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

Our research regarding side-chain fluorinated vitamin D3 analogues has explored a series of efficient fluorination methods. In this study, a new electrophilic stereo-selective fluorination methodology at C24 and C22 positions of the vitamin D3 side-chain was developed using N-fluorobenzenesulfonimide (NFSI) and CD-ring imides with an Evans chiral auxiliary (26,27,30).


Conclusions
In conclusion, we developed an improved stereo-selective fluorination method at C24 and C22 positions to synthesize C24-and C22-fluoro-CD-rings utilizing an Evans chiral auxiliary for a cationic fluorination reaction as a key step.The side-chain carboxylic acids (28,31) were prepared from the Inhoffen-Lythgoe diol.These synthetic routes are more efficient than previous ones reported regarding both total yields and reaction steps.
nBuLi (1.59 M in hexane, 5.3 mL, 8.40 mmol) was added to a precooled solution of (R)-4-isopropyloxazolidinone (1.09 g, 8.40 mmol) in THF (20 mL) at −78 • C, and the mixture was stirred at the same temperature for 10 min.The above acyl chloride in THF (3 mL) was added to the solution and stirred at the same temperature for 10 min.After the reaction was quenched with H 2 O and saturated aqueous NH 4 Cl at room temperature, the mixture was extracted with EtOAc three times.The organic layer was dried over Na 2 SO 4 , filtered, and concentrated.The residue was purified via flash column chromatography on silica gel (hexane:EtOAc = 3:1) to obtain 26 (513.6 mg, 99%, in 2 steps) as a colorless oil.
nBuLi (1.59 M in hexane, 5.9 mL, 9.42 mmol) was added to a precooled solution of (S)-4-isopropyloxazolidinone (1.24 g, 9.60 mmol) in THF (20 mL) at −78 • C, and the mixture was stirred at the same temperature for 10 min.The above acyl chloride in THF (4 mL) was added to the solution and stirred at the same temperature for 20 min.After the reaction was quenched with H 2 O and saturated aqueous NH 4 Cl at room temperature, the mixture was extracted with EtOAc three times.The organic layer was dried over Na 2 SO 4 , filtered, and concentrated.The residue was purified via flash column chromatography on silica gel (hexane:EtOAc = 3:1) to obtain 27 (729.5 mg, 93%, in 2 steps) as a colorless oil.To a solution of 26 (168.9mg, 0.34 mmol) in THF (2 mL) and hexamethylphosphoric triamide (HMPA) (200 µL) was added LHMDS (lithium hexamethyldisilazide) (359 µL, 1 M THF solution, 0.36 mmol) at −78 • C, the mixture was stirred at the same temperature for 10 min, and N-fluorobenzenesulfonimide (NFSI) (117.8 mg, 0.37 mmol) was added.After being stirred at the same temperature for 40 min, the reaction mixture was quenched with H 2 O and saturated aqueous NH 4 Cl at −78 • C. The mixture was extracted with EtOAc three times.The layer was washed with brine, dried over Na 2 SO 4 , filtered, and concentrated.Crude 24 was used for the next reaction without further purification.
To a solution of the above crude 24 in THF (10 mL) was added MeMgCl (1.14 mL, 3.0 M THF solution, 3.42 mmol) at 0 • C, and the mixture was stirred at 0 • C for 10 min.After the reaction was quenched with H 2 O, the mixture was extracted with EtOAc three times.The organic layer was washed with saturated aqueous NH 4 Cl, dried over Na 2 SO 4 , filtered, and concentrated.The crude residue was used for the next reaction without further purification.
To the above crude residue in MeOH (15 mL) was added p-toluenesulfonic acid monohydrate (479.9 mg, 2.52 mmol), and the mixture was stirred at room temperature for 63 h under air.After the reaction was quenched with H 2 O and saturated aqueous NaHCO 3 at room temperature, the mixture was extracted with EtOAc three times.The organic layer was dried over Na 2 SO 4 , filtered, and concentrated.The residue was purified via flash column chromatography on silica gel (hexane:EtOAc = 2:1) to obtain 5 (77.5 mg, 75%, in 3 steps) as a white powder.The spectral data matched with those reported in the literature [5].
To a solution of the above crude 25 in THF (7 mL) was added MeMgCl (0.75 mL, 3.0 M THF solution, 2.25 mmol) at 0 • C, and the mixture was stirred at 0 • C for 10 min.After the reaction was quenched with H 2 O, the mixture was extracted with EtOAc three times.The organic layer was washed with saturated aqueous NH 4 Cl, dried over Na 2 SO 4 , filtered, and concentrated.The crude residue was used for the next reaction without further purification.
To the above crude residue in MeOH (10 mL) was added p-toluenesulfonic acid monohydrate (558.3 mg, 2.94 mmol), and the mixture was stirred at room temperature for 18 h under air.After the reaction was quenched with H 2 O and saturated aqueous NaHCO 3 at room temperature, the mixture was extracted with EtOAc three times.The organic layer was dried over Na 2 SO 4 , filtered, and concentrated.The residue was purified via flash column chromatography on silica gel (hexane:EtOAc = 2:1) to obtain 6 (45.9 mg, 68%, in 3 steps) as a white powder.The spectral data matched with those reported in the literature [5].
nBuLi (1.59 M in hexane, 3.3 mL, 5.19 mmol) was added to a precooled solution of (S)-4-isopropyloxazolidinone (673.3 mg, 5.21 mmol) in THF (6 mL) at −78 • C, and the mixture was stirred at the same temperature for 15 min.The above acyl chloride in THF (6 mL) was added to the solution and stirred at the same temperature for 15 min.After the reaction was quenched with H 2 O and saturated aqueous NH 4 Cl at room temperature, the mixture was extracted with EtOAc three times.The organic layer was dried over Na 2 SO 4 , filtered, and concentrated.The residue was purified via flash column chromatography on silica gel (hexane:EtOAc = 4:1) to obtain 30 (679.3 mg, 84%, in 2 steps) as a colorless oil.To a solution of 30 (207.6 mg, 0.45 mmol) in THF (3 mL) was added LHMDS (lithium hexamethyldisilazide) (472 µL, 1 M THF solution, 0.472 mmol) at −78 • C, the mixture was stirred at 0 • C for 1 h, and N-fluorobenzenesulfonimide (NFSI) (168.6 mg, 0.53 mmol) was added to the mixture at −78 • C.After being stirred at the same temperature for 2 h, the reaction was quenched with H 2 O and saturated aqueous NH 4 Cl at −78 • C. The mixture was extracted with EtOAc three times.The organic layer was washed with brine, dried over Na 2 SO 4 , filtered, and concentrated.The residue was purified via flash column chromatography on silica gel (hexane:EtOAc = 2:1) to obtain 29 (108.4mg, 50%) (less polar) and 33 (74.9 mg, 35%) (more polar), each as a colorless oil.

Scheme 4 .
Scheme 4. Electrophilic fluorination at the C22-position of the CD-ring side-chain.