural hormone 1, but the binding, differentiation, and transcriptional activities of analogue 5 are markedly higher than that of 4 constrained in the alpha-chair conformation. Surprisingly, in vivo tests in mice showed that the analogue 4 significantly increases serum calcium at dose levels similar to 1alpha,25-(OH)2D3. These seemingly discordant results are discussed.

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