406457-39-4Relevant articles and documents
Synthesis and NMR studies of 13C-labeled vitamin D metabolites
Okamura, William H.,Zhu, Gui-Dong,Hill, David K.,Thomas, Richard J.,Ringe, Kerstin,Borchardt, Daniel B.,Norman, Anthony W.,Mueller, Leonard J.
, p. 1637 - 1650 (2002)
Isotope-labeled drug molecules may be useful for probing by NMR spectroscopy the conformation of ligand associated with biological hosts such as membranes and proteins. Triple-labeled [7,9,19-13C3]-vitamin D3 (56), its 25-hydroxylated and 1α,25-dihydroxylated metabolites (58 and 68, respectively), and other labeled materials have been synthesized via coupling of [9-13C]-Grundmann's ketone 39 or its protected 25-hydroxy derivative 43 with labeled A ring enyne fragments 25 or 26. The labeled CD-ring fragment 39 was prepared by a sequence involving Grignard addition of [13C]-methylmagnesium iodide to Grundmann's enone 28, oxidative cleavage, functional group modifications leading to seco-iodide 38, and finally a kinetic enolate SN2 cycloalkylation. The C-7,19 double labeling of the A-ring enyne was achieved by the Corey-Fuchs/Wittig processes on keto aldehyde 11. By employing these labeled fragments in the Wilson-Mazur route, the C-7,9,19 triple-13C-labeled metabolites 56, 58, and 68 as well as other 13C-labeled metabolites have been prepared. In an initial NMR investigation of one of the labeled metabolites prepared in this study, namely [7,9,19-13C3]-25-hydroxyvitamin D3 (58), the three 13C-labeled carbons of the otherwise water insoluble steroid could be clearly detected by 13C NMR analysis at 0.1 mM in a mixture of CD3OD/D2O (60/40) or in aqueous dimethylcyclodextrin solution and at 2 mM in 20 mM sodium dodecyl sulfate (SDS) aqueous micellar solution. In the SDS micellar solution, a double half-filter NOESY experiment revealed that the distance between the H19Z and H7 protons is significantly shorter than that of the corresponding distance calculated from the solid state (X-ray) structure of the free ligand. The NMR data in micelles reveals that 58 exists essentially completely in the α-conformer with the 3β-hydroxyl equatorially oriented, just as in the solid state. The shortened distance (H19Z-H7) in micellar solutions as compared to that in the solid state is most easily rationalized on the basis that the 5(10)-torsion angle in 58 is decreased in micellar solutions as compared to that in the solid state.
