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T. Kondo et al. / Bioorg. Med. Chem. 15 (2007) 2631–2650
m/z 293 (M+H)+; IR (KBr) 3568, 3449, 1663, 1655,
4.43–4.58 (m, 1H), 4.81 (dd, J = 7.8, 4.7 Hz, 1H), 9.59
(s, 2H); HRMS (FAB) calcd for C17H27N4O2:
319.2134. Found: 319.2135.
1
1646, 1638, 1451, 1214, 1190, 684, 569 cmÀ1; H NMR
(300 MHz, DMSO-d6) d 0.95–1.06 (m, 3H), 1.07–1.18
(m, 3H), 1.69–1.84 (m, 1H), 1.97–2.07 (m, 2H), 2.09–
2.25 (m, 2H), 2.28 (s, 3H), 2.73–2.88 (m, 1H), 3.17–
3.50 (m, 7H), 3.51–3.64 (m, 2H), 4.43–4.60 (m, 1H),
4.83 (dd, J = 7.78, 4.8 Hz, 1H), 7.10 (d, J = 7.8 Hz,
2H), 7.40–7.54 (m, 2H), 8.84 (s, 1H), 9.37 (s, 1H);
HRMS (FAB) calcd for C14H23N4O2: 293.1978. Found:
293.1981.
4.1.38. (2S)-1-{[(2S,4S)-4-(1-Azocanylcarbonyl)-2-pyrro-
lidinyl]carbonyl}-2-pyrrolidinecarbonitrile 4-methylben-
zenesulfonate (24). Yield 87%. A beige powder. TLC
Rf = 0.22 (CHCl3/MeOH, 9/1); MS (APCI, pos. 20 V)
m/z 333 (M+H)+; IR (KBr) 2927, 2242, 1662, 1636,
1
1450, 1214, 1174, 1123, 1033, 1010, 682, 568 cmÀ1; H
NMR (300 MHz, DMSO-d6) d 1.34–1.72 (m, 10H),
1.74–1.90 (m, 1H), 1.93–2.09 (m, 2H), 2.09–2.25 (m,
2H), 2.27 (s, 3H), 2.38–2.62 (m, 1H), 2.67–2.92 (m,
1H), 3.27–3.66 (m, 8H), 4.44–4.57 (m, 1H), 4.82 (dd,
J = 7.6, 4.9 Hz, 1H), 7.10 (d, J = 8.0 Hz, 2H), 7.46 (d,
J = 8.0 Hz, 2H), 8.85 (s, 1H), 9.38 (s, 1H); HRMS
(FAB) calcd for C18H29N4O2: 333.2291. Found:
333.2288.
4.1.34. (2S)-1-{[(2S,4S)-4-(1-Azetidinylcarbonyl)-2-pyr-
rolidinyl]carbonyl}-2-pyrrolidinecarbonitrile 4-methylben-
zenesulfonate (20). Yield 98%. A white powder. TLC
Rf = 0.19 (CHCl3/MeOH, 9:1); MS (APCI, pos. 20 V)
m/z 277 (M+H)+; IR (KBr) 3439, 2242, 1654, 1648,
1
1446, 1188, 1123, 1034, 1010, 683, 568 cmÀ1; H NMR
(300 MHz, DMSO-d6) d 1.67–1.86 (m, 1H), 1.95–2.08
(m, 2H), 2.11–2.26 (m, 4H), 2.28 (s, 3H), 2.66–2.87 (m,
1H), 3.07–3.22 (m, 1H), 3.22–3.36 (m, 2H), 3.49–3.65
(m, 2H), 3.86 (t, J = 7.6 Hz, 2H), 4.18 (t, J = 7.6 Hz,
2H), 4.38–4.59 (m, 1H), 4.83 (dd, J = 7.6, 4.7 Hz, 1H),
7.10 (d, J = 7.8 Hz, 2H), 7.42–7.50 (m, 2H), 8.88 (s,
1H), 9.40 (s, 1H); HRMS (FAB) calcd for
C14H21N4O2: 277.1665. Found: 277.1667.
4.1.39.
(2S)-1-{[(2S,4S)-4-(4-Morpholinylcarbonyl)-2-
pyrrolidinyl]carbonyl}-2-pyrrolidinecarbonitrile 4-methyl-
benzenesulfonate (25). Yield 97%. A white powder. TLC
Rf = 0.19 (CHCl3/MeOH, 9:1); MS (APCI, pos. 20 V)
m/z 307 (M+H)+; IR (KBr) 3449, 2243, 1654, 1647,
1
1450, 1217, 1188, 1121, 1034, 1010, 683, 568 cmÀ1; H
NMR (300 MHz, DMSO-d6) d 1.70–1.89 (m, 1H), 1.96–
2.09 (m, 2H), 2.09–2.26 (m, 2H), 2.28 (s, 3H), 2.67–2.88
(m, 1H), 3.40–3.77 (m, 13H), 4.39–4.62 (m, 1H), 4.83
(dd, J = 7.7, 4.6 Hz, 1H), 7.06–7.15 (m, 2H), 7.43–7.50
(m, 2H), 8.88 (s, 1H), 9.41 (s, 1H); HRMS (FAB) calcd
for C15H23N4O3: 307.1770. Found: 307.1769.
4.1.35.
(2S)-1-{[(2S,4S)-4-(1-Pyrrolidinylcarbonyl)-2-
pyrrolidinyl]carbonyl}-2-pyrrolidinecarbonitrile 4-methyl-
benzenesulfonate (21). Yield 96%. A white powder. TLC
Rf = 0.67 (CHCl3/MeOH/AcOH, 3:1:1); MS (APCI,
pos. 20 V) m/z 291 (M+H)+; IR (KBr) 3434, 3061,
2974, 2881, 1660, 1633, 1450, 1187, 1123, 1034, 1010,
683 cmÀ1; H NMR (300 MHz, DMSO-d6) d 1.68–2.08
4.1.40. (2S)-1-{[(2S,4S)-4-(4-Thiomorpholinylcarbonyl)-
2-pyrrolidinyl]carbonyl}-2-pyrrolidinecarbonitrile 4-meth-
ylbenzenesulfonate (26). Yield 97%. An ivory powder.
TLC Rf = 0.38 (CHCl3/MeOH, 5:1); MS (APCI, pos.
20 V) m/z 323 (M+H)+; IR (KBr) 3449, 2243, 1655,
1
(m, 7H), 2.09–2.26 (m, 2H), 2.27 (s, 3H), 2.50–2.61 (m,
1H), 2.77–2.93 (m, 1H), 3.28 (t, J = 6.7 Hz, 2H), 3.42–
3.79 (m, 6H), 4.44–4.61 (m, 1H), 4.82 (dd, J = 7.8,
4.7 Hz, 1H), 7.09 (d, J = 8.0 Hz, 2H), 7.45 (d,
J = 8.0 Hz, 2H), 8.86 (s, 1H), 9.41 (s, 1H); HRMS
(FAB) calcd for C15H23N4O2: 291.1821. Found:
291.1821.
1
1451, 1222, 1195, 1122, 1033, 1009, 682, 568 cmÀ1; H
NMR (300 MHz, DMSO-d6) d 1.73–1.87 (m, 1H),
1.94–2.08 (m, 2H), 2.09–2.25 (m, 2H), 2.28 (s, 3H),
2.52–2.59 (m, 2H), 2.60–2.69 (m, 2H), 2.70–2.83 (m,
1H), 3.40–3.90 (m, 9H), 4.40–4.57 (m, 1H), 4.83 (dd,
J = 7.7, 4.6 Hz, 1H), 7.10 (d, J = 8.0 Hz, 2H), 7.46 (d,
J = 8.0 Hz, 2H), 8.87 (s, 1H), 9.39 (s, 1H); HRMS
(FAB) calcd for C15H23N4O2S: 323.1542. Found:
323.1545.
4.1.36. (2S)-1-{[(2S,4S)-4-(1-Piperidinylcarbonyl)-2-pyr-
rolidinyl]carbonyl}-2-pyrrolidinecarbonitrile 4-methylben-
zenesulfonate (22). Yield 98%. A white powder. TLC
Rf = 0.61 (CHCl3/MeOH/AcOH, 3:1:1); MS (APCI,
pos. 20 V) m/z 305 (M+H)+; IR (KBr) 2938, 2241,
1662, 1636, 1448, 1218, 1186, 1123, 1033, 1010,
682 cmÀ1; H NMR (300 MHz, DMSO-d6) d 1.37–1.69
4.1.41. Methyl (2S)-1-(benzyloxycarbonyl)-4-oxo-2-pyr-
rolidinecarboxylate (49). To a stirred solution of 48
(15.5 g, 55 mmol) in EtOAc (40 mL) were added trieth-
ylamine (15.4 mL, 110 mmol), DMSO (20 mL), and sul-
fur trioxide–pyridine complex (17.5 g, 110 mmol) at
0 °C. After being stirred for 88 h at room temperature,
the reaction mixture was quenched with water, and
extracted with EtOAc. The organic layer was successive-
ly washed with water, brine, dried over MgSO4, and
concentrated in vacuo. The resulting residue was puri-
fied by silica gel chromatography using EtOAc/hexane
(1:2) as an eluant to yield 49 (8.81 g, 58%) as a colorless
oil. TLC Rf = 0.35 (hexane/EtOAc, 2:1); 1H NMR
(300 MHz, CDCl3) d 2.57–2.64 (m, 1H), 2.88–3.02 (m,
1H), 3.63 and 3.77 (s, 3H), 3.95 (s, 2H), 4.80–4.92 (m,
1H), 5.08–5.26 (m, 2H), 7.26–7.42 (m, 5H).
1
(m, 7H), 1.94–2.23 (m, 4H), 2.36 (s, 3H), 2.61–2.80 (m,
1H), 3.22–3.82 (m, 9H), 4.76–4.88 (m, 1H), 4.93–5.10
(m, 1H), 7.18 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 8.0 Hz,
2H), 8.24 (s, 1H), 9.59 (s, 1H); HRMS (FAB) calcd
for C16H25N4O2: 305.1978. Found: 305.1977.
4.1.37. (2S)-1-{[(2S,4S)-4-(1-Azepanylcarbonyl)-2-pyrro-
lidinyl]carbonyl}-2-pyrrolidinecarbonitrile hydrochloride
(23). Yield 97%. A white powder. TLC Rf = 0.22
(CHCl3/MeOH, 9/1); MS (APCI, pos. 20 V) m/z 319
(M+H)+; IR (KBr) 3411, 2927, 2722, 1634, 1448, 1369,
1267, 1191, 1101, 1046, 730 cmÀ1
;
1H NMR
(300 MHz, DMSO-d6) d 1.39–1.72 (m, 8H), 1.72–1.88
(m, 1H), 1.91–2.06 (m, 2H), 2.08–2.32 (m, 2H), 2.36–
2.60 (m, 1H), 2.67–2.86 (m, 1H), 3.33–3.82 (m, 8H),