Methyl N-Boc-4-hydroxypiperidine-2-carboxylate

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

Procedure: To a stirred solution of the alcohol from step D (3.8 g, 15.0 mmol) in anhydrous dichloromethane (50 mL) was added dihydropyran (7.5 mL, 88.6 mmol) followed by p-toluenesulfonic acid monohydrate (71 mg, 0.4 mmol). After 3 h, triethylamine (0.42 mL, 3.0 mmol) was added and the reaction mixture was concentrated in vacuo. Ethyl acetate (100 mL) was added and the resulting solution was washed with brine (3×50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue purified by column chromatography (SiO2, 9:1 to 7:3, hexanes/ethyl acetate) to afford 1-tert-butyl 2-methyl 4-((tetrahydro-2H-pyran-2-yl)oxy)piperidine-1,2-dicarboxylate (5.0 g, 96%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 5.00-4.62 (m, 2H), 4.15-4.02 (m, 1H), 3.71 (t, J=7.2 Hz, 3H), 3.50-3.47 (m, 1H), 2.49 (br s, 1H), 1.95-1.70 (m, 4H), 1.60-1.42 (m, 13H), 1.27-1.24 (m, 4H). the reaction mixture was concentrated in vacuo Ethyl acetate (100 mL) was added the resulting solution was washed with brine (3×50 mL) dried over Na2SO4 filtered The filtrate was concentrated in vacuo the residue purified by column chromatography (SiO2, 9:1 to 7:3, hexanes/ethyl acetate)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of oxalyl chloride ((15 mL, 30 mmol, 2 M dichloromethane) in CH2Cl2 (100 mL) cooled to −78° C. was added DMSO (4.5 mL, 63.4 mmol). The mixture was stirred at this temperature for 1 h, after which 4-hydroxy-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (2.0 g, 7.71 mmol dissolved in CH2Cl2) as added. The mixture stirred for a further 1 h and Et3N (20 mL) was then added and the mixture stirred for another 30 min. The mixture was then allowed to warm to −40° C. and poured into a solution of 10% NaHSO4. The reaction mixture was then extracted with ethyl acetate. The organic extract was then washed with brine and dried over MgSO4 (anhydrous) and the solvent was removed in vacuo and the crude residue was purified by silica gel flash column chromatography giving 1.75 g (88%) of the product as a yellow oil. 1H-NMR (CDCl3), δ(ppm): 4.85 (br, d, 1H), 4.02 (m, 1H), 3.61 (s, 3H), 3.58 (br, 1H), 2.75 (m, 2H), 2.44 (br, 2H), 1.43 (br, s, 9H). The mixture stirred for a further 1 h the mixture stirred for another 30 min to warm to −40° C. The reaction mixture was then extracted with ethyl acetate The organic extract was then washed with brine dried over MgSO4 (anhydrous) the solvent was removed in vacuo the crude residue was purified by silica gel flash column chromatography