[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][C@H:9]1[CH:15]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21].[BH4-].[Na+]>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][C@H:9]1[CH2:15][NH:21][C:20]1[CH:22]=[CH:23][CH:24]=[C:18]([Cl:17])[CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]Solution of (S)-4,4-difluoro-2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1 g, 0.0042 mol) and 3-chloroaniline (0.53 mL, 0.0042 mol) in titanium tetraisopropoxide (5 mL) was allowed to stir for 12 h. The reaction was monitored by TLC. After disappearance of starting reaction on TLC, the mixture was diluted with methanol (20 mL) followed by the addition of sodium borohydride (0.33 g, 0.0084 mol) in portions. The reaction mixture was stirred for 6 h. The reaction was quenched with water and extracted with DCM (3×50 mL). The organic layer was dried over anhydrous Na2SO4 and the volatiles were removed using a rotary evaporator to give a crude oil, which was then purified via column chromatography (5% methanol: DCM, mesh Size—100-200 silica, diameter of column—2.5 cm, height of silica—approx. 4 inch) to afford the desired (S)-2-[(3-chloro-phenylamino)-methyl]-4,4-difluoro-pyrrolidine-1-carboxylic acid tert-butyl ester as a sticky solid (0.15 g, 12%).
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