title: Optimization of Chemical Syntheses of Vitamin D C3-Epimers.
abstract: Due to the widespread impact of vitamin D on human health, the development of appropriate assays to detect deficiency of all vitamin D metabolites of pharmacological interest is being continuously improved. Although over 50 naturally-occurring metabolites of vitamin D are known to date, only very few are routinely detected in commercially available assays. This is particularly true regarding C3-epimers of vitamin D3 and D2, which not only may interfere in analytical measurements with other metabolites of interest, but also have controversial and not yet fully understood physiological functions. In this study we optimized a synthetic method to obtain various vitamin D3 and D2 C3-epimers in order to make them available in gram quantities for further evaluation and for their use in assay development or drug discovery. Particularly, the inversion of the C3-OH group at the A-ring of vitamin D2, which, in turn, serves as a suitable starting material for most of chemical syntheses of vitamin D metabolites, can be converted to the corresponding C3-epimer under so-called "Mitsunobu conditions". Thus, the C3-OH group is converted into the corresponding ester by treatment with an aromatic acid, subsequent addition of an azodicarboxlate and triphenylphoshine, leading to the corresponding ester, concomitant to the inversion of the stereogenic center at C3. Reduction or saponification of the resulting ester finally leads to the corresponding C3-epimer, that may serve as starting material for a wide variety of vitamin D3 and D2 C3-epimers.
authors.affiliation: Endotherm Life Science Molecules, Saarbrücken, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Kattner
authors.affiliation: Endotherm Life Science Molecules, Saarbrücken, Germany.
authors.forename: Erik
authors.initials: E
authors.lastname: Rauch
mesh_terms: D002762:Cholecalciferol / Q000138:chemical synthesis*; D004872:Ergocalciferols / Q000138:chemical synthesis; D006801:Humans
chemical_list: D004872:Ergocalciferols; D002762:Cholecalciferol
keywords: Cancer prevention; assay development; epimers; stereoselective synthesis; vitamin D metabolites