I. Panov et al. / Tetrahedron: Asymmetry 22 (2011) 215–221
219
(100 MHz, DMSO-d6): d 176.1, 175.5, 171.8, 154.3, 153.7, 136.8,
136.7, 128.4, 128.2, 127.8, 127.6, 127.5, 127.2, 66.1, 65.8, 59.9,
59.0, 47.1, 46.6, 37.1, 36.3, 35.4, 30.9, 29.5, 24.2, 24.1, 23.9. Anal.
Calcd for C19H25N3O4: C, 63.49; H, 7.01; N, 11.69. Found: C,
63.52; H, 6.95; N, 11.72.
7.64–7.59 (m, 2H. NH), 7.42–7.38 (m, 2H, NH), 7.07 (s, 2H, NH),
4.23–4.21 (m, 2H, CH), 4.14–4.10 (m, 2H, CH), 3.42–3.33 (m, 2H),
3.32–3.25 (m, 2H), 2.18–2.07 (m, 1H), 2.06–1.90 (m, 3H), 1.89–
1.69 (m, 6H), 1.40–1.25 (m, 18H, 2 ꢂ (CH3)C), 0.89–0.84 (m, 12H,
2 ꢂ iPr–CH3); 13C NMR (100 MHz, DMSO-d6): d 172.8, 172.1,
171.6, 153.9, 153.3, 78.7, 78.4, 59.4, 59.3, 57.3, 57.1, 46.6, 46.5,
31.1, 30.5, 29.2, 28.0, 27.9, 23.9, 22.9, 19.3, 19.2, 18.0, 17.6. Anal.
Calcd for C15H27N3O4: C, 57.49; H, 8.68; N, 13.41. Found: C,
57.55; H, 8.57; N, 13.49.
4.1.2. 1-Cbz-N-((1S)-1-carbamoyl-1,2-dimethylpropyl)-(S)-
prolinamide 1b
Yield: 78%; mp: 67–69 °C (propan-2-ol/water); ½a D20
¼ ꢁ54:7 (c
ꢀ
1, CH3OH); 1H NMR of two rotamers (400 MHz, DMSO-d6): d 7.60–
7.58 (m, 2H, 2 ꢂ NH), 7.37–7.31 (m, 10H, 2 ꢂ Ar), 7.00–6.91 (m, 4H,
2 ꢂ NH2), 5.09–5.02 (m, 4H, 2 ꢂ CH2), 4.34–4.32 (m, 1H, CH), 4.26–
4.25 (m, 1H, CH), 3.52–3.25 (m, 4H), 2.19–1.97 (m, 4H), 1.97–1.84
(m, 2H), 1.84–1.73 (m, 4H), 1.33 (s, 3H, CH3), 1.26 (s, 3H, CH3),
0.93–075 (m, 12H, 2 ꢂ iPr–CH3); 13C NMR (100 MHz, DMSO-d6):
d 174.9, 171.5, 171.0, 156.3, 153.8, 136.9, 136.8, 128.3, 128.1,
127.7, 127.4, 127.3, 127.0, 65.9, 65.7, 62.4, 62.3, 60.2, 59.4, 47.1,
46.5, 33.7, 33.6, 30.8, 29.3, 23.9, 22.9, 17.7, 17.3, 17.2, 17.1, 17.0,
16.8. Anal. Calcd for C19H27N3O4: C, 63.14; H, 7.53; N, 11.63. Found:
C, 63.18; H, 7.48; N, 11.67.
4.1.7. 1-Bn-N-((1S)-1-carbamoyl-1,2-dimethylpropyl)-(S)-
prolinamide 1g
Yield: 87%; mp: 93–95 °C (ethyl acetate/hexane); ½a D20
¼ ꢁ32:1
ꢀ
(c 1, CH3OH); 1H NMR (400 MHz, DMSO-d6): d 7.75 (s, 1H, NH),
7.42–7.35 (m, 4H, Ar), 7.31–7.28 (m, 1H, Ar), 6.93 (s, 1H, NH),
6.85 (s, 1H, NH), 3.94–3.90 (m, 1H, CH2), 3.52–3.44 (m, 2H, CH2
and CH), 3.17–3.08 (m, 1H), 3.00–2.91 (m, 1H), 2.40–2.31 (m,
1H), 2.16–2.07 (m, 2H), 2.03–1.90 (m, 1H), 1.88–1.74 (m, 4H),
1.69–1.56 (m, 4H); 13C NMR (100 MHz, DMSO-d6): d 175.5, 173.0,
139.0, 128.7, 128.4, 127.2, 67.0, 35.8, 58.7, 53.4, 36.6, 35.5, 29.6,
24.0, 23.9, 23.4. Anal. Calcd for C18H25N3O2: C, 68.54; H, 7.99; N,
13.32. Found: C, 68.60; H, 8.05; N, 13.45.
4.1.3. 1-Cbz-N-((1S)-1-carbamoyl-2-methylpropyl)-(S)-
prolinamide 1c
Yield: 74%; mp: 192–193 °C (propan-2-ol/water); ½a D20
¼ ꢁ68:3
ꢀ
4.2. General procedure for the cyclisation of protected (S)-
prolinamides 1d,g
(c 1, CH3OH); 1H NMR of two rotamers (400 MHz, DMSO-d6): d 7.87
(d, J = 8.9 Hz, 1H, NH), 7.79 (d, J = 8.9 Hz, 1H, NH), 7.43–7.26 (m,
12H, 2 ꢂ Ar and 2 ꢂ Val-NH), 7.07 (m, 2H, Val-NH), 5.12–4.95 (m,
4H, 2 ꢂ CH2), 4.42–4.39 (m, 2H, 2 ꢂ CH), 4.16–4.12 (m, 2H,
2 ꢂ CH), 3.52–3.31 (m, 4H), 2.19–1.73 (m, 10H), 0.88–0.74 (m,
12H, 2 ꢂ iPr–CH3); 13C NMR (100 MHz, DMSO-d6): d 172.9, 171.9,
171.6, 154.1, 153.8, 137.0, 136.9, 128.3, 128.1, 127.7, 127.4,
127.3, 127.0, 65.8, 65.7, 59.7, 59.0, 57.3, 47.1, 46.5, 31.3, 30.5,
30.4, 30.3, 29.8, 19.3, 19.1, 17.9. Anal. Calcd for C18H25N3O4: C,
62.23; H, 7.25; N, 12.10. Found: C, 62.19; H, 7.31; N, 12.01.
A mixture of 1d or 1g (3.1 mmol) and sodium methoxide in
methanol (20 ml; 1.5 M) was refluxed for 2 h. Then, the solvent
was evaporated and the residue was dissolved in water (20 ml).
The aqueous solution was neutralised with concentrated HCl to
pH ꢃ 7 and extracted with DCM (4 ꢂ 20 ml). The solution was
dried over sodium sulfate and concentrated in vacuo. The residue
was crystallised from ethyl acetate/hexane.
4.2.1. ( )-2-(1-Boc-pyrrolidin-2-yl)-1,3-diazaspiro[4.4]non-1-
en-4-one 2d
4.1.4. 1-Boc-N-(1-carbamoyl-cyclopentyl)-(S)-prolinamide 1d
Yield: 81%; mp: 116–118 °C (ethyl acetate/hexane);
Yield: 92%; mp: 151–153 °C (ethyl acetate/hexane); 1H NMR
(400 MHz, DMSO-d6): two conformers d 10.28 (br s, 2H, NH),
4.54–4.47 (m, 2H, 2 ꢂ CH), 3.50–3.44 (m, 2H), 3.36–3.27 (m, 2H),
2.31–2.14 (m, 2H), 1.94–1.69 (m, 22H), 1.41–1.33 (m, 18H,
½
a 2D0
ꢀ
¼ ꢁ68:9 (c 1, CH3OH); 1H NMR of two rotamers (400 MHz,
DMSO-d6): d 8.15 (s, 1H, NH), 7.93 (s, 1H, NH), 6.94 (br s, 2H,
NH2), 6.89 (s, 1H, NH2), 6.64 (s, 1H, NH2), 4.09–4.04 (m, 2H,
2 ꢂ CH), 3.34–3.23 (m, 4H, 2 ꢂ CH2), 2.19–1.96 (m, 4H), 1.95–
1.81 (m, 8H), 1.80–1.68 (m, 4H), 1.66–1.51 (m, 8H), 1.39 (s, 9H,
(CH3)3C), 1.34 (s, 9H, (CH3)3C); 13C NMR (100 MHz, DMSO-d6): d
176.7, 176.1, 172.8, 172.7, 154.6, 153.8, 79.6, 78.9, 66.6, 66.5,
60.0, 59.7, 47.2, 47.0, 37.9, 37.0, 35.9, 35.8, 31.3, 29.8, 28.6, 28.5.
Anal. Calcd for C16H27N3O4: C, 59.06; H, 8.36; N, 12.91. Found: C,
59.11; H, 8.32; N, 12.85.
2 ꢂ (CH3)3C); 13C NMR (100 MHz, DMSO-d6):
d 186.8, 185.5,
169.1, 153.5, 152.7, 79.1, 74.6, 74.4, 55.3, 55.0, 46.4, 36.8, 36.3,
31.3, 30.2, 27.9, 25.3, 23.9, 23.1. Anal. Calcd for C16H25N3O3: C,
62.52; H, 8.20; N, 13.67. Found: C, 62.48; H, 8.14; N, 13.73.
4.2.2. ( )-2-(1-Benzylpyrrolidin-2-yl)-1,3-diazaspiro[4.4]non-4-
on 2g
Yield: 81%; mp: 140–141 °C (ethyl acetate/hexane); 1H NMR
(400 MHz, DMSO-d6): d 10.67 (s, 1H, NH), 7.32–7.19 (m, 5H, Ar),
3.75–3.72 (m, 1H, CH2), 3.44–3.58 (m, 2H, CH2 and CH), 3.24–
3.18 (m, 1H), 2.95–2.87 (m, 1H), 2.27–2.16 (m, 1H), 2.11–2.00
(m, 1H), 1.88–1.63 (m, 8H), 1.58–1.52 (m, 1H), 1.49–1.41 (m,
1H); 13C NMR (100 MHz, DMSO-d6): d 187.2, 162.9, 138.7, 128.7,
128.0, 126.9, 76.9, 63.1, 57.7, 53.3, 36.9, 36.6, 28.9, 25.5, 25.4,
22.7. Anal. Calcd for C18H23N3O: C, 72.70; H, 7.80; N, 14.13. Found:
C, 72.71; H, 7.71; N, 14.21.
4.1.5. 1-Boc-N-((1S)-1-carbamoyl-1,2-dimethylpropyl)-(S)-
prolinamide 1e
Yield: 83%; mp: 92–94 °C (ethyl acetate/hexane); ½a D20
¼ ꢁ51:0
ꢀ
(c 1, CH3OH); 1H NMR of two rotamers (400 MHz, DMSO-d6): d
7.53–7.47 (m, 2H, 2 ꢂ NH), 7.03–6.98 (m, 4H, 2 ꢂ NH2), 4.14–
4.13 (m, 1H, CH), 4.12–4.11 (m, 1H, CH), 3.29–3.21 (m, 4H),
2.23–2.05 (m, 4H), 1.93–1.75 (m, 6H), 1.40–1.33 (m, 24H,
2 ꢂ CH3 and 2 ꢂ (CH3)3C), 0.87–0.81 (m, 12H, 2 ꢂ iPr–CH3); 13C
NMR (100 MHz, DMSO-d6): d 174.8, 172.0, 171.0, 154.1, 153.2,
78.9, 78.2, 62.4, 62.1, 59.9, 59.5, 46.6, 46.4, 33.8, 33.5, 30.8, 30.6,
28.8, 27.9, 23.9, 22.9, 18.0, 17.2, 17.1, 17.0, 16.9, 16.8. Anal. Calcd
for C16H29N3O4: C, 58.69; H, 8.93; N, 12.83. Found: C, 58.73; H,
8.85; N, 12.75.
4.3. General procedure for the synthesis of N-(1-carbamoyl-1,1-
dialkyl-methyl)-(S)-prolinamides 3a–c
A mixture of Cbz-protected (S)-prolinamide (1a–c) (7.5 mmol)
and 5% Pd/C (250 mg) in 50 ml methanol was stirred under an
atmosphere of hydrogen at room temperature for 12 h. After this
time, the mixture was filtered through Celite and the product
was isolated by the evaporation of methanol.
4.1.6. 1-Boc-N-((1S)-1-carbamoyl-2-methylpropyl)-(S)-
prolinamide 1f
Yield: 89%; mp: 87–90 °C (ethyl acetate/hexane); ½a D20
¼ ꢁ74:7
ꢀ
(c 1, CH3OH); 1H NMR of two rotamers (400 MHz, DMSO-d6): d