tert-butyl formate

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

Procedure: To a solution of [(3R,4S,5S)-5-(3,5-difluoro-4-nitro-benzyl)-4-hydroxy-tetrahydro-thiopyran-3-yl]-carbamic acid tert-butyl ester (1 g, 2.47 mmol) and (R)-1,1,1-trifluoro-3-methoxy-propan-2-ol (392 mg, 2.72 mmol) in THF (13 mL) was added tert-BuOK (277 mg, 2.47 mmol) in small portions at 0° C. over a period of 30 min. After 1 h the cooling bath was removed and the orange solution was stirred at room temperature for 5 h. The reaction mixture was diluted with EtOAc (500 mL) and washed with ice cooled K2CO3 solution and cold brine. The organic phase was dried over Na2SO4, filtered and evaporated to yield a brown-yellowish foam: TLC Rf=0.50 (toluene-ETA 85:15); HPLC RtE=1.157 min; ESIMS [M+H-Boc]+=429; 1H NMR (600 MHz, DMSO-d6): δ 7.28 (s, 1H), 7.10 (d, 1H), 6.71 (d, 1H), 5.65 (broad, 1H), 4.95 (d, 1H), 3.83 (dd, 1H), 3.73 (dd, 1H), 3.42 (m, 1H), 3.31 (s, 3H), 3.25 (dd, 1H), 2.93 (m, 1H), 2.54 (d, 1H), 2.48-2.35 (m, 2H), 2.32-2.20 (m, 2H), 1.94 (m, 1H), 1.37 (s, 9H). After 1 h the cooling bath was removed The reaction mixture was diluted with EtOAc (500 mL) washed with ice cooled K2CO3 solution and cold brine The organic phase was dried over Na2SO4 filtered evaporated to yield a brown-yellowish foam HPLC RtE=1.157 min

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

Procedure: To a solution of methyl (1R,4S)-4-[(tert-butoxycarbonyl)amino]-1-[(3R)-tetrahydrofuran-3-yl]cyclopent-2-ene-1-carboxylate (1.60 g, 5.14 mmol) in tetrahydrofuran (27.8 mL), methanol (27.8 mL) and water (6.0 mL) was added lithium hydroxide monohydrate (0.346 g, 8.25 mmol). The pink mixture was heated to reflux for 18 h. The organic solvents were removed in vacuo and the aqueous layer was extracted once with ether and then acidified slowly with 6 M HCl until the pH reached 3-4. The resulting suspension was extracted with CH2Cl2 three times. The combined organic layers were dried over MgSO4, filtered and concentrated to give the product as a mixture of two cis/trans isomers (1.59 g) as a light yellow solid. MS calculated for C15H24NO5: (M+H) 298.2; found 198.2 (M+H-Boc). The pink mixture was heated to reflux for 18 h The organic solvents were removed in vacuo the aqueous layer was extracted once with ether The resulting suspension was extracted with CH2Cl2 three times The combined organic layers were dried over MgSO4 filtered concentrated to give the product as a mixture of two cis/trans isomers (1.59 g) as a light yellow solid

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

Procedure: To a solution of methyl (1R,4S)-4-[(tert-butoxycarbonyl)amino]-1-[(3R)-tetrahydrofuran-3-yl]cyclopent-2-ene-1-carboxylate (1.60 g, 5.14 mmol) in tetrahydrofuran (27.8 mL), methanol (27.8 mL) and water (6.0 mL) was added lithium hydroxide monohydrate (0.346 g, 8.25 mmol). The pink mixture was heated to reflux for 18 h. The organic solvents were removed in vacuo and the aqueous layer was extracted once with ether and then acidified slowly with 6 M HCl until the pH reached 3-4. The resulting suspension was extracted with CH2Cl2 three times. The combined organic layers were dried over MgSO4, filtered and concentrated to give the product as a mixture of two cis/trans isomers (1.59 g) as a light yellow solid. MS calculated for C15H24NO5: (M+H) 298.2; found 198.2 (M+H-Boc). The pink mixture was heated to reflux for 18 h The organic solvents were removed in vacuo the aqueous layer was extracted once with ether The resulting suspension was extracted with CH2Cl2 three times The combined organic layers were dried over MgSO4 filtered concentrated to give the product as a mixture of two cis/trans isomers (1.59 g) as a light yellow solid

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

Procedure: The title compound was prepared from ethyl acrylate (1.09 ml, 10 mmol) and cyclopropylamine (0.69 ml, 10 mmol) according to Example 2a. Yield: 2.06 g (80%). ESI-MS: 258.2 (M+H)+, 202.2 (M+H—C4H8)+, 158.2 (M+H-Boc)+. Rf (silica gel; ethyl acetate/heptane, 1:4, v/v): 0.38.

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

Procedure: The title compound was prepared from ethyl acrylate (1.09 ml, 10 mmol) and cyclobutylamine (0.85 ml, 10 mmol) according to Example 2a. Yield: 1.71 9 (63%). ESI-MS: 272.2 (M+H)+, 216.2 (M+H—C4H8)+, 172.2 (M+H-Boc)+. Rf (silica gel; ethyl acetate/heptane, 1:4, v/v): 0.44.

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

Procedure: This compound was prepared from N-tert-butoxycarbonyl-3-cyclopentylamino-propanoate (3a, 2.28 g, 8.0 mmol) using the procedure described in Example 2b. Yield: 1.34 g (69%). ESI-MS: 244.2 (M+H)+, 266.3 (M+Na)+, 188.2 (M+H—C4H8)+, 144.2 (M+H-Boc)+. Rf (silica gel; ethyl acetate/heptane, 1:4, v/v): 0.30.

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

Procedure: This compound was prepared from N-tert-butoxycarbonyl-3-cyclopentylamino-propanoate (3a, 2.28 g, 8.0 mmol) using the procedure described in Example 2b. Yield: 1.34 g (69%). ESI-MS: 244.2 (M+H)+, 266.3 (M+Na)+, 188.2 (M+H—C4H8)+, 144.2 (M+H-Boc)+. Rf (silica gel; ethyl acetate/heptane, 1:4, v/v): 0.30.

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

Procedure: The title compound was prepared from ethyl acrylate (1.09 ml, 10 mmol) and cyclopentylamine (0.99 ml, 10 mmol) according to Example 2a. Yield: 2.28 g (80%). ESI-MS: 286.2 (M+H)+, 230.2 (M+H—C4H8)+, 186.2 (M+H-Boc)+. Rf (silica gel; ethyl acetate/heptane, 1:4, v/v): 0.45.

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

Procedure: To a solution of methyl (1R,4S)-4-[(tert-butoxycarbonyl)amino]-1-[(3R)-tetrahydrofuran-3-yl]cyclopent-2-ene-1-carboxylate (1.60 g, 5.14 mmol) in tetrahydrofuran (27.8 mL), methanol (27.8 mL) and water (6.0 mL) was added lithium hydroxide, monohydrate (0.346 g, 8.25 mmol). The pink mixture was heated to reflux for 18 h. The organic solvents were removed in vacuo and the aqueous layer was extracted once with ether and then acidified slowly with 6 M HCl until the pH reached 3-4. The resulting suspension was extracted with CH2Cl2 three times. The combined organic layers were dried over MgSO4, filtered and concentrated to give the product as a mixture of two cis/trans isomers (1.59 g) as a light yellow solid. MS calculated for C15H24NO5: (M+H) 298.2; found 198.2 (M+H-Boc). The pink mixture was heated to reflux for 18 h The organic solvents were removed in vacuo the aqueous layer was extracted once with ether The resulting suspension was extracted with CH2Cl2 three times The combined organic layers were dried over MgSO4 filtered concentrated to give the product as a mixture of two cis/trans isomers (1.59 g) as a light yellow solid

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 25 mL round-bottomed flask, (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (279 mg, 1.3 mmol, Eq: 1.00) and (S)-methyl 3-(4-(allyloxy)-3-chlorophenyl)-2-aminopropanoate (350 mg, 1.3 mmol, Eq: 1.00) were combined with DMF (6 mL) to give a colorless solution. HATU (986 mg, 2.59 mmol, Eq: 2.00) and Hunig's base (335 mg, 453 μL, 2.59 mmol, Eq: 2.00) were added. The reaction mixture was stirred at 25° C. for 20 h. The reaction mixture was poured into saturated aqueous NaHCO3 solution and extracted with DCM (2×). The organic layers were combined, washed with water (3×) and brine (1×). The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20 g, n-heptane/AcOEt 3/1, 2/1) to yield a yellow oil (570 mg; 94%). m/z=467.2 [M+H]+; 367.1 [M+H-Boc]+. to give a colorless solution extracted with DCM (2×) washed with water (3×) and brine (1×) The organic layers were dried over Na2SO4 concentrated in vacuo The crude material was purified by flash chromatography (silica gel, 20 g, n-heptane/AcOEt 3/1, 2/1) to yield a yellow oil (570 mg; 94%)

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 10 mL round-bottomed flask, (S)-2-(tert-butoxycarbonylamino)-3-(3-chloro-4-hydroxyphenyl)propanoate dicyclohexylammonium salt (300 mg, 604 μmol, Eq: 1.00) was combined with dry THF (2 mL) to give a white suspension. LiOH hydrate (38.4 mg, 905 μmol, Eq: 1.50) was added and the mixture was stirred for 30 min at 25° C. Then Me2SO4 (80.1 mg, 60.7 μL, 604 μmol, Eq: 1.00) was added. The reaction mixture was heated to 80° C. and stirred for 2 h. After that the mixture was stirred for 18 h at 50° C. The crude reaction mixture was concentrated in vacuo. The reaction mixture was poured into saturated aqueous NaHCO3 solution and extracted with AcOEt (2×). The organic layers were combined and washed with brine (1×). The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20 g, n-heptane/AcOEt 4/1, 3/1) to yield a colorless oil (132 mg; 66%). m/z=330.2 [M+H]+; 274.1 [M+H-tBu]+; 230.2 [M+H-Boc]+. to give a white suspension The reaction mixture was heated to 80° C. stirred for 2 h After that the mixture was stirred for 18 h at 50° C The crude reaction mixture was concentrated in vacuo The reaction mixture was poured into saturated aqueous NaHCO3 solution extracted with AcOEt (2×) washed with brine (1×) The organic layers were dried over Na2SO4 concentrated in vacuo The crude material was purified by flash chromatography (silica gel, 20 g, n-heptane/AcOEt 4/1, 3/1) to yield a colorless oil (132 mg; 66%)

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S)-3-(4-(allyloxy)phenyl)-2-(tert-butoxycarbonylamino)propanoic acid (5 g, 15.6 mmol, Eq: 1.00) was dissolved in DMF (30 ml). HATU (11.8 g, 31.1 mmol, Eq: 2.00), Hunig's Base (4.02 g, 5.43 ml, 31.1 mmol, Eq: 2.00) and 1-amino-1-cyclopropanecarbonitrile hydrochloride (2.21 g, 18.7 mmol, Eq: 1.20) were added to the above suspension and stirred at 25° C. for 24 h. The reaction mixture was poured into 0.1M HCl (250 mL) and extracted with AcOEt (3×75 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was dissolved in CH2Cl2 (10 mL), 2 minutes later it began to precipitate. The suspension was filtered. The filtered solution was purified by flash chromatography (silica gel, 80 g, 0% to 90% AcOEt in heptane) to yield a light yellow solid (3.0 g; 50%). m/z=286.1 [M+H-Boc]+. extracted with AcOEt (3×75 mL) The organic layers were dried over Na2SO4 concentrated in vacuo The crude material was dissolved in CH2Cl2 (10 mL), 2 minutes later it to precipitate The suspension was filtered The filtered solution was purified by flash chromatography (silica gel, 80 g, 0% to 90% AcOEt in heptane) to yield a light yellow solid (3.0 g; 50%)