The First Convergent Synthesis of 23,23-Difluoro-25-hydroxyvitamin D 3 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 ₃ ( 5 ) and its 24-hydroxylated analogues ( 7 , 8 ), which are candidates for the CYP24A1 main metabolites of 5 . The key fragments, 23,23-difluoro-CD-ring precursors ( 9 - 11 ), were synthesized starting from Inhoffen-Lythgoe diol ( 12 ), and introduction of the C23 difluoro unit to α-ketoester ( 19 ) was achieved using N , N -diethylaminosulfur trifluoride (DAST). Preliminary biological evaluation revealed that 23,23-F ₂ -25(OH)D ₃ ( 5 ) showed approximately eight times higher resistance to CYP24A1 metabolism and 12 times lower VDR-binding affinity than its nonfluorinated counterpart 25(OH)D ₃ ( 1 ).