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E. A. A. Wallen et al. / Bioorg. Med. Chem. 10 (2002) 2199–2206
2204
starting from 990 mg (3.6 mmol) N-BOC-2(S)-benzoyl-
pyrrolidine. Yield 620 mg (1.9 mmol, 53%). 1H NMR: d
1.8–2.5 (m, 8H), 2.69 (t, 2H, J=7.5 Hz), 3.4–3.8 (m,
2H), 5.17 (dd, 0.1H, J=9.3 Hz, J=3.0 Hz), 5.52 (dd,
0.9H, J=9.1 Hz, J=3.8 Hz), 7.0–8.1 (m, 10H). 13C
NMR: d 24.70, 26.04, 29.13, 33.40, 35.14, 47.20, 60.83,
125.81, 128.31, 128.54, 128.59, 128.62, 133.20, 135.30,
141.87, 171.23, 198.10. ESI-MS: m/z=322 (M+H)+.
anhydrous Na2SO4 and evaporated. The product was
vacuum distilled at 45 ꢀC/10 mbar. Yield 2.34 g (15.0
mmol, 60%).
4 - Phenylbutanoyl - 2(S) - (2 - oxocyclopentanecarbonyl) -
pyrrolidine (2g). A solution of 0.53 mL (2.96 mmol)
(cyclopent-1-enyloxy)trimethylsilane in 13 mL dichloro-
methane was added to a solution of 800 mg (3.26 mmol)
4-phenylbutanoyl-l-prolinal and 0.36 mL (3.26 mmol)
titanium tetrachloride. The reaction was allowed to
proceed 1 h at À80 ꢀC. 6 mL Water was added at
À80 ꢀC and the reaction was stirred 10 min at À80 ꢀC
before it was warmed to rt. The phases were separated
and the aqueous phase was extracted with dichloro-
methane. The organic phases were combined and
washed with water. The organic phase was dried with
anhydrous Na2SO4 and evaporated. The intermediate
product was purified by flash chromatography. Yield
550 mg (1.67 mmol, 56%). 0.21 mL (1.46 mmol)
Trifluoroacetic anhydride was added to a solution of
ꢁ
Anal. (C21H23NO2 0.2H2O) Calcd C: 77.60, H: 7.26, N:
4.31; found C: 77.68, H: 7.29, N: 4.33.
4-Phenylbutanoyl-2(S)-(phenylacetyl)pyrrolidine (2e). The
synthesis was performed according to procedures C and
D starting from 1.03 g (3.5 mmol) N-BOC-2(S)-(pheny-
1
lacetyl)pyrrolidine. Yield 880 mg (2.6 mmol, 72%). H
NMR: d 1.7–2.5 (m, 8H), 2.46 (s, 2H), 2.69 (t, 2H,
J=7.5 Hz), 3.4–3.8 (m, 2H), 5.04 (dd, 0.1H, J=9.4 Hz,
J=2.6 Hz), 5.30 (dd, 0.9H, J=8.6 Hz, J=4.0 Hz), 7.1–
7.9 (m, 10H). 13C NMR: d 20.68, 24.64, 26.08, 28.58,
33.42, 35.14, 47.32, 63.29, 125.61, 125.82, 128.30,
128.58, 128.64, 131.23, 131.59, 136.86, 138.21, 141.84,
171.30, 202.50. ESI-MS: m/z=336 (M+H)+. Anal.
0.14 mL dimethylsulfoxide and
1 mL dichloro-
methane at À65 ꢀC. After 10 min, 320 mg inter-
mediate product dissolved in 1 mL dichloromethane
was added. After 30 min, 0.4 mL triethyl amine was
added and the reaction mixture was stirred at rt for 40
min. The reaction mixture was washed with water and
the organic phase was dried with anhydrous Na2SO4.
The product was purified by flash chromatography.
ꢁ
(C22H25NO2 0.1H2O) Calcd C: 78.35, H: 7.53, N: 4.15;
found C: 78.27, H: 7.69, N: 3.96.
4-Phenylbutanoyl-2(S)-(3-phenylpropionyl)pyrrolidine (2f).
The synthesis was performed according to procedures C
and D starting from 550 mg (1.8 mmol) N-BOC-2(S)-(3-
phenylpropionyl)pyrrolidine. Yield 320 mg (0.92 mmol,
1
Yield 150 mg (0.46 mmol, 47%). H NMR: d 1.8–2.9
1
51%). H NMR: d 1.6–2.4 (m, 8H), 2.68 (t, 2H, J=7.5
(m, 16H), 3.3–3.7 (m, 2H), 3.89 (t, ꢂ0.3H, J=8.4 Hz),
4.2–5.0 (m, 1H), 7.1–7.3 (m, 5H), 13.7 (s very broad
ꢂ0.7H). ESI-MS: m/z=328 (M+H)+. Anal.
Hz), 2.7–3.0 (m, 4H), 3.3–3.6 (m, 2H), 4.20 (dd, 0.1H,
J=9.3 Hz, J=3.3 Hz), 4.55 (dd, 0.9H, J=8.6 Hz,
J=4.6 Hz), 7.1–7.3 (m, 10H). 13C NMR: d 24.73, 26.02,
27.80, 29.43, 33.37, 35.13, 41.79, 47.20, 64.36, 125.87,
126.05, 128.34, 128.37, 128.44, 128.54, 141.26, 141.71,
171.51, 208.08. ESI-MS: m/z=350 (M+H)+. Anal.
.
(C20H25NO3 0.2H2O) Calcd C: 72.57, H: 7.73, N: 4.23;
found C: 72.39, H: 7.70, N: 4.23.
4-Phenylbutanoyl-L-proline. 2.30 g (20.0 mmol) l-Proline
was dissolved in 40 mL 1 M Na2CO3 at 0 ꢀC. 4-Phe-
nylbutanoyl chloride, prepared from 3.28 g (20.0 mmol)
4-phenylbutanoic acid, was dissolved in 5 mL diethy-
lether and the solution was added at 0 ꢀC. The reaction
mixture was then stirred vigorously 2 h at rt. The phases
were separated and the aqueous phase was washed once
with dietylether. The aqueous phase was then made
acidic with 2 M HCl. The product was extracted with
diethyl ether. The diethyl ether phase (after the acid-
ification) was dried with anhydrous Na2SO4 and eva-
porated. Yield 3.97 g (15.2 mmol, 76%).
.
(C23H27NO2 0.1H2O) Calcd C: 78.64, H: 7.80, N: 3.99;
found C: 78.60, H: 7.89, N: 3.88.
4-Phenylbutanoyl-L-prolinal. 1.04 g (10.3 mmol) l-Proli-
nol was dissolved in 20 mL 10% Na2CO3. A solution of
4-phenylbutanoyl chloride, prepared from 1.64 g (10.0
mmol) 4-phenylbutanoic acid, in diethyl ether was
added at 0 ꢀC. The reaction was stirred for 2 h at rt.
Diethyl ether was added and the phases were separated.
The diethyl ether phase was washed with 30% citric
acid, saturated NaCl and saturated NaHCO3. T he
organic phase was dried with anhydrous Na2SO4 and
evaporated. Yield 1.58 g (6.4 mmol, 64%). 1.53 g (6.2
mmol) 4-Phenylbutanoyl-l-prolinol was oxidized
according to synthesis procedure B. Yield 830 mg (3.6
mmol, 55%).
4-Phenylbutanoyl-L-prolyl-2(S)-(cyclopentanecarbonyl)-
pyrrolidine (3a). The synthesis was performed accord-
ing to procedures C and E starting from 600 mg (2.3
mmol) N-BOC-2(S)-(cyclopentanecarbonyl)pyrrolidine.
Yield 780 mg (1.9 mmol, 83%). 1H NMR: d 1.5–2.4 (m,
20H), 2.66 (dt, 2H, J=7.5 Hz, J=2.1 Hz), 3.01 (qui,
1H, J=8.1 Hz), 3.2–3.9 (m, 4H), 4.28 (dd, 0.1H, J=8.7
Hz, J=3.2 Hz), 4.65 (dd, 1H, J=8.0 Hz, J=3.9 Hz),
4.77 (dd, 0.9H, J=8.8 Hz, J=4.5 Hz), 7.1–7.3 (m, 5H).
13C NMR: d 24.75, 24.86, 25.90, 26.00, 26.12, 27.90,
28.30, 28.57, 29.61, 33.57, 35.26, 47.01, 47.28, 49.09,
57.60, 63.86, 125.80, 128.29, 128.53, 141.86, 170.45,
171.43, 211.18. ESI-MS: m/z=411 (M+H)+. Anal.
(Cyclopent-1-enyloxy)trimethylsilane. A solution of 4.66
g (31 mmol) NaI in 31 mL acetonitrile was added to a
mixture of 2.2 mL (25 mmol) cyclopentanone, 4.3 mL
(31 mmol) triethylamine and 3.9 mL (31 mmol)
chlorotrimethylsilane. The reaction was allowed to
proceed 2 h at rt. 25 mL Cold hexane and 25 mL
cold water was added, and the aqueous phase was
extracted with hexane. The organic phases were com-
bined and washed with 10% NH4Cl until the organic
phase was neutral. The organic phase was dried with
.
(C25H34N2O3 0.3H2O) Calcd C: 72.19, H: 8.38, N: 6.73;
found C: 72.14, H: 8.37, N: 6.67.