tert-butyl N-[(2S)-1-hydroxy-4-methylpentan-2-yl]carbamate

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of sulfur trioxide pyridine complex (7.8 g, 49.1 mmol, 3.0 equiv) in a 1:1 mixture of DMSO and CH2Cl2 (100 mL) was added to a solution of BOC-L-Leucinol (3.56 g, 16.4 mmol. 1 equiv) and Et3N (8 mL) in a 1:1 mixture of DMSO and CH2Cl2 (100 mL) at 0° C. The reaction mixture was stirred at 23° C. for 30 min, then poured into ice water (300 mL), and extracted with Et2O (2×200 mL). The combined organic layers were washed with 0.5M HCl (150 mL), half saturated NaHCO3 (150 mL) and H2O (2×150 mL), then dried over Na2SO4, and concentrated to afford crude BOC-L-Leucinal as pale yellow oil (3.48 g, 99%). This material was used without further purification. 1H NMR (CDCl3) δ 0.92-0.94 (m, 6H), 1.44 (s, 9H), 1.59-1.64 (m, 1H), 1.67-1.85 (m, 2H), (4.21 (m, 1H), 5.12 (s, br, 1H), 9.57 (s, 1H). extracted with Et2O (2×200 mL) The combined organic layers were washed with 0.5M HCl (150 mL), half saturated NaHCO3 (150 mL) and H2O (2×150 mL) dried over Na2SO4 concentrated

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of BOC-Leu-OH (15.09 g, 65 mmol, 1 equiv) in THF (150 mL) at 0° C. was added BH3 ·THF (163 mL of a 1.0M solution in THF, 163 mmol, 2.51 equiv). The reaction mixture was stirred at 23° C. for 3 h and then cooled to 0° C. Brine (100 mL) was added carefully, and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (gradient elution, 25→35% EtOac in hexanes) to afford BOC-L-Leucinol as a colorless oil (12.59 g, 89%): IR (cm-1): 3434, 1699, 1256, 739; 1H NMR (CDCl3) δ 0.93 (dd, 6H, J=6.6, 1.5), 1.29-1.31 (m, 2H), 1.45 (s, 9H), 1.60-2.05 (m, 2H), 3.47-3.53 (m, 1H), 3.65-3.72 (m, 2H), 4.56 (s, br, 1H); Anal. (C11H23NO3) C, H, N. cooled to 0° C the aqueous layer was extracted with EtOAc (2×100 mL) The combined organic layers were dried over Na2SO4 concentrated The residue was purified by flash column chromatography (gradient elution, 25→35% EtOac in hexanes)

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

Procedure: To a stirred solution of (S)-tert-butyl (1-hydroxy-4-methylpentan-2-yl)carbamate (1.6 g, 7.36 mmol) in dichloromethane (15 mL) was added triethyl amine (2.052 mL, 14.73 mmol) at 0° C. and the solution was stirred for 5 min. To this mixture at 0° C. was added methanesulfonyl chloride (0.574 mL, 7.36 mmol) dropwise and the reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with water (15 mL) and extracted with DCM (2×15 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulphate, concentrated under reduced pressure to yield (S)-2-((tert-butoxycarbonyl)amino)-4-methylpentyl methanesulfonate (1.7 g, 5.75 mmol, 78% yield) as a yellow solid which was carried on without further purification. 1H NMR (400 MHz, CDCl3) δ 4.55 (m, 1H), 4.25 (m, 1H), 4.16 (m, 1H), 3.92 (m, 1H), 3.05 (s, 3H), 1.66 (m, 2H), 1.56 (m, 10H), 0.92 (m, 6H). the reaction mixture was stirred at room temperature for 1 h The reaction was quenched with water (15 mL) extracted with DCM (2×15 mL) The combined organic layers were washed with brine (10 mL) dried over sodium sulphate concentrated under reduced pressure

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

Procedure: To a stirred solution of (S)-tert-butyl (1-hydroxy-4-methylpentan-2-yl)carbamate (1.6 g, 7.36 mmol) in dichloromethane (15 mL) was added triethyl amine (2.052 mL, 14.73 mmol) at 0° C. and the solution was stirred for 5 min. To this mixture at 0° C. was added methanesulfonyl chloride (0.574 mL, 7.36 mmol) dropwise and the reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with water (15 mL) and extracted with DCM (2×15 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulphate, concentrated under reduced pressure to yield (S)-2-((tert-butoxycarbonyl)amino)-4-methylpentyl methanesulfonate (1.7 g, 5.75 mmol, 78% yield) as a yellow solid which was carried on without further purification. 1H NMR (400 MHz, CDCl3) δ 4.55 (m, 1H), 4.25 (m, 1H), 4.16 (m, 1H), 3.92 (m, 1H), 3.05 (s, 3H), 1.66 (m, 2H), 1.56 (m, 10H), 0.92 (m, 6H). the reaction mixture was stirred at room temperature for 1 h The reaction was quenched with water (15 mL) extracted with DCM (2×15 mL) The combined organic layers were washed with brine (10 mL) dried over sodium sulphate concentrated under reduced pressure

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 8-chloro-2-methyl-5H-chromeno[3,4-c]pyridine (0.2 g, 0.863 mmol), (S)-tert-butyl (1-hydroxy-4-methylpentan-2-yl)carbamate (0.225 g, 1.036 mmol), palladium(II) acetate (5.81 mg, 0.026 mmol), Cs2CO3 (0.422 g, 1.295 mmol) and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (0.022 g, 0.052 mmol) in toluene (5 mL) was heated to 110° C. for 18 h. After cooling, the mixture was filtered through celite and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (70% EtOAc in pet. ether) to afford (S)-tert-butyl (4-methyl-1-((2-methyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)pentan-2-yl)carbamate, as a semi-solid (0.12 g, 0.291 mmol, 34% yield). LCMS (ESI) m/e 413.4 [(M+H)+, calcd for C24H33N2O4 413.2]; LC/MS retention time (Method D): tR=2.42 min. After cooling the mixture was filtered through celite and concentrated under reduced pressure The crude product was purified by silica gel chromatography (70% EtOAc in pet. ether)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 8-chloro-2-methyl-5H-chromeno[3,4-c]pyridine (0.2 g, 0.863 mmol), (S)-tert-butyl (1-hydroxy-4-methylpentan-2-yl)carbamate (0.225 g, 1.036 mmol), palladium(II) acetate (5.81 mg, 0.026 mmol), Cs2CO3 (0.422 g, 1.295 mmol) and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (0.022 g, 0.052 mmol) in toluene (5 mL) was heated to 110° C. for 18 h. After cooling, the mixture was filtered through celite and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (70% EtOAc in pet. ether) to afford (S)-tert-butyl (4-methyl-1-((2-methyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)pentan-2-yl)carbamate, as a semi-solid (0.12 g, 0.291 mmol, 34% yield). LCMS (ESI) m/e 413.4 [(M+H)+, calcd for C24H33N2O4 413.2]; LC/MS retention time (Method D): tR=2.42 min. After cooling the mixture was filtered through celite and concentrated under reduced pressure The crude product was purified by silica gel chromatography (70% EtOAc in pet. ether)

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

Procedure: Prepared as described in Example 18, Part H using (S)-tert-butyl (1-hydroxy-4-methylpentan-2-yl)carbamate and N-(8-chloro-7-methoxy-5H-chromeno[3,4-c]pyridin-2-yl)acetamide to afford (S)-tert-butyl (1-((2-acetamido-7-methoxy-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (112 mg, 0.089 mmol, 60% yield) as a brown oil. LCMS (ESI) m/e 486.2 [(M+H)+, calcd for C26H36N3O6 486.2]; LC/MS retention time (Method F): tR=0.91 min. Prepared

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

Procedure: Prepared as described in Example 18, Part H using (S)-tert-butyl (1-hydroxy-4-methylpentan-2-yl)carbamate and N-(8-chloro-7-methoxy-5H-chromeno[3,4-c]pyridin-2-yl)acetamide to afford (S)-tert-butyl (1-((2-acetamido-7-methoxy-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (112 mg, 0.089 mmol, 60% yield) as a brown oil. LCMS (ESI) m/e 486.2 [(M+H)+, calcd for C26H36N3O6 486.2]; LC/MS retention time (Method F): tR=0.91 min. Prepared

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

Procedure: Prepared as described in Example 8, Part C using (S)-tert-butyl (1-hydroxy-4-methylpentan-2-yl)carbamate and N-(8-chloro-7-methyl-5H-chromeno[3,4-c]pyridin-2-yl)acetamide to afford (S)-tert-butyl (1-((2-acetamido-7-methyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (168 mg, 0.037 mmol, 11% yield) as a brown oil. LCMS (ESI) m/e 470.3 [(M+H)+, calcd for C26H36N3O5 470.3]; LC/MS retention time (Method F): tR=0.96 min. Prepared

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 8-chloro-4-methyl-5H-chromeno[3,4-c]pyridine (60 mg, 0.259 mmol), (S)-(−)-2-(tert-butoxycarbonylamino)-4-methyl-1-pentanol (113 mg, 0.518 mmol), 2-di-t-butylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl (6.60 mg, 0.016 mmol), Cs2CO3 (127 mg, 0.388 mmol) and Pd(OAc)2 (1.744 mg, 7.77 μmol) in toluene (5 mL) was heated at 80° C. for 16 h. After cooling to rt, the mixture was diluted with EtOAc (10 mL) and water (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford (S)-tert-butyl (4-methyl-1-((4-methyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)pentan-2-yl)carbamate, (0.2 g, 0.485 mmol, 30% yield) as a yellow solid. LCMS (ESI) m/e 413.39 [(M+H)+, calcd for C24H33N2O4 413.24]; LC/MS retention time (Method F): tR=0.97 min. After cooling to rt The organic layer was dried over Na2SO4 filtered concentrated under reduced pressure

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

Procedure: Prepared as described in Example 8, Part C using (S)-tert-butyl (1-hydroxy-4-methylpentan-2-yl)carbamate and N-(8-chloro-5-methyl-5H-chromeno[3,4-c]pyridin-2-yl)acetamide to afford tert-butyl ((2S)-1-((2-acetamido-5-methyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (290 mg, 0.617 mmol, 33% yield) as a yellow oil. LCMS (ESI) m/e 470.3 [(M+H)+, calcd for C26H36N3O5 470.3]; LC/MS retention time (Method F): tR=0.99 min. Prepared

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

Procedure: Prepared as described in Example 8, Part C using (S)-tert-butyl (1-hydroxy-4-methylpentan-2-yl)carbamate and 8-chloro-5-(trifluoromethyl)-5H-chromeno[3,4-c]pyridine to afford tert-butyl ((2S)-4-methyl-1-((5-(trifluoromethyl)-5H-chromeno[3,4-c]pyridin-8-yl)oxy)pentan-2-yl)carbamate (0.28 g, 0.516 mmol, 49% yield) as a yellow solid. LCMS (ESI) m/e 467.2 [(M+H)+, calcd for C24H30F3N2O4 467.2]; LC/MS retention time (Method C): tR=2.19 min. Prepared