Synthesis and NMR Studies of 13C-Labeled Vitamin D Metabolites1

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-lab...