tert-butyl N-[(1S)-1-cyanoethyl]carbamate

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of tert-butyl[(1S)-1-cyanoethyl]carbamate (Step 2, 250 mg, 1.5 mmol) in ethanol (3 mL) were added triethylamine (0.41 mL, 2.9 mmol) and hydroxylamine (58 mg, 1.8 mmol). The mixture was stirred at 50° C. overnight. The reaction mixture was concentrated to afford the desired crude product (300 mg) which was directly used in the next step reaction without further purification. 1H-NMR (300 MHz, DMSO-d6): 8.94 (s, 1H), 6.80 (d, J=8.5 Hz, 1H), 5.24 (s, 2H), 4.01 (m, 1H), 1.36 (s, 9H), 1.15 (d, J=7.0 Hz, 3H). The reaction mixture was concentrated

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

Procedure: To a stirred solution of tert-butyl[(1S)-2-amino-1-methyl-2-oxoethyl]carbamate (Step 1, 0.7 g, 0.004 mol) in N,N-dimethylformamide (5 mL) was added 343 mg of cyanuric chloride (0.00186 mol) at once. The reaction mixture was stirred for 4 h. Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with EtOAc in hexane (30-50%) to yield the desired product (400 mg, 63%). 1H-NMR (300 MHz, DMSO-d6): 7.74 (d, J=7.0 Hz, 1H), 4.48 (m, 1H), 1.40 (s, 9H), 1.35 (d, J=7.0 Hz, 3H). the mixture was extracted with ethyl acetate The combined organic layers were washed with brine dried over MgSO4 filtered concentrated under reduced pressure The residue was purified by flash chromatography on a silica gel column with EtOAc in hexane (30-50%)

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

Procedure: To a stirred solution of tert-butyl[(1S)-2-amino-1-methyl-2-oxoethyl]carbamate (Step 1, 0.7 g, 0.004 mol) in N,N-dimethylformamide (5 mL) was added 343 mg of cyanuric chloride (0.00186 mol) at once. The reaction mixture was stirred for 4 h. Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with EtOAc in hexane (30-50%) to yield the desired product (400 mg, 63%). 1H-NMR (300 MHz, DMSO-d6): 7.74 (d, J=7.0 Hz, 1H), 4.48 (m, 1H), 1.40 (s, 9H), 1.35 (d, J=7.0 Hz, 3H). the mixture was extracted with ethyl acetate The combined organic layers were washed with brine dried over MgSO4 filtered concentrated under reduced pressure The residue was purified by flash chromatography on a silica gel column with EtOAc in hexane (30-50%)

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

Procedure: General procedure D was used to deprotect 0.210 g (1.23 mmols) of 4. The product was immediately carried on using general procedure F and coupled to 1.23 mmols of 10. The title product was purified with flash chromatography using a solvent system of ethyl acetate and hexanes (1:3) to yield 0.106 g (0.41 mmols). 1H NMR (500 MHz, CDCl3) δ 7.74-7.68 (m, 2H), 7.25 (d, J=8.2, 2H), 6.61 (s, 1H), 5.20-5.11 (m, 1H), 2.70-2.61 (m, 2H), 1.66 (t, J=6.6, 3H), 1.60 (dd, J=7.3, 14.9, 2H), 1.37-1.22 (m, 6H), 0.88 (t, J=6.8, 3H). 13C NMR (126 MHz, CDCl3) δ 173.95, 166.58, 148.00, 148.00, 131.31, 129.95, 128.78, 128.62, 127.20, 127.03, 119.42, 77.27, 77.02, 76.76, 52.57, 48.42, 36.24, 35.85, 31.63, 31.10, 28.87, 22.56, 19.57, 18.68, 14.07. The title product was purified with flash chromatography to yield 0.106 g (0.41 mmols)

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

Procedure: General procedure D and E were used to deprotect 1.17 mmols of (S)-tert-butyl 1-cyanoethylcarbamate and couple the resulting amine to 1.17 mmols of 31. After standard purification techniques 0.35 mmols of the title product were recovered. 1H NMR (500 MHz, CDCl3) δ 7.74 (d, J=8.9, 2H), 6.90 (d, J=8.8, 2H), 6.67 (s, 1H), 5.30-5.05 (m, 1H), 3.98 (t, J=6.6, 2H), 1.85-1.74 (m, 2H), 1.64 (d, J=7.2, 3H), 1.45 (s, 3H), 1.30 (d, J=19.1, 7H), 0.88 (t, J=6.9, 3H). 13C NMR (126 MHz, CDCl3) δ 166.26, 162.49, 129.11, 124.52, 119.58, 114.40, 68.26, 36.25, 31.77, 29.30, 29.19, 29.07, 25.95, 22.63, 19.53, 14.08.

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

Procedure: General procedure D was used to deprotect 0.65 mmol of 4 and immediately coupled to 0.975 mmol of 40. After flash chromatography 0.96 g (0.25 mmol) of the title product was recovered. 1H NMR (300 MHz, CDCl3) δ 7.76 (d, J=8.8, 2H), 7.49-7.21 (m, 6H), 7.00 (d, J=8.7, 2H), 6.80 (d, J=8.3, 1H), 6.65 (d, J=12.0, 3H), 5.22-5.08 (m, 1H), 5.03 (s, 2H), 1.65 (d, J=7.2, 3H).

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

Procedure: General procedure D was used to deprotect 0.65 mmol of 4 and immediately coupled to 0.975 mmol of 40. After flash chromatography 0.96 g (0.25 mmol) of the title product was recovered. 1H NMR (300 MHz, CDCl3) δ 7.76 (d, J=8.8, 2H), 7.49-7.21 (m, 6H), 7.00 (d, J=8.7, 2H), 6.80 (d, J=8.3, 1H), 6.65 (d, J=12.0, 3H), 5.22-5.08 (m, 1H), 5.03 (s, 2H), 1.65 (d, J=7.2, 3H).

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

Procedure: General procedure D was used to deprotect 1.15 mmol of 4 and was then immediately coupled to 1.15 mmol of 35. After flash chromatography 0.115 g (0.4 mmol) of the title product was recovered. 1H NMR (500 MHz, CDCl3) δ 7.68-7.55 (m, 2H), 7.34 (dd, J=2.9, 9.5, 2H), 6.73 (d, J=7.7, 1H), 5.16 (p, J=7.2, 1H), 2.63 (t, J=7.7, 2H), 1.66 (d, J=7.2, 2H), 1.61 (s, 2H), 1.30 (dd, J=21.4, 28.1, 10H), 0.87 (t, J=7.0, 3H). 13C NMR (126 MHz, CDCl3) δ 166.89, 143.81, 143.59, 132.58, 132.52, 128.60, 127.34, 124.32, 119.40, 52.60, 48.47, 36.28, 35.81, 31.86, 31.43, 31.38, 29.42, 29.27, 29.23, 22.66, 19.54, 18.65, 14.11.

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

Procedure: General procedure D was used to deprotect 1.15 mmol of 4 and was then immediately coupled to 1.15 mmol of 35. After flash chromatography 0.115 g (0.4 mmol) of the title product was recovered. 1H NMR (500 MHz, CDCl3) δ 7.68-7.55 (m, 2H), 7.34 (dd, J=2.9, 9.5, 2H), 6.73 (d, J=7.7, 1H), 5.16 (p, J=7.2, 1H), 2.63 (t, J=7.7, 2H), 1.66 (d, J=7.2, 2H), 1.61 (s, 2H), 1.30 (dd, J=21.4, 28.1, 10H), 0.87 (t, J=7.0, 3H). 13C NMR (126 MHz, CDCl3) δ 166.89, 143.81, 143.59, 132.58, 132.52, 128.60, 127.34, 124.32, 119.40, 52.60, 48.47, 36.28, 35.81, 31.86, 31.43, 31.38, 29.42, 29.27, 29.23, 22.66, 19.54, 18.65, 14.11.

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

Procedure: General procedure D was used to deprotect 0.62 mmols of 4 and immediately coupled to 0.62 mmols of 28 using general procedure F. After flash chromatography, 0.29 mmols (0.087 g) of the title product was recovered. 1H NMR (500 MHz, CDCl3) δ 7.77 (d, J=8.9, 2H), 7.27 (dd, J=6.7, 9.6, 1H), 7.00 (d, J=8.9, 2H), 6.83 (d, J=8.0, 1H), 6.73 (dd, J=2.4, 8.3, 1H), 6.64-6.55 (m, 2H), 5.13 (dq, J=7.2, 14.5, 1H), 3.78 (s, 3H), 1.65 (d, J=7.2, 3H). 13C NMR (126 MHz, CDCl3) δ 166.03, 161.07, 156.72, 130.44, 129.26, 128.99, 126.89, 119.48, 117.83, 111.97, 110.17, 105.93, 77.29, 77.04, 76.78, 55.41, 36.33, 19.46, 18.59.

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

Procedure: General procedure D was used to deprotect 0.62 mmols of 4 and immediately coupled to 0.62 mmols of 28 using general procedure F. After flash chromatography, 0.29 mmols (0.087 g) of the title product was recovered. 1H NMR (500 MHz, CDCl3) δ 7.77 (d, J=8.9, 2H), 7.27 (dd, J=6.7, 9.6, 1H), 7.00 (d, J=8.9, 2H), 6.83 (d, J=8.0, 1H), 6.73 (dd, J=2.4, 8.3, 1H), 6.64-6.55 (m, 2H), 5.13 (dq, J=7.2, 14.5, 1H), 3.78 (s, 3H), 1.65 (d, J=7.2, 3H). 13C NMR (126 MHz, CDCl3) δ 166.03, 161.07, 156.72, 130.44, 129.26, 128.99, 126.89, 119.48, 117.83, 111.97, 110.17, 105.93, 77.29, 77.04, 76.78, 55.41, 36.33, 19.46, 18.59.

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

Procedure: General procedure D was used to deprotect 1.2 mmols of 4 and immediately coupled to 1.2 mmols of 25 using general procedure F. The title product was purified by flash chromatography with ethyl acetate and hexanes to yield 0.53 mmol (0.14 g). 1H NMR (300 MHz, CDCl3) δ 7.87-7.65 (m, 3H), 7.39 (t, J=7.8, 2H), 7.20 (d, J=6.7, 1H), 7.10-6.90 (m, 5H), 6.76 (s, 2H), 5.26-5.03 (m, 1H), 1.65 (d, J=7.2, 3H). The title product was purified by flash chromatography with ethyl acetate and hexanes to yield 0.53 mmol (0.14 g)