(2R)-3-methyl-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]butanoic acid

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

Procedure: (S)-4-(4-chlorophenyl)-3,3-dimethylpiperidin-4-ol (100 mg, 0.417 mmol), (R)-2-(tert-butoxycarbonyl(methyl)amino)-3-methylbutanoic acid (116 mg, 0.501 mmol), HOBT (77 mg, 0.501 mmol), EDC (96 mg, 0.501 mmol) and triethylamine (0.116 mL, 0.834 mmol) were mixed in methylene chloride (3 mL) at 25° C. with stirring. The reaction was stirred for 20 hours then washed with sat'd sodium bicarbonate. The methylene chloride layer was dried over sodium sulfate and concentrated in vacuo to give a white glass which was purified over silica gel (9:1 to 3:1 to 1:1 Hexanes/EtOAc) to obtain tert-butyl (R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl(methyl)carbamate (190 mg, 0.417 mmol, 100% yield) as a white glass. MS found: (M+H)+=453.15. The reaction was stirred for 20 hours then washed with sat'd sodium bicarbonate The methylene chloride layer was dried over sodium sulfate concentrated in vacuo to give a white glass which was purified over silica gel (9:1 to 3:1 to 1:1 Hexanes/EtOAc)

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

Procedure: (S)-4-(4-chlorophenyl)-3,3-dimethylpiperidin-4-ol (100 mg, 0.417 mmol), (R)-2-(tert-butoxycarbonyl(methyl)amino)-3-methylbutanoic acid (116 mg, 0.501 mmol), HOBT (77 mg, 0.501 mmol), EDC (96 mg, 0.501 mmol) and triethylamine (0.116 mL, 0.834 mmol) were mixed in methylene chloride (3 mL) at 25° C. with stirring. The reaction was stirred for 20 hours then washed with sat'd sodium bicarbonate. The methylene chloride layer was dried over sodium sulfate and concentrated in vacuo to give a white glass which was purified over silica gel (9:1 to 3:1 to 1:1 Hexanes/EtOAc) to obtain tert-butyl (R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl(methyl)carbamate (190 mg, 0.417 mmol, 100% yield) as a white glass. MS found: (M+H)+=453.15. The reaction was stirred for 20 hours then washed with sat'd sodium bicarbonate The methylene chloride layer was dried over sodium sulfate concentrated in vacuo to give a white glass which was purified over silica gel (9:1 to 3:1 to 1:1 Hexanes/EtOAc)

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

Procedure: To a solution of N-Boc-D-Val-OH (1.0 g, 4.60 mmol) in THF (15.3 mL) at 0° C. was added MeI (2.88 mL, 46.0 mmol, 10.0 equiv). NaH (60%, 1.84 g, 46.0 mmol, 10.0 equiv) was added as a solid to the suspension over a period of 2 hours. After stirring for 12 hours at room temperature, the reaction mixture was diluted with diethyl ether and quenched with water slowly. Aqueous layer was extracted with diethyl ether followed by acidified to pH 3 with 10% citric acid and extraction with ethyl acetate. Combined organic layer was washed with brine, dried with Na2SO4, filtered and concentrated in vacuo to afford compound 3.3a (1.07 g) which was used for the next step without further purification. MS m/z (M+Na) 254.2. 1H NMR (400 MHz, CDCl3) 4.02-4.17 (m, 1H), 2.88 (s, 3H), 2.40-2.14 (m, 1H), 1.54-1.39 (m, 9H), 1.03 (d, J=6.60 Hz, 3H), 0.92 (d, J=6.70 Hz, 3H). quenched with water slowly Aqueous layer was extracted with diethyl ether by acidified to pH 3 with 10% citric acid and extraction with ethyl acetate Combined organic layer was washed with brine dried with Na2SO4 filtered concentrated in vacuo

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

Procedure: A mixture of compound 7B (240 mg, 0.702 mmol), Boc-N-methyl-D-valine (176 mg, 0.762 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (208 mg, 1.085 mmol), 1-hydroxybenzotriazole (146 mg, 1.085 mmol), dichloromethane (5 mL) and THF (2.5 mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in minimum amount of dichloromethane and purified on silica gel column, which was eluted with 0.5% ammonium hydroxide and 5% methanol in dichloromethane to give the desired product (282 mg, 72% yield). The solvent was evaporated under reduced pressure the residue was dissolved in minimum amount of dichloromethane purified on silica gel column, which was eluted with 0.5% ammonium hydroxide and 5% methanol in dichloromethane

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

Procedure: (S)-4-(4-chlorophenyl)-3,3-dimethylpiperidin-4-ol (100 mg, 0.417 mmol), (R)-2-(tert-butoxycarbonyl(methyl)amino)-3-methylbutanoic acid (116 mg, 0.501 mmol), HOBT (77 mg, 0.501 mmol), EDC (96 mg, 0.501 mmol) and triethylamine (0.116 mL, 0.834 mmol) were mixed in methylene chloride (3 mL) at 25° C. with stirring. The reaction was stirred for 20 hours then washed with sat'd sodium bicarbonate. The methylene chloride layer was dried over sodium sulfate and concentrated in vacuo to give a white glass which was purified over silica gel (9:1 to 3:1 to 1:1 Hexanes/EtOAc) to obtain tert-butyl (R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl(methyl)carbamate (190 mg, 0.417 mmol, 100% yield) as a white glass. MS found: (M+H)+=453.15. The reaction was stirred for 20 hours then washed with sat'd sodium bicarbonate The methylene chloride layer was dried over sodium sulfate concentrated in vacuo to give a white glass which was purified over silica gel (9:1 to 3:1 to 1:1 Hexanes/EtOAc)