Synthesis of Novel γ-Lactams, Short Peptides and Keppra®
53.3, 51.0, 38.8, 28.2, 25.2, 23.2, 21.4 ppm. C14H21Cl2NO3 (322.23): C15H20Cl2N2O4 (363.24): calcd. C 46.60, H 5.55, Cl 19.52, N 7.71;
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calcd. C 52.18, H 6.57, Cl 22.00, N 4.35; found C 52.25, H 6.59,
Cl 22.23, N 4.27.
found C 49.50, H 5.53, Cl 19.87, N 7.61.
Methyl 2-{[(2S)-2-(3,4-Dichloro-2,5-dihydro-2-oxo-1H-pyrrol-1-yl)-
butanoyl]amino}acetate (24): Yield 1.5 g, 50 %. 1H NMR
(400 MHz, CDCl3): δ = 6.89 (br. s, 1 H), 4.68 (dd, J = 8.4, 7.41 Hz,
1 H), 4.40 (d, J = 19.1 Hz, 1 H), 4.05 (d, J = 18.9 Hz, 1 H), 3.99
(d, J = 5.7, 2 H), 3.73 (s, 3 H), 2.04 (m, 1 H), 1.77 (m, 1 H), 0.96
(t, J = 7.4 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.1,
170.0, 165.3, 141.7, 124.8, 59.9, 52.6, 51.3, 41.3, 22.8, 10.6 ppm.
HRMS (ESI): calcd. for C11H15Cl2N2O4 309.0409 [MH+], found
309.0449.
Benzyl
(2S)-2-(3,4-Dichloro-2,5-dihydro-2-oxo-1H-pyrrol-1-yl)-3-
methylbutanoate (17): Yield 1.7 g, 50%. 1H NMR (400 MHz,
CDCl3): δ = 7.36 (m, 5 H), 5.20 (d, J = 12.0 Hz, 1 H), 5.14 (d J =
12.0 Hz, 1 H), 4.70 (d, J = 9.9 Hz, 1 H), 4.43 (d, J = 18.9 Hz, 1
H), 4.04 (d, J = 18.7 Hz, 1 H), 2.21 (m, 1 H), 0.97 (d, J = 6.6 Hz,
3 H), 0.91 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 170.6, 165.0, 141.3, 135.2, 128.9, 128.6, 125.1, 67.3, 60.4, 51.4,
29.6, 19.4 ppm. C16H17Cl2NO3 (342.22): calcd. C 56.15, H 5.01, Cl
20.72, N 4.09; found C 55.95, H 5.02, Cl 20.90, N 4.09.
Methyl (3S)-4-{[(1S)-1-Benzyl-2-methoxy-2-oxoethyl]amino}-3-(3,4-
dichloro-2,5-dihydro-2-oxo-1H-pyrrol-1-yl)-4-oxobutanoate (25):
(2S)-2-(3,4-Dichloro-2,5-dihydro-2-oxo-1H-pyrrol-1-yl)-3-phenylpro-
panamide (18): Yield 1.5 g, 50%. 1H NMR (400 MHz, CDCl3): δ
= 7.33–7.17 (m, 5 H), 6.33 (br. s, 1 H), 5.57 (br. s, 1 H), 5.00 (m,
1 H), 4.32 (d, J = 18.9 Hz, 1 H), 4.08 (d, J = 18.9 Hz, 1 H), 3.33
(dd, J = 14.2, 7.6 Hz, 1 H), 3.10 (dd, J = 14.2, 8.6 Hz, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 171.2, 165.2, 141.8, 135.9, 129.1,
128.9, 127.5, 125.0, 56.7, 51.9, 35.5 ppm. LRMS (APCI): m/z =
299.1 [MH+], 300.1 [M+2]H+.
1
Yield 1.9 g, 42%. H NMR (400 MHz, CDCl3): δ = 7.22 (m, 3 H),
7.08 (m, 2 H), 6.63 (d, J = 8.6 Hz, 1 H), 5.08 (t, J = 7.6 Hz, 1 H),
4.90 (m, 1 H), 3.86 (d, J = 18.5 Hz, 1 H), 3.78 (s, 3 H), 3.66 (s, 3
H), 3.55 (d, J = 18.5 Hz, 1 H), 3.26 (dd, J = 14.0, 4.7 Hz, 1 H),
2.94 (dd, J = 16.4, 7.4 Hz, 1 H), 2.87 (dd, J = 14.1, 9.5 Hz, 1 H),
2.67 (dd, J = 16.3, 7.9 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 171.5, 170.3, 167.8, 164.7, 141.8, 136.0, 129.2, 128.7,
127.2, 125.0, 53.0, 52.8, 52.5, 52.0, 51.1, 38.3, 33.7 ppm.
C19H20Cl2N2O6 (443.28): calcd. C 51.48, H 4.55, Cl 16.00, N 6.32;
found C 51.45, H 4.52, Cl 16.30, N 6.24.
(2S)-2-(3,4-Dichloro-2,5-dihydro-2-oxo-1H-pyrrol-1-yl)-4-methyl-
1
pentanamide (19): Yield 1.2 g, 45%. H NMR (400 MHz, CDCl3):
δ = 6.50 (br. s, 1 H), 5.66 (br. s, 1 H), 4.84 (dd, J = 8.9, 6.9 Hz, 1
H), 4.40 (d, J = 19.1 Hz, 1 H), 4.04 (d, J = 18.9 Hz, 1 H), 1.74 (m,
2 H), 1.51 (m, 1 H), 0.97 (d, J = 6.8 Hz, 3 H), 0.95 (d, J = 7.0 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.1, 165.1, 141.7,
125.0, 53.3, 51.3, 38.2, 25.0, 23.0, 22.2 ppm. LRMS (APCI): m/z =
265.1 [MH+], 267.1 [M+2]H+.
(2S)-2-(3,4-Dichloro-2,5-dihydro-2-oxo-1H-pyrrol-1-yl)-3-phenyl-
propanoic Acid (26): TFA (15 mL, 93.9 mmol) was added to a solu-
tion of 19 (3.3 g, 9.3 mmol) and Et3SiH (1.6 mL, 10.0 mmol) in
CH2Cl2 (40 mL). The reaction mixture was stirred at room tem-
perature for 3.5 h after which the volatilities were removed under
high vacuum. The resulting white solid was dried in a vacuum oven
at ca. 40 °C overnight to yield 2.7 g (96%) of the desired product.
1H NMR (400 MHz, [D6]DMSO): δ = 7.30–7.19 (m, 5 H), 4.93
(dd, J = 11.1, 8.9 Hz, 1 H), 4.33 (d, J = 20.0 Hz, 1 H), 4.24 (d, J
= 20.0 Hz, 1 H), 3.30 (dd, J = 14.4, 4.9 Hz, 1 H), 3.13 (dd, J =
14.4, 11.1 Hz, 1 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
171.2, 163.7, 141.7, 137.1, 128.6, 126.6, 123.3, 55.9, 51.5, 34.4 ppm.
C13H11Cl2NO3 (300.14): calcd. C 52.02, H 3.69, Cl 23.62, N 4.67;
found C 51.90, H 3.53, Cl 23.35, N 4.59.
Ethyl 3-(3,4-Dichloro-2,5-dihydro-2-oxo-1H-pyrrol-1-yl)propanoate
1
(20): Yield 1.5 g, 60%. H NMR (400 MHz, CDCl3): δ = 4.15 (m,
4 H), 3.75 (t, J = 6.2 Hz, 2 H), 2.67 (t, J = 6.2 Hz, 2 H), 1.26 (t, J
= 7.1 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.9,
164.6, 140.2, 125.6, 61.2, 54.8, 39.3, 33.5, 14.3 ppm. C9H11Cl2NO3
(252.09): calcd. C 42.88, H 4.40, Cl 28.13, N 5.56; found C 42.60,
H 4.77, Cl 28.00, N 5.47.
Ethyl cis-2-(3,4-Dichloro-2,5-dihydro-2-oxo-1H-pyrrol-1-yl)cyclo-
hexanecarboxylate (21): Yield 1.9 g, 64%. 1H NMR (400 MHz,
CDCl3): δ = 4.37 (d, J = 19.3 Hz, 1 H), 4.16–3.98 (m, 4 H), 3.18
(m, 1 H), 2.21 (m, 1 H), 2.06 (m, 1 H), 1.86 (m, 1 H), 1.68 (m, 2
H), 1.55 (m, 1 H), 1.37 (m, 2 H), 1.19 (t, J = 7.1 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 174.0, 164.5, 140.7, 125.1, 60.5,
52.8, 52.3, 43.0, 28.4, 25.9, 25.5, 21.5, 14.3 ppm. C13H17Cl2NO3
(306.18): calcd. C 51.00, H 5.60, Cl 23.16, N 4.57; found C 50.94,
H 5.57, Cl 23.42, N 4.47.
General Procedure for Peptide Coupling (Scheme 3): Equimolar
amounts of all the reactants were stirred in CH2Cl2 (10 mL for a
1.3 mmol scale) at room temperature for 5 min followed by drop-
wise addition of DIEA. The reaction mixture was stirred overnight,
and the solvent was removed under high vacuum. The crude prod-
uct was purified by column chromatography (SiO2, 25–60% ethyl
acetate in hexanes) to yield the desired product.
Ethyl (2S)-2-{[(2S)-2-(3,4-Dichloro-2,5-dihydro-2-oxo-1H-pyrrol-1-
yl)-3-phenylpropanoyl]amino}-3-phenylpropanoate (27): Yield 0.6 g,
Methyl (2S)-2-{[(2S)-2-(3,4-Dichloro-2,5-dihydro-2-oxo-1H-pyrrol-
1
1
1-yl)propanoyl]amino}propanoate (22): Yield 1.8 g, 60%. H NMR
93%. H NMR (400 MHz, CDCl3): δ = 7.29–7.19 (m, 6 H), 7.15
(400 MHz, CDCl3): δ = 6.69 (br. s, 1 H), 4.87 (q, J = 7.2 Hz, 1 H),
4.49 (q, J = 7.2 Hz, 1 H), 4.41 (d, J = 18.9 Hz, 1 H), 4.11 (d, J =
18.9 Hz, 1 H), 3.75 (s, 3 H), 1.48 (d, J = 7.2 Hz, 3 H), 1.40 (d, J =
7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.1, 170.1,
164.9, 141.6, 125.1, 52.7, 51.2, 50.9, 48.5, 18.1, 15.6 ppm. HRMS
(ESI): calcd. for C11H15Cl2N2O4 309.0409 [MH+], found. 309.0414.
(m, 2 H), 7.06 (m, 2 H), 6.38 (br. d, J = 8.6 Hz, 1 H), 4.92 (dd, J
= 8.9, 7.3 Hz, 1 H), 4.85 (m, 1 H), 4.18 (q, J = 8.0 Hz, 2 H), 3.84
(d, J = 16.0 Hz, 1 H), 3.68 (d, J = 20.0 Hz, 1 H), 3.25–3.19 (m, 2
H), 2.96 (dd, J = 14.5, 8.9 Hz, 1 H), 2.84 (dd, J = 14.0, 9.0 Hz, 1
H), 1.25 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 171.0, 168.3, 164.8, 141.5, 135.9, 135.8, 129.3, 129.0, 128.8,
128.6, 127.3, 127.2, 125.0, 61.9, 56.2, 53.0, 51.1, 38.5, 34.8,
14.3 ppm. C24H24Cl2N2O4 (475.36): calcd. C 60.64, H 5.09, Cl
14.92, N 5.89; found C 60.38, H 4.97; Cl, 14.96, N 5.82.
Methyl (2S)-1-[(2S)-2-(3,4-Dichloro-2,5-dihydro-2-oxo-1H-pyrrol-1-
yl)-3-methylbutanoyl]pyrrolidine-2-carboxylate (23): Yield 1.5 g,
41%. 1H NMR (400 MHz, CDCl3): δ = 4.73 (d, J = 11.1 Hz, 1 H),
4.60 (d, J = 19.7 Hz, 1 H), 4.42 (dd, J = 8.6, 5.1 Hz, 1 H), 4.04 (m,
2 H), 3.77 (m, 1 H), 3.74 (s, 3 H), 2.28 (m, 2 H), 2.05 (m, 1 H),
1.99 (m, 2 H), 1.09 (d, J = 6.6 Hz, 3 H), 0.92 (d, J = 6.6 Hz, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 172.2, 168.9, 164.9, 141.6,
124.4, 59.0, 58.4, 52.2, 51.1, 47.5, 29.2, 29.0, 24.8, 19.1, 18.5 ppm.
(2S)-2-{[(2S)-2-(3,4-Dichloro-2,5-dihydro-2-oxo-1H-pyrrol-1-yl)-3-
phenylpropanoyl]amino}-3-phenylpropanamide (28): Yield 0.5 g,
1
88%. H NMR (400 MHz, CDCl3): δ = 7.28–7.14 (m, 10 H), 6.93
(d, J = 8.6 Hz, 1 H), 5.67 (br. s, 1 H), 5.55 (br. s, 1 H), 4.96 (t, J
= 8.1 Hz, 1 H), 4.73 (m, 1 H), 3.91 (d, J = 18.9 Hz, 1 H), 3.67 (d,
Eur. J. Org. Chem. 2006, 3730–3737
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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