Synthesis and biological evaluation of calcioic acid

Synthesis of (22R)-, (22S)-22-Fluoro-, and 22,22-Difluoro-25-hydroxyvitamin D3 and Effects of Side-Chain Fluorination on Biological Activity and CYP24A1-Dependent Metabolism

“…Aldehyde 15 was first prepared from Inhoffen−Lythgoe diol as a starting material in 3 steps. 15 The obtained aldehyde 15 was treated with vinylmagnesium bromide to give C22-alcohol as a diastereomer mixture, a less polar major product of 22S-form (16), and a more polar minor product of 22R-form (17). 16 After the separation of 16 and 17, both 16 and 17 were protected with a triethylsilyl (TES) group, followed by dihydroxylation of the olefin unit using ADmix β to yield diols 18 and 19, respectively.…”

“…We next synthesized 22,22-difluoro-CD-ring (10). As shown in Scheme 7, the known methyl ester 14 17 was subjected to cationic fluorination twice to obtain C22-difluoroester 34 via monofluoroester 24 in which the first monofluorination step proceeded stereoselectively, and 25 was not obtained in this reaction. This might be a typical 1,2-asymmetric induction with a large alkyl group (CD-ring), a medium alkyl group (C21-methyl), and a small hydrogen atom at C20 next to the enolate C22 sp 2 carbon, and the electrophile NFSI approached to the most vacant space of the enolate.…”

“…To a solution of 14 17 (102.7 mg, 0.28 mmol) in THF (400 μL) and hexamethylphosphoric triamide (HMPA) (200 μL) was added lithium diisopropylamide (LDA) (176 μL, 2 M THF/heptane/ethylbenzene solution, 0.35 mmol) at −78 °C, the mixture was stirred at the same temperature for 1 h, and N-fluorobenzenesulfonimide (NFSI) (116.5 mg, 0.37 mmol) was added to the mixture. After being stirred at the same temperature for 2 h, the reaction mixture was quenched with H 2 O and saturated aqueous NH 4 Cl at −78 °C.…”

Efficient Stereo-Selective Fluorination on Vitamin D3 Side-Chain Using Electrophilic Fluorination

“…The synthetic route to the (22R)-fluoro-CD-ring (11) started from carboxylic acid (31), which was readily available from the Inhoffen-Lythgoe diol in five steps [32]. This was converted to amide (30) followed by fluorination at the C22-position using NFSI in the presence of LHMDS to give the desired (22S)-fluoro-CD-ring (29) as a major product, along with (22R)-fluoro-CD-ring (33) at a ratio of 1.4:1.…”

“…Carboxylic acid 31 [32] (613.8 mg, 1.73 mmol) was dissolved in thionyl chloride (2.5 mL, 4.12 g, 34.6 mmol) at room temperature, and the solution was refluxed for 1 h 30 min. The mixture was evaporated in vacuo, and the crude acyl chloride was used for the next reaction without further purification.…”