Benzyl 3-formylpiperidine-1-carboxylate → (R,R)-3-(1-Hydroxyethyl)-piperidine-1-carboxylic acid benzyl ester

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Using Schlenck glassware and air-free conditions, anhydrous ethyl ether freshly distilled from sodium/benzophenone (2.43 mL) was added to catalyst 14 prepared according to Example 15, protocol 1. Freshly distilled titanium tetraisopropoxide (0.430 mL, 1.46 mmol) was added, and the reaction was cooled to −78° C. Commercial Me2Zn (1.21 mL, 2 M in toluene) was added, and the reaction was stirred at −78° C. for 1 hour. Aldehyde 9 (0.300 g, 1.21 mmol) in Et2O (0.3 mL) was added, and the reaction was warmed to −30° C. and stirred overnight. The reaction was then quenched at −30° C. with saturated aqueous NH4Cl. Et2O was added, and the reaction was filtered through Celite wet with Et2O. The reaction was dried with sodium sulfate, filtered, concentrated, and purified using an ISCO CombiFlash column (silica, 2:1 Hexane:EtOAc) to obtain 16 (0.167 g, 52%). HLPC analysis of the product is depicted in the Figures. 1H NMR (CDCl3, 300 MHz) 7.42-7.30 (5H, broad s), 5.15 (2H, s), 4.08 (2H, broad d, J=12.8 Hz), 3.67 (1H, dq, J=6.2, 6.2 Hz), 2.81 (1H, td, J=12.4, 3.1 Hz), 3.90-2.60 (1H, broad), 2.40-1.90 (2H, broad), 1.80-1.68 (1H, m), 1.56-1.40 (2H, m), 1.23 (3H, d, J=6.3 Hz) ppm. 13C NMR (CDCl3, 75 MHz) 155.58, 137.06, 128.61, 128.07, 127.91, 69.38, 67.14, 46.94, 44.81, 43.14, 25.71, 24.95, 21.03 ppm.

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