The First Convergent Synthesis of 23,23-Difluoro-25-hydroxyvitamin D<sub>3</sub> and Its 24-Hydroxy Derivatives: Preliminary Assessment of Biological Activities
Sayuri Mototani,
Fumihiro Kawagoe,
Kaori Yasuda,
Hiroki Mano,
Toshiyuki Sakaki,
Atsushi Kittaka
Affiliations
Sayuri Mototani
Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan
Fumihiro Kawagoe
Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan
Kaori Yasuda
Faculty of Engineering, Toyama Prefectural University, Imizu 939-0398, Toyama, Japan
Hiroki Mano
Faculty of Engineering, Toyama Prefectural University, Imizu 939-0398, Toyama, Japan
Toshiyuki Sakaki
Faculty of Engineering, Toyama Prefectural University, Imizu 939-0398, Toyama, Japan
Atsushi Kittaka
Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan
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).
