tert-butyl (2S)-2-amino-3-methylbutanoate

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

Procedure: To a solution of 1.73 g of L-Valine t-butyl ester in 10 ml of methanol was added 9.0 ml of methyl acrylate. The solution was heated to reflux overnight. Another 9.0 ml of methyl acrylate was added and continued the reflux for 24 h. The solvent was evaporated in vacuo and the crude product was purified by silica gel column chromatography (20% ethyl acetate in hexane) to provide 2.435 g of desired compound (93.9%). 300 MHz 1H NMR (CDCl3) δ 0.91 (d, J=3.5 Hz, 3H), 0.93 (d, J=3.5 Hz, 3H), 1.47 (s, 9H), 1.85 (m, 1H), 2.47 (t, J=7 Hz, 2H), 2.68 (m, 1H), 2.81 (d, J=6 Hz, 1H), 2.95 (m, 1H), 3.68 (s, 3H). Mass spectrum: (M+H)+=260. The solution was heated to reflux overnight reflux for 24 h The solvent was evaporated in vacuo the crude product was purified by silica gel column chromatography (20% ethyl acetate in hexane)

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

Procedure: To a solution of 1.73 g of L-Valine t-butyl ester in 10 ml of methanol was added 9.0 ml of methyl acrylate. The solution was heated to reflux overnight. Another 9.0 ml of methyl acrylate was added and continued the reflux for 24 h. The solvent was evaporated in vacuo and the crude product was purified by silica gel column chromatography (20% ethyl acetate in hexane) to provide 2.435 g of desired compound (93.9%). 300 MHz 1H NMR (CDCl3) δ 0.91 (d, J=3.5 Hz, 3H), 0.93 (d, J=3.5 Hz, 3H), 1.47 (s, 9H), 1.85 (m, 1H), 2.47 (t, J=7 Hz, 2H), 2.68 (m, 1H), 2.81 (d, J=6 Hz, 1H), 2.95 (m, 1H), 3.68 (s, 3H). Mass spectrum: (M+H)+=260. The solution was heated to reflux overnight reflux for 24 h The solvent was evaporated in vacuo the crude product was purified by silica gel column chromatography (20% ethyl acetate in hexane)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 511 mg of cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexanecarbaldehyde, 0.9 ml of HOAc and 310 mg of tert-butyl (S)-valinate are dissolved in 5 ml of abs. dichloromethane. 500 mg of molecular sieve 4 Å are then added, and the suspension is cooled to 0° C. 414 mg of sodium triacetoxyborohydride are added a little at a time. This suspension is stirred at 0° C. for 2 h, 3 ml of saturated NH4Cl solution are then added and the suspension is stirred for a further 10 min. In each case 10 ml of water and dichloromethane are added, the phases are separated, the aqueous phase is extracted with dichloromethane and the combined organic phases are dried over MgSO4 and concentrated, which gives 760 mg of tert-butyl (S)-3-methyl-2-{[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]-amino}butyrate. C28H42N2O4 (470.66); MS (ESI): 471.50 (MH+). 500 mg of molecular sieve 4 Å are then added the suspension is stirred for a further 10 min the phases are separated the aqueous phase is extracted with dichloromethane the combined organic phases are dried over MgSO4 concentrated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 511 mg of cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexanecarbaldehyde, 0.9 ml of HOAc and 310 mg of tert-butyl (S)-valinate are dissolved in 5 ml of abs. dichloromethane. 500 mg of molecular sieve 4 Å are then added, and the suspension is cooled to 0° C. 414 mg of sodium triacetoxyborohydride are added a little at a time. This suspension is stirred at 0° C. for 2 h, 3 ml of saturated NH4Cl solution are then added and the suspension is stirred for a further 10 min. In each case 10 ml of water and dichloromethane are added, the phases are separated, the aqueous phase is extracted with dichloromethane and the combined organic phases are dried over MgSO4 and concentrated, which gives 760 mg of tert-butyl (S)-3-methyl-2-{[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]-amino}butyrate. C28H42N2O4 (470.66); MS (ESI): 471.50 (MH+). 500 mg of molecular sieve 4 Å are then added the suspension is stirred for a further 10 min the phases are separated the aqueous phase is extracted with dichloromethane the combined organic phases are dried over MgSO4 concentrated

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

Procedure: To a solution of 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (2.0 g, 8.1 mmol) and (S)-tert-butyl 2-amino-3-methylbutanoate (2.0 g, 9.5 mmol) in DMF (10 mL) were added HATU (6.1 g, 16 mmol) and DIEA (4.2 g, 33 mmol). The reaction mixture was stirred at rt overnight. The reaction was then quenched with water (100 mL). The resulting mixture was extracted with DCM (2×100 mL), and the organic layer was concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (EtOAc/petroleum ether (1:50)) to obtain compound 43a as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C22H34BNO5: 404.3 (M+H). Found 404.1. The reaction was then quenched with water (100 mL) The resulting mixture was extracted with DCM (2×100 mL) the organic layer was concentrated under reduced pressure The residue obtained was purified by flash column chromatography on silica gel (EtOAc/petroleum ether (1:50))

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To (4-(5-(2′-methyl-2-(trifluoromethyl)biphenyl-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol (84 mg; 0.2 mmol) in DCM (2 mL) was added DIEA (71 μL; 0.4 mmol) and mesyl chloride (17 μL; 0.22 mmol), at 0° C. The resulting mixture was stirred at 0° C. for 10 minutes, allowed to warm to RT and stirred for 2 hours. The mixture was diluted with DCM (20 mL) and saturated aqueous NaHCO3 solution was added. The aqueous layer was extracted with DCM (3×20 mL), the combined organic fractions were dried (MgSO4), filtered and the solvent removed in vacuo. The crude residue was all used in the next step without further purification. It was dissolved in dioxan (2 mL). Potassium carbonate (165 mg, 1.2 mmol) and (S)-tert-butyl 2-amino-3-methylbutanoate (104 mg; 0.60 mmol) were added. The mixture was heated at 130° C. for 72 hours, diluted with DCM (5 mL) and water (5 mL). The aqueous layer was extracted with DCM (3×20 mL), the combined organic fractions were dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by flash chromatography eluting with petrol containing increasing amounts of EtOAc to give the title compound as a colourless gum (86 mg; 72%). 1H NMR (CDCl3, 400 MHz) δ 8.63 (1H, s), 8.39 (1H, dd, J=8.0, 1.7 Hz), 8.12 (2H, d, J=8.1 Hz), 7.47 (1H, d, J=8.0 Hz), 7.43-7.21 (5H, m), 7.16 (1H, d, J=7.6 Hz), 2.99-2.68 (5H, m), 2.07 (3H, s), 1.94-1.79 (1H, m), 1.46 (9H, s), 0.94 (6H, dd, J=6.8, 3.7 Hz). LC/MS (Method B): 580 (M+H)+. HPLC (Method D) Rt 3.7 min (Purity: 94.9%). at 0° C to warm to RT stirred for 2 hours was added The aqueous layer was extracted with DCM (3×20 mL) the combined organic fractions were dried (MgSO4) filtered the solvent removed in vacuo all used in the next step without further purification It was dissolved in dioxan (2 mL) The mixture was heated at 130° C. for 72 hours The aqueous layer was extracted with DCM (3×20 mL) the combined organic fractions were dried (MgSO4) filtered the solvent removed in vacuo The residue was purified by flash chromatography eluting with petrol containing increasing amounts of EtOAc

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

Procedure: To a solution of 1.73 g of L-Valine t-butyl ester in 10 ml of methanol was added 9.0 ml of methyl acrylate. The solution was heated to reflux overnight. Another 9.0 ml of methyl acrylate was added and continued the reflux for 24 h. The solvent was evaporated in vacuo and the crude product was purified by silica gel column chromatography (20% ethyl acetate in hexane) to provide 2.435 g of desired compound (93.9%). 300 MHz 1H NMR (CDCl3) δ 0.91 (d, J=3.5 Hz, 3H), 0.93 (d, J=3.5 Hz, 3H), 1.47 (s, 9H), 1.85 (m, 1H), 2.47 (t, J=7 Hz, 2H), 2.68 (m, 1H), 2.81 (d, J=6 Hz, 1H), 2.95 (m, 1H), 3.68 (s, 3H). Mass spectrum: (M+H)+=260. The solution was heated to reflux overnight reflux for 24 h The solvent was evaporated in vacuo the crude product was purified by silica gel column chromatography (20% ethyl acetate in hexane)

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

Procedure: To a solution of 1.73 g of L-Valine t-butyl ester in 10 ml of methanol was added 9.0 ml of methyl acrylate. The solution was heated to reflux overnight. Another 9.0 ml of methyl acrylate was added and continued the reflux for 24 h. The solvent was evaporated in vacuo and the crude product was purified by silica gel column chromatography (20% ethyl acetate in hexane) to provide 2.435 g of desired compound (93.9%). 300 MHz 1H NMR (CDCl3) δ 0.91 (d, J=3.5 Hz, 3H), 0.93 (d, J=3.5 Hz, 3H), 1.47 (s, 9H), 1.85 (m, 1H), 2.47 (t, J=7 Hz, 2H), 2.68 (m, 1H), 2.81 (d, J=6 Hz, 1H), 2.95 (m, 1H), 3.68 (s, 3H). Mass spectrum: (M+H)+=260. The solution was heated to reflux overnight reflux for 24 h The solvent was evaporated in vacuo the crude product was purified by silica gel column chromatography (20% ethyl acetate in hexane)

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

Procedure: To a solution of 1.73 g of L-Valine t-butyl ester in 10 ml of methanol was added 9.0 ml of methyl acrylate. The solution was heated to reflux overnight. Another 9.0 ml of methyl acrylate was added and continued the reflux for 24 h. The solvent was evaporated in vacuo and the crude product was purified by silica gel column chromatography (20% ethyl acetate in hexane) to provide 2.435 g of desired compound (93.9%). 300 MHz 1H NMR (CDCl3) δ 0.91 (d, J=3.5 Hz, 3H), 0.93 (d, J=3.5 Hz, 3H), 1.47 (s, 9H), 1.85 (m, 1H), 2.47 (t, J=7 Hz, 2H), 2.68 (m, 1H), 2.81 (d, J=6 Hz, 1H), 2.95 (m, 1H), 3.68 (s, 3H). Mass spectrum: (M+H)+=260. The solution was heated to reflux overnight reflux for 24 h The solvent was evaporated in vacuo the crude product was purified by silica gel column chromatography (20% ethyl acetate in hexane)

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

Procedure: L-valine tert-butyl ester hydrochloride (3.2 g, 15.259 mmol) was partitioned between dichloromethane and a saturated solution of sodium bicarbonate. The aqueous layer was extracted with dichloromethane. The organics were combined, filtered through a phase separator and the volatiles were removed in vacuo to provide L-valine tert-butyl ester as a colourless oil which was dissolved in anhydrous dichloroethane (40 mL). This solution was treated with a solution of trimethylaluminum (15.2 mL, 30.516 mmol, 2 M in toluene). After stirring at room temperature for 1.5 h, the mixture was treated with a solution of 3-methyl-3-vinyl-dihydro-furan-2-one (641.7 mg, 5.086 mmol) in dichloroethane (10 mL). After stirring at 85° C. for 15 h, the reaction was cooled to 0° C., slowly quenched with hydrochloric acid (2 M). The aqueous layer was extracted with ethyl acetate (3×), the organics were combined, dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo to provide the title compound (1.053 g, 85%) as a white solid and as a 1:1 mixture of diastereoisomers. The aqueous layer was extracted with dichloromethane filtered through a phase separator the volatiles were removed in vacuo

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

Procedure: L-valine tert-butyl ester hydrochloride (3.2 g, 15.259 mmol) was partitioned between dichloromethane and a saturated solution of sodium bicarbonate. The aqueous layer was extracted with dichloromethane. The organics were combined, filtered through a phase separator and the volatiles were removed in vacuo to provide L-valine tert-butyl ester as a colourless oil which was dissolved in anhydrous dichloroethane (40 mL). This solution was treated with a solution of trimethylaluminum (15.2 mL, 30.516 mmol, 2 M in toluene). After stirring at room temperature for 1.5 h, the mixture was treated with a solution of 3-methyl-3-vinyl-dihydro-furan-2-one (641.7 mg, 5.086 mmol) in dichloroethane (10 mL). After stirring at 85° C. for 15 h, the reaction was cooled to 0° C., slowly quenched with hydrochloric acid (2 M). The aqueous layer was extracted with ethyl acetate (3×), the organics were combined, dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo to provide the title compound (1.053 g, 85%) as a white solid and as a 1:1 mixture of diastereoisomers. The aqueous layer was extracted with dichloromethane filtered through a phase separator the volatiles were removed in vacuo

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

Procedure: When in the procedure of Example 1, Step (b), thianthrene-2-sulfonyl chloride is replaced by phenoxathiine-2-sulfonyl chloride and (L)-valine-t-butyl ester is replaced with (L)-asparagine-t-butyl ester, (S)-2-(phenoxathiine-2-sulfonylamino)-succinamic acid is obtained; mp 165-175° C.