The First Convergent Synthesis of 23,23-Difluoro-25-hydroxyvitamin D and Its 24-Hydroxy Derivatives: Preliminary Assessment of Biological Activities.

In this paper, we report an efficient synthetic route for the 23,23-difluoro-25-hydroxyvitamin D () and its 24-hydroxylated analogues (,), which are candidates for the CYP24A1 main metabolites of . The key fragments, 23,23-difluoro-CD-ring precursors (-), were synthesized starting from Inhoffen-Lythgoe diol (), and introduction of the C23 difluoro unit to α-ketoester () was achieved using ,-diethylaminosulfur trifluoride (DAST). Preliminary biological evaluation revealed that 23,23-F-25(OH)D () showed approximately eight times higher resistance to CYP24A1 metabolism and 12 times lower VDR-binding affinity than its nonfluorinated counterpart 25(OH)D ().