P. Moutevelis-Minakakis et al. / Bioorg. Med. Chem. 19 (2011) 2888–2902
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1H NMR (CDCl3) d: 8.01(d, J = 8.2 Hz, 2H, Ph), 7.77–7.71(m, 2H,
NCHNCH), 7.41–7.30(m, 7H, Ph), 5.35(s, 2H, CH2Ph), 4.88(d,
J = 15.2 Hz, 1H, NCHHPh), 4.60(dd, J1 = 4.5 Hz, J2 = 13.3 Hz, 1H,
CHCHHN), 4.04(m, 2H, CHCHHN, NCHHPh), 3.89(m, 1H, NCHCH2),
3.81(s, 3H, CH3), 2.60–1.78(m, 4H, 2 ꢂ CH2).
13C NMR d: 177.8(CON), 160.6(NCN), 138.0, 136.7, 131.3, 131.2,
130.7, 129.2, 129.1, 124.7, 123.0, 58.7(CHCH2N), 50.5(CHCH2N),
43.3(CH2Ph), 29.8(CH2CO), 22.8(CH2CH2CO). MS (ESI) m/z (%): 324
[(M+H+), 100].
NP Analytical HPLC in solvent A: tR = 18.5 min. HPLC purity
>99%.
13C NMR d: 175.2(CH2CON), 166.0(COOPh), 160.5(COO CH3),
142.2, 137.6, 135.9, 130.1, 129.5, 128.6, 128.2, 128.1, 128.0,
66.7(CH2Ph), 57.3(CHCH2N), 51.8(CH2CH), 49.0(CH3), 44.9(CH2Ph),
28.9(CH2CO), 22.5(CH2CH2CO).
Anal. Calcd for C16H17N7O: C, 59.43; H, 5.30; N, 30.32. Found: C,
59.57; H, 5.39; N, 30.41.
MS (ESI) m/z (%): 358 [(M+H+), 100].
Anal. Calcd for C18H19N3O5: C, 60.50; H, 5.36; N, 11.76. Found: C,
60.72; H, 5.47; N, 11.69.
4.11.3. 1H-Imidazole-5-carboxylic acid, 1-[[5-oxo-1-
(phenylmethyl)-(2S)-pyrrolidinyl]methyl] (7g)
Compound 6d was hydrogenated according to the general pro-
cedure. The product was obtained as a mixture of the two consti-
tutional isomers. It was purified using silica gel column
chromatography and EtOAc–MeOH, 1:1 as eluent. The pure isomer
with the carboxylic group at position 5 on the imidazole ring was
4.10.11. Methyl 1-[((2S)-1-4-[(benzyloxy)carbonyl]benzyl-5-
oxotetrahydro-1H-pyrrol-2-yl)methyl]-1H-imidazole-4-
carboxylate (13g⁄)
Yield 26%; colorless oil.
obtained as a colorless oil. Yield 65%; [a] +22.5 (c 0.93, MeOH).
D
1H NMR (CDCl3) d: 8.04(d, J = 8.2 Hz, 2H, Ph), 7.44–7.24(m, 9H,
Ph, NCHNCH), 5.35(s, 2H, CH2Ph), 4.99(d, J = 15.3 Hz, 1H, NCHHPh),
4.12–3.91(m, 3H, NCHCH2, NCHHPh), 3.86(s, 3H, CH3), 3.75(m, 1H,
NCHCH2), 2.30–1.67(m, 4H, 2 ꢂ CH2).
1H NMR (CD3OD) d: 7.63(s, 1H, NCHN), 7.52(s, 1H, NCHCCOO),
7.32–7.23(m, 5H, Ph), 4.85(dd, J1 = 5.1 Hz, J2 = 13.5 Hz, 1H,
CHCHHN), 4.82(d, J = 15.0 Hz, 1H, CHHPh), 4.35(dd, J1 = 6.2 Hz,
J2 = 13.5 Hz, 1H, CHCHHN), 4.00(m, 1H, CHCH2N), 3.94(d,
J = 15.0 Hz, 1H, CHHPh), 2.34–1.95(m, 4H, 2 ꢂ CH2).
13C NMR d: 178.1(CON), 167.1(COOH), 141.6, 138.2, 134.7,
130.6, 129.8, 129.1, 128.7, 59.6(CHCH2N), 47.7(CHCH2N),
45.9(CH2Ph), 30.3(CH2CO), 23.2(CH2CH2CO).
13C NMR d: 175.0(CH2CON), 166.0(COOPh), 162.6(COOCH3),
141.1, 138.1, 135.8, 134.3, 130.4, 130.0, 128.6, 128.3, 128.2,
127.8, 125.1, 66.8(CH2Ph), 56.9(CHCH2N), 51.8(CH2CH), 49.4(CH3),
44.9(CH2Ph), 28.9(CH2CO), 22.3(CH2CH2CO).
MS (ESI) m/z (%): 358 [(M+H+), 100].
MS (ESI) m/z (%): 300 [(M+H+),100].
Anal. Calcd for C16H17N3O3: C, 64.20; H, 5.72; N, 14.04. Found: C,
64.48; H, 5.87; N, 14.12.
4.11. Compounds 7e–g and 14d–g: General procedure
A mixture of a compound possessing a benzyl ether (6b), benzyl
ester (6d, 13d, 13e, 13f, and 13g) and benzyl protected tetrazole
group (6c) (1 mmol) in MeOH (10 mL) and 10% palladium on acti-
vated carbon (0.02 g) or Pd(OH)2 (0.02 g) for compound 6c, was
hydrogenated for 1.5–3 h under atmospheric conditions. After fil-
tration through a pad of Celite, the solvent was removed in vacuo
to give the deprotected final compound in almost quantitative
yield and high purity.
4.11.4. 4-[(2S)-2-(1H-Imidazol-1-ylmethyl)-5-oxotetrahydro-
1H-pyrrol-1-yl]methylbenzenecarboxylic acid (14d)
Prepared from the compound 13d. Yield 96%; colorless oil; [
+19.8 (c 1.00, MeOH).
a]
D
1H NMR (CD3OD) d: 8.80(s, 1H, NCHN), 7.87(d, J = 8.0 Hz, 2H,
Ph), 7.48(d, J = 10 Hz, 2H, Ph), 7.24 (d, J = 8.0 Hz, 2H, Ph), 4.7(d,
1H, J = 15.9 Hz, CH2Ph), 4.37–4.32(m, 2H, CHCH2), 4.23(d,
J = 15.9 Hz, 2H, CH2Ph), 3.85(d, J = 15.4 Hz, 1H, CHHPhCOO), 3.99–
3.92(m, 1H, CHCH2N), 2.28–1.73(m, 4H, 2 ꢂ CH2).
13C NMR d: 178.1(NCO), 170.2(COOH), 142.5, 138.9, 132.5,
4.11.1. 1-[(3-Hydroxyphenyl)methyl]-(5S)-(1H-imidazol-1-
ylmethyl)-2-pyrrolidinone (7e)
131.3,
128.9,
128.4,
121.9(CH2NCHCHN),
58.9(CHCH2N),
Prepared from the compound 6b. Yield 93%; colorless oil; [
ꢁ1.1 (c 1.5, CH3OH).
a]
D
49.6(CH2CHCH2), 45.3(NCH2Ph), 30.0(CH2CO), 23.1(CH2CH2CO).
MS (ESI) m/z (%): 300 [(M+H+), 100].
1H NMR (CD3OD) d: 8.89(s, 1H, NCHN), 7.60(s, 2H, NCHCHN),
7.17(t, J1 = 8.1 Hz, J2 = 7.4 Hz, 1H, Ph), 6.76–6.69(m, 3H, Ph),
4.79(d, J = 15.4 Hz, 1H, CHHPh), 4.46(m, 2H, CH2N), 4.19(d,
J = 15.4 Hz, 1H, CHHPh), 4.06(m, 1H, CH), 2.30–1.88(m, 4H,
2 ꢂ CH2).
NP Analytical HPLC in solvent B: tR = 5.9 min. HPLC purity >98%.
Anal. Calcd for C16H17N3O3: C, 64.20; H, 5.72; N, 14.04. Found: C,
64.39; H, 5.85; N, 14.12.
4.11.5. 1-((2S)-1-[4-(Methoxycarbonyl)benzyl]-5-
oxotetrahydro-1H-pyrrol-2-ylmethyl)-1H-imidazole-5-
carboxylic acid (14e)
13C NMR d: 177.9(CH2CON), 159.2, 139.0, 137.3, 131.1, 123.8,
121.9, 119.8, 115.9, 115.5, 58.6(CH2N), 51.6(CH2Ph), 45.9(NCH),
30.1(CH2CO), 22.8(CH2CH2CO).
Prepared from the compound 13e. Yield 99%; colorless oil; [
+43.7 (c 1.00, MeOH).
a]
D
MS (ESI) m/z (%): 272 [(M+Y+), 100].
NP Analytical HPLC in solvent A: tR = 13.8 min. HPLC purity
>96%.
Anal. Calcd for C15H17N3O2: C, 66.40; H, 6.32; N, 15.49. Found: C,
66.22; H, 6.17; N, 15.33.
1H NMR (CD3OD) d: 8.09(s, 1H, NCHN), 7.96(d, J = 8.1 Hz, 2H,
Ph), 7.74(s, 1H, NCHCCOO), 7.37(d, J = 8.1 Hz, 2H, Ph), 4.87(d,
J = 15.6 Hz, 1H, NCHHPh), 4.78(dd, J1 = 4.4 Hz, J2 = 13.6 Hz, 1H,
CHCHHN), 4.31(dd, J1 = 7.3 Hz, J2 = 13.6 Hz, 1H, CHCHHN), 4.15(d,
J = 15.6 Hz, 1H, NCHHPh), 4.00(m, 1H, NCHCH2), 3.88(s, 3H, CH3),
2.45–1.74(m, 4H, 2 ꢂ CH2).
4.11.2. 2-Pyrrolidinone, (5S)-(1H-imidazol-1-ylmethyl)-1-[[2-
(1H-1,2,3,4-tetrazol-5-yl)phenyl]methyl] (7f)
13C NMR d: 178.2(CH2CON), 168.2(COOH), 162.6(COOCH3)
143.7, 143.4, 136.1, 130.9, 129.0, 125.5, 62.2(CHCH2N),
Prepared from the compound 6c. Yield 90%; colorless oil; [
+18.6 (c 1.0, MeOH).
a]
D
59.2(CHCH2N),
52.7(COCH3),
45.7(CH2Ph),
29.9(CH2CO),
1H NMR (CD3OD) d: 8.77(s, 1H, NCHN), 7.72(d, J = 8.0 Hz, 2H,
NCHCHN), 7.56–7.46(m, 4H, Ph), 5.07(d, J = 15.6 Hz, 1H, CHHPh),
4.63(d, J = 15.6 Hz, 1H, CHHPh), 4.48(dd, J1 = 4.1 Hz, J2 = 14.0 Hz,
1H, CHCHHN), 4.34(dd, J1 = 6.3 Hz, J2 = 14.0 Hz, 1H, CHCHHN),
4.01(m, 1H, CHCH2N), 2.25–1.87(m, 4H, 2 ꢂ CH2).
23.1(CH2CH2CO). MS (ESI) m/z (%): 356 [(MꢁH+), 100].
RP Analytical HPLC in solvent E: tR = 14.4 min. HPLC purity
>95%.
Anal. Calcd for C18H19N3O5: C, 60.50; H, 5.36; N, 11.76. Found: C,
60.38; H, 5.22; N, 11.80.