1-O-tert-butyl 2-O-methyl 5-oxopiperidine-1,2-dicarboxylate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-(tert-Butoxycarbonyl)-5-oxopiperidine-2-carboxylic acid (2.0 g, 8.22 mmol) was dissolved in DMF (20 mL) under nitrogen and potassium carbonate (1.7 g, 12.33 mmol) was added, followed by iodomethane (620 μL, 9.95 mmol). The reaction mixture was stirred at room temperature under nitrogen for 23 h. Additional methyl iodide (256 μL, 4.11 mmol) was added and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate solution (2×25 mL) and brine (2×25 mL), then dried over sodium sulfate and concentrated to dryness. The crude residue was purified by flash column chromatography (Biotage), eluting with 0 to 100% ethyl acetate in heptanes, to afford the title compound (2.42 g, 53%) as a pale yellow oil. δH (250 MHz, CDCl3) 4.70 (dt, J 59.4, 6.3 Hz, 1H), 4.35 (dd, J 27.3, 19.0 Hz, 1H), 3.90 (dd, J 19.0, 12.4 Hz, 1H), 3.77 (s, 3H), 2.56-1.95 (m, 4H), 1.45 (s, 9H). the reaction mixture was stirred at room temperature for 24 h washed with saturated aqueous sodium bicarbonate solution (2×25 mL) and brine (2×25 mL) dried over sodium sulfate concentrated to dryness The crude residue was purified by flash column chromatography (Biotage) eluting with 0 to 100% ethyl acetate in heptanes

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Cerium chloride (0.21 g, 0.86 mmol) was dried in vacuo at 90° C. for 1 hour, then at 140° C. for 1.5 hours. After cooling to room temperature, 2.8 mL of THF was added, and the suspension was stirred for 1 hour. 5-Oxo-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.10 g, 0.39 mmol) was added, and the mixture was stirred at 0° C. for 2 hour. Methyl magnesium bromide (0.14 mL of a 3M solution in ether) was added dropwise at −50° C, and the mixture was immediately warmed to room temperature and stirred for 30 minutes. Additional methyl magnesium bromide was added following the preceeding procedure until the reaction was complete as determined by 1H NMR of an aliquot worked up as described below. The mixture was diluted with saturated aqueous NH4Cl, extracted 3 times with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered and concentrated, affording ca. 0.08 g of crude 5-hydroxy-5-methyl-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester as a colorless oil. the mixture was stirred at 0° C. for 2 hour the mixture was immediately warmed to room temperature stirred for 30 minutes extracted 3 times with ethyl acetate the combined organic layers were dried over Na2SO4 filtered concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Cerium chloride (0.21 g, 0.86 mmol) was dried in vacuo at 90° C. for 1 hour, then at 140° C. for 1.5 hours. After cooling to room temperature, 2.8 mL of THF was added, and the suspension was stirred for 1 hour. 5-Oxo-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.10 g, 0.39 mmol) was added, and the mixture was stirred at 0° C. for 2 hour. Methyl magnesium bromide (0.14 mL of a 3M solution in ether) was added dropwise at −50° C, and the mixture was immediately warmed to room temperature and stirred for 30 minutes. Additional methyl magnesium bromide was added following the preceeding procedure until the reaction was complete as determined by 1H NMR of an aliquot worked up as described below. The mixture was diluted with saturated aqueous NH4Cl, extracted 3 times with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered and concentrated, affording ca. 0.08 g of crude 5-hydroxy-5-methyl-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester as a colorless oil. the mixture was stirred at 0° C. for 2 hour the mixture was immediately warmed to room temperature stirred for 30 minutes extracted 3 times with ethyl acetate the combined organic layers were dried over Na2SO4 filtered concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-(tert-Butoxycarbonyl)-5-oxopiperidine-2-carboxylic acid (2.0 g, 8.22 mmol) was dissolved in DMF (20 mL) under nitrogen and potassium carbonate (1.7 g, 12.33 mmol) was added, followed by iodomethane (620 μL, 9.95 mmol). The reaction mixture was stirred at room temperature under nitrogen for 23 h. Additional methyl iodide (256 μL, 4.11 mmol) was added and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate solution (2×25 mL) and brine (2×25 mL), then dried over sodium sulfate and concentrated to dryness. The crude residue was purified by flash column chromatography (Biotage), eluting with 0 to 100% ethyl acetate in heptanes, to afford the title compound (2.42 g, 53%) as a pale yellow oil. δH (250 MHz, CDCl3) 4.70 (dt, J 59.4, 6.3 Hz, 1H), 4.35 (dd, J 27.3, 19.0 Hz, 1H), 3.90 (dd, J 19.0, 12.4 Hz, 1H), 3.77 (s, 3H), 2.56-1.95 (m, 4H), 1.45 (s, 9H). the reaction mixture was stirred at room temperature for 24 h washed with saturated aqueous sodium bicarbonate solution (2×25 mL) and brine (2×25 mL) dried over sodium sulfate concentrated to dryness The crude residue was purified by flash column chromatography (Biotage) eluting with 0 to 100% ethyl acetate in heptanes