Water → (3R)-[1,4']Bipiperidinyl-3,1'-dicarboxylic acid 1'-tert-butyl ester 3-ethyl ester

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To a mixture of tert-butyl 4-oxo-1-piperidinecarboxylate (12.40 g, 62.2 mmol) and (R)-ethyl nipecotate (1.05 eq, 65.3 mmol, 10.27 g) was added titanium tetraisopropoxide (1.25 eq, 23 mL) under nitrogen. A viscous, clear golden yellow solution was formed. After 1 h a solution of sodium cyanoborohydride (0.7 eq, 2.74 g) in anhydrous ethanol (65 mL) was added. An exothermic reaction took place and some gas evolution occurred. The solution was stirred overnight at ambient temperature then water (13 mL) was added slowly, along with additional ethanol as necessary to permit stirring to continue. The mixture was stirred for 30 minutes then filtered through a large pad of Celite®, washing through with ethanol. The filtrate was evaporated to dryness, toluene added and again evaporated to dryness. The residue was purified by chromatography on 150 g silica gel eluting with 5% methanol-dichloromethane. Fractions containing product were combined and evaporated to dryness to give an oil which became semi-solid on standing. The product was dissolved in dichloromethane, washed with dilute sodium hydroxide solution to remove titanium-containing impurities, dried over anhydrous sodium sulfate and evaporated to yield the title compound as a colorless oil, 21.14 g (containing a small amount of the isopropyl ester from transesterification).

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