Cl.[F:2][C:3]1([F:8])[CH2:7][CH2:6][NH:5][CH2:4]1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O)C.[BH3-]C#N.[Na+]>C1COCC1.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([N:5]2[CH2:6][CH2:7][C:3]([F:8])([F:2])[CH2:4]2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]A mixture of 3,3-difluoro-pyrrolidine hydrochloride (2.02 mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (2.02 mmol) and Ti(OiPr)4 (2.42 mmol) in THF is stirred at room temperature for 1 h. To the resulting mixture are added ethanol (3 mL) and NaBH3CN (1.21 mmol). After stirring for 17 h, the reaction is quenched by the addition of sat. aq. NaHCO3 and the resulting precipitate is filtered out. After the filtrate is diluted with AcOEt, the mixture is washed with brine, dried over MgSO4, and concentrated in vacuo. The residue is purified by silica gel column chromatography to give 4-(3,3-difluoro-pyrrolidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester; 1H NMR (CDCl)3 δ: 1.34-1.52 (2H, m), 1.45 (9H, s), 1.79 (2H, bd), 2.19-2.33 (3H, m), 2.78 (2H, dd), 2.83 (2H, dd), 2.95 (2H, dd), 4.00 (2H, bs).
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