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5.1.29. (2S,4S)-1-{N-[1-(1-Benzofuran-2-yl)-1-methyleth-
C, 50.11; H, 7.37; N, 15.89; Cl, 13.38; F, 7.19. ½aꢀ
D
yl]glycyl}-4-fluoropyrrolidine-2-carbonitrile (12d). The ti-
tle compound was obtained as a pale yellow solid in a
manner similar to method used to prepare 12a. 1H
NMR (300 MHz, DMSO-d6) d 7.59–7.48 (2H, m),
7.28–7.26 (2H, m), 6.70 (1H, s), 5.38 (1H, br d,
J = 52.2 Hz, H-4), 4.90–4.83 (1H, m, H-2), 3.85 (1H,
dd, J = 23.2, 12.3 Hz, H-5), 3.60 (1H, ddd, J = 39.6,
12.5, 3.4 Hz, H-5), 3.38–3.04 (2H, m, COCH2), 2.60–
2.18 (2H, m, H-3), 1.48 (6H, s, CH3). MS(ESI pos.) m/
z 352 ([M+Na]+); (ESI neg.) m/z 328 ([MꢁH]ꢁ). HRMS
calcd for C18H20FN3O2Na[M+Na]+ 352.1437; found:
(m/z) 352.1454.
ꢁ101.5 (c 0.3, MeOH).
5.1.33. (2S,4S)-4-Fluoro-1-(N-isopropylglycyl)pyrroli-
dine-2-carbonitrile hydrochloride (12h). The title com-
pound was obtained as a colorless powder in a manner
similar to method used to prepare 2a. 1H NMR
(300 MHz, DMSO-d6) d 5.52 (1H, br d, J = 51.4 Hz,
H-4), 5.03–4.97 (1H, m, H-2), 3.98 (1 H, dd, J = 23.2,
12.4 Hz, H-5), 3.84–3.64 (1H, m, H-5), 3.74 and 3.55
(2H, ABq, J = 16.6 Hz, COCH2), 3.02–2.88 (1H, m,
CHMe2), 2.62–2.26 (2H, m, H-3), 1.09 (6H, d, J = 6.2
Hz, CH3). MS(ESI pos.) m/z 214 ([M+H]+), 236
([M+Na]+); (ESI neg.) m/z 212 ([MꢁH]ꢁ), 248
([M+Cl]ꢁ). HRMS calcd for C10H16FN3O [M]+
213.1277; found: (m/z) 213.1297.
5.1.30. (2S,4S)-1-{N-[(2E)-1,1-Dimethyl-3-phenylprop-2-
en-1-yl]glycyl}-4-fluoropyrrolidine-2-carbonitrile (12e).
The title compound was obtained as a colorless amor-
phous substance in a manner similar to method used
to prepare 12a. 1H NMR (300 MHz, DMSO-d6) d
7.44–7.38 (2H, m), 7.35–7.27 (2H, m), 7.25–7.17 (1H,
m), 6.40 (1H, d, J = 16.3 Hz, C@CH), 6.21 (1H, d,
J = 16.3 Hz, C@CH), 5.42 (1H, br d, J = 51.8 Hz, H-
4), 4.91 (1H, d, J = 8.9 Hz, H-2), 3.90 (1H, dd,
J = 23.5, 12.4 Hz, H-5), 3.78–3.56 (1H, m, H-5), 3.44–
3.14 (2H, m, COCH2), 2.60–2.20 (2H, m, H-3), 2.06–
1.98 (1H, m), 1.22 (6H, s, CH3). MS(ESI pos.) m/z 338
([M+Na]+). HRMS calcd for C18H22FN3ONa[M+Na]+
338.1645; found: (m/z) 338.1641.
5.1.34. (2S,4S)-4-Fluoro-1-[N-(3-isopropoxypropyl)gly-
cyl]pyrrolidine-2-carbonitrile hydrochloride (12i). The ti-
tle compound was obtained as a colorless powder in a
manner similar to method used to prepare 2a. 1H
NMR (300 MHz, DMSO-d6) d 9.23 (2H, br s, NH2þ),
5.54 (1H, br d, J = 52.5 Hz, H-4), 5.10–5.03 (1H, m,
H-2), 4.21 and 3.96 (2H, ABq, J = 16.6 Hz, COCH2),
4.04–3.90 (1H, m, H-5), 3.84–3.76 (1H, m, H-5), 3.58–
3.48 (1H, m, CHMe2), 3.43 (2H, t, J = 5.8 Hz, OCH2),
3.10–2.85 (2H, m, NCH2), 2.67–2.31 (2H, m, H-3),
1.95–1.82 (2H, m, CH2), 1.09 (6H, d, J = 6.2 Hz,
CH3). MS(ESI pos.) m/z 294 ([M+Na]+); (ESI neg.) m/
z 270 ([MꢁH]ꢁ) 306 ([M+Cl]ꢁ). HRMS calcd for
C13H23FN3O2 [M+H]+ 272.1774; found: (m/z)
272.1785. Anal. Calcd for C13H22FN3O2 HCl: C,
50.73; H, 7.53; N, 13.65; Cl, 11.52; F, 6.17. Found: C,
50.44; H, 7.49; N, 13.44; Cl, 11.39; F, 5.92.
5.1.31. (2S,4S)-1-{N-[2-(3,4-Dimethoxyphenyl)ethyl]gly-
cyl}-4-fluoropyrrolidine-2-carbonitrile hydrochloride (12f).
The title compound was obtained as a colorless powder
1
in a manner similar to method used to prepare 2a. H
NMR (300 MHz, DMSO-d6) d 6.89 (1H, d, J = 8.2
Hz), 6.83 (1H, d, J = 1.9 Hz), 6.74 (1H, dd, J = 8.2,
1.9 Hz), 5.52 (1H, br d, J = 53.0 Hz, H-4), 5.05–5.00
(1H, m, H-2), 4.02–3.61 (4H, m, H-5 and COCH2),
3.75 (3H, s, OCH3), 3.72 (3H, s, OCH3), 3.07–2.92
(2H, m, NCH2), 2.87–2.77 (2H, m, PhCH2), 2.64–2.30
(2H, m, H-3). MS(ESI pos.) m/z 336 ([M+H]+), 358
([M+Na]+); (ESI neg.) m/z 334 ([MꢁH]ꢁ), 370
([M+Cl]ꢁ). HRMS calcd for C17H22FN3O3Na
[M+Na]+ 335.1645; found: (m/z) 335.1670.
5.1.35. (2S,4S)-4-Fluoro-1-[N-(2-methoxy-1,1-dimethyl-
ethyl)glycyl]pyrrolidine-2-carbonitrile hydrochloride (12j).
The title compound was obtained as a colorless powder
1
in a manner similar to method used to prepare 2a. H
NMR (300 MHz, DMSO-d6) d 8.82 (2H, br s, NH2þ),
5.56 (1H, br d, J = 53.0 Hz, H-4), 5.09–5.04 (1H, m,
H-2), 4.18–3.66 (4H, m, H-5 and COCH2), 3.42 (2H, s,
OCH2), 3.32 (3H, s, OCH3), 2.58–2.32 (2H, m, H-3),
1.27 (6H, s, CH3). MS(ESI pos.) m/z 258 ([M+H]+),
280 ([M+Na]+); (ESI neg.) m/z 292 ([M+Cl]ꢁ). HRMS
calcd for C12H21FN3O2 [M+H]+258.1618; found: (m/z)
258.1603.
5.1.32. (2S,4S)-1-[N-(tert-Butyl)glycyl]-4-fluoropyrroli-
dine-2-carbonitrilehydrochloride (12g). The title com-
pound was obtained as a colorless powder in a
manner similar to method used to prepare 2a. Mp
247–250 ꢁC (decomp.). 1H NMR (500 MHz, DMSO-
d6) d 9.10 (2H, br s, NH2þ), 5.56 (1H, br d,
J = 52.9 Hz, H-4), 5.09–5.06 (1H, m, H-2),4.16 (1H,
dd, J = 24.4, 12.5 Hz, H-5), 4.12 and 3.88 (2H, ABq,
J = 16.5 Hz, COCH2), 3.86 (1H, ddd, J = 39.9, 12.5,
3.3 Hz, H-5), 2.54–2.40 (2H, m, H-3),1.33 (9H, s,
CH3); 13C NMR (125.4 MHz, DMSO-d6) d 165.1,
118.4, 93.0 (d, JC–F = 174.7 Hz), 56.4, 52.1 (d, JC–
F = 22.7 Hz), 44.8, 42.0, 35.7 (d, JC–F = 19.6 Hz),
25.0; 19F NMR (282.2 MHz, DMSO-d6) d ꢁ174.5.
MS(ESI pos.) m/z 250 ([M+Na]+); (ESI neg.) m/z
226 ([MꢁH]ꢁ), 262 ([M+Cl]ꢁ). HRMS calcd for
5.1.36. (2S,4S)-4-Fluoro-1-[N-(2-hydroxy-1,1-dimethyl-
ethyl)glycyl]pyrrolidine-2-carbonitrile hydrochloride (12k).
The title compound was obtained as a pale pink powder
1
in a manner similar to method used to prepare 2a. H
NMR (300 MHz, DMSO-d6) d 8.75 (2H, br s, NH2þ),
5.57 (1H, br s, OH), 5.56 (1H, br d, J = 52.7 Hz, H-4),
5.10–5.04 (1H, m, H-2), 4.20–3.70 (4H, m, H-5 and
COCH2), 3.48 (2H, s, OCH2), 2.70–2.30 (2H, m, H-3),
1.24 (6H, s, CH3). MS(ESI pos.) m/z 244 ([M+H]+),
266 ([M+Na]+); (ESI neg.) m/z 242 ([MꢁH]ꢁ), 278
([M+Cl]ꢁ). HRMS calcd for C11H18FN3O2 [M+H]+
244.1461; found: (m/z) 244.1449. Anal. Calcd for
C11H18FN3O2 HCl 0.3H2O: C, 46.33; H, 6.93; N, 4.74;
Cl, 12.43; F, 6.66. Found: C, 46.68; H, 6.98; N, 14.29;
Cl, 12.20; F, 6.43.
C11H19FN3O[M+H]+
228.1512;
found:
(m/z)
228.1515. Anal. Calcd for C11H18FN3O HCl: C,
50.09; H, 7.26; N, 15.93; Cl, 13.44; F, 7.20. Found: