Stereoselective Synthesis of 24-Fluoro-25-Hydroxyvitamin D₃ Analogues and Their Stability to hCYP24A1-Dependent Catabolism

Abstract

Two 24-fluoro-25-hydroxyvitamin D3 analogues (3,4) were synthesized in a convergent manner. The introduction of a stereocenter to the vitamin D3 side-chain C24 position was achieved via Sharpless dihydroxylation, and a deoxyfluorination reaction was utilized for the fluorination step. Comparison between (24R)- and (24S)-24-fluoro-25-hydroxyvitamin D3 revealed that the C24-R-configuration isomer 4 was more resistant to CYP24A1-dependent metabolism than its 24S-isomer 3. The new synthetic route of the CYP24A1 main metabolite (24R)-24,25-dihydroxyvitamin D3 (6) and its 24S-isomer (5) was also studied using synthetic intermediates (30,31) in parallel.

Keywords

• human CYP24A1
• synthesis
• vitamin D₃ metabolite
• 24-fluoro-25-hydroxyvitamin D₃ analogues
• Sharpless dihydroxylation