The First Convergent Synthesis of 23,23-Difluoro-25-hydroxyvitamin D₃ and Its 24-Hydroxy Derivatives: Preliminary Assessment of Biological Activities

Abstract

In this paper, we report an efficient synthetic route for the 23,23-difluoro-25-hydroxyvitamin D3 (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-F2-25(OH)D3 (5) showed approximately eight times higher resistance to CYP24A1 metabolism and 12 times lower VDR-binding affinity than its nonfluorinated counterpart 25(OH)D3 (1).

Keywords

• 23,23-difluorovitamin D₃ analogues
• synthesis
• DAST
• CYP24A1
• VDR
• vitamin D₃ metabolite