M.-C. Tseng, Y.-H. Chu / Tetrahedron 64 (2008) 9515–9520
9519
NHCH, 1H), 5.51 (q, J¼7.1 Hz, COCH, 1H), 6.77 (s, NH, 1H), 7.51 (t,
4.2.9. (1S,4S)-4-Benzyl-1-isopropyl-2,4-dihydro-1H-pyrazino-
J¼7.3 Hz, ArH,1H), 7.70 (d, J¼8.0 Hz, ArH,1H), 7.70 (d, J¼7.2 Hz, ArH,
[2,1-b]quinazoline-3,6-dione (1i)
1H), 8.29 (d, J¼7.8 Hz, ArH, 1H); 13C NMR (100 MHz, CDCl3)
d
16.5,
White solid; mp 81–82 ꢀC; 1H NMR (400 MHz, CDCl3)
d 0.84 (d,
17.6, 49.3, 52.4, 120.4, 126.8, 127.3, 127.5, 134.6, 147.0, 150.7, 160.4,
170.0; FAB-HRMS m/z [MþH]þ calcd for C13H14N3O2 244.1086,
found 244.1083.
J¼6.5 Hz, CH3, 3H), 0.96 (d, J¼6.5 Hz, CH3, 3H), 1.16 (m, (CH3)2CH,
1H), 3.49 (d, J¼5.2 Hz, CH2Ph, 2H), 4.04 (d, J¼5.1 Hz, NHCH, 1H),
5.48 (t, J¼5.3 Hz, COCH, 1H), 6.97 (br s, NH, 1H), 7.17–7.23 (m, ArH,
5H), 7.53 (t, J¼7.4 Hz, ArH, 1H), 7.66 (d, J¼8.0 Hz, ArH, 1H), 7.80 (t,
J¼7.5 Hz, ArH, 1H), 8.33 (d, J¼7.8 Hz, ArH, 1H); 13C NMR (100 MHz,
4.2.4. (4S)-4-Methyl-1H-pyrazino[2,1-b]quinazoline-3,6-dione (1d)
White solid; mp 196–197 ꢀC; 1H NMR (400 MHz, DMSO-d6)
CDCl3)
d 18.9, 20.0, 35.0, 38.1, 57.6, 62.0, 120.1, 126.8, 127.2, 127.3,
d
1.50 (d, J¼6.8 Hz, CH3, 3H), 4.23 (d, J¼16.7 Hz, NHCH2, 1H), 4.78 (d,
128.7, 129.9, 134.8, 136.0, 146.8, 149.2, 161.1, 167.4; FAB-HRMS m/z
J¼16.6 Hz, NHCH2, 1H), 5.01 (q, J¼7.2 Hz, COCH, 1H), 7.52 (t,
J¼7.5 Hz, ArH, 1H), 7.62 (d, J¼8.2 Hz, ArH, 1H), 7.82 (t, J¼7.5 Hz, ArH,
1H), 8.12 (d, J¼8.0 Hz, ArH, 1H), 8.59 (br s, NH, 1H); 13C NMR
[MþH]þ calcd for C21H22N3O2 348.1712, found 348.1714.
4.2.10. (1R,4S)-4-Benzyl-1-isopropyl-2,4-dihydro-1H-pyrazino-
(100 MHz, DMSO-d6)
d
16.3, 44.2, 51.8, 120.1, 126.4, 126.9, 127.1,
[2,1-b]quinazoline-3,6-dione (1j)
134.9, 147.3, 149.5, 159.8, 168.5; FAB-HRMS m/z [MþH]þ calcd for
White solid; mp 189–190 ꢀC; 1H NMR (400 MHz, CDCl3)
d 0.73
C
12H12N3O2 230.0930, found 230.0929.
(d, J¼6.8 Hz, CH3, 3H), 0.90 (d, J¼6.8 Hz, CH3, 3H), 2.74–2.78 (m,
NHCH, (CH3)2CH, 2H), 3.47 (br s, CH2Ph, 2H), 5.66 (t, J¼4.0 Hz,
COCH, 1H), 6.13 (br s, NH, 1H), 6.93 (d, J¼7.2 Hz, ArH, 2H), 7.18 (t,
J¼7.6 Hz, ArH, 3H), 7.54 (t, J¼7.6 Hz, ArH, 1H), 7.62 (d, J¼8.4 Hz, ArH,
1H), 7.79 (t, J¼7.2 Hz, ArH, 1H), 8.35 (d, J¼8.0 Hz, ArH, 1H); 13C NMR
4.2.5. (4S)-4-((Indol-2-yl)methyl)-1,2-dihydro-4H-pyrazino[2,1-b]-
quinazoline-3,6-dione (1e, ent-glyantrypine)
White solid; mp 156–158 ꢀC; 1H NMR (400 MHz, CDCl3)
d 2.82
(d, J¼16.8 Hz, NHCH2,1H), 3.65 (dq, J¼18.0, 5.2 Hz, indolyl-CH2, 2H),
3.80 (dd, J¼16.8, 3.6 Hz, NHCH2, 1H), 5.63 (q, J¼2.9 Hz, COCH, 1H),
6.20 (br s, NH,1H), 6.69 (d, J¼2.1 Hz, ArH, 1H), 6.93 (t, J¼7.6 Hz, ArH,
1H), 7.13 (t, J¼7.7 Hz, ArH, 1H), 7.30 (t, J¼8.2 Hz, ArH, 1H), 7.40 (d,
J¼8.0 Hz, ArH, 1H), 7.54 (q, J¼7.8 Hz, ArH, 1H), 7.78 (t, J¼6.4 Hz, ArH,
1H), 8.37 (br s, NH, 1H), 8.39 (d, J¼1.5 Hz, NH, 1H); 13C NMR
(100 MHz, CDCl3) d 14.8, 18.9, 29.5, 37.2, 57.0, 57.9, 120.0, 126.9,
127.1, 127.3, 127.8, 128.7, 129.8, 134.8, 134.9, 147.0, 149.9, 160.8,
168.5; FAB-HRMS m/z [MþH]þ calcd for C21H22N3O2 348.1712,
found 348.1718.
4.2.11. 1,2-Dihydro-[1,4]diazepino[7,1-b]quinazolin-4,7(3H,5H)-
(100 MHz, CDCl3)
d
27.1, 44.6, 56.8, 109.0, 111.2, 118.4, 120.0, 120.1,
dione (1k)
122.6, 123.7, 126.7, 126.9, 127.1, 127.2, 134.9, 136.0, 147.1, 148.3, 160.1,
169.5; FAB-HRMS m/z [MþH]þ calcd for C20H17N4O2 345.1352,
found 345.1350.
White solid; mp 226–228 ꢀC; 1H NMR (400 MHz, CD3OD)
d 3.46
(dd, J¼5.6, 7.6 Hz, CH2, 2H), 3.53–3.61 (m, CH2, 2H), 5.23 (s, COCH2,
2H), 7.52 (t, J¼7.8 Hz, ArH, 1H), 7.63 (d, J¼8.1 Hz, ArH, 1H), 7.80 (dt,
J¼11.2, 7.0 Hz, ArH, 1H), 8.19 (d, J¼8.0 Hz, ArH, 1H); 13C NMR
4.2.6. (4S)-4-(2-Methylpropyl)-2,4-dihydro-1H-pyrazino[2,1-b]-
quinazoline-3,6-dione (1f)
(100 MHz, CD3OD) d 34.3 42.3, 46.6, 121.3, 127.7, 128.0, 128.3, 136.0,
148.4, 158.3, 162.3, 169.4; FAB-HRMS m/z [MþH]þ calcd for
White solid; mp 151–153 ꢀC; 1H NMR (400 MHz, CDCl3)
d
1.00
C12H12N3O2 230.0930, found 230.0929.
(d, J¼5.8 Hz, CH3, 3H), 1.05 (d, J¼5.8 Hz, CH3, 3H), 1.76–1.86 (m,
(CH3)2CH, 1H), 1.89 (t, J¼5.7 Hz, (CH3)2CHCH2, 2H), 4.42 (d,
J¼18.4 Hz, COCH, 1H), 4.56–4.60 (m, NHCH, 1H), 5.03 (d, J¼18.4 Hz,
COCH, 1H), 7.49 (t, J¼7.7 Hz, ArH, 1H), 7.67 (d, J¼8.1 Hz, ArH, 1H),
7.77 (t, J¼7.3 Hz, ArH, 1H), 8.04 (br s, NH, 1H), 8.27 (d, J¼7.9 Hz, ArH,
4.2.12. (5S)-1,2-Dihydro-5-benzyl[1,4]diazepino[7,1-b]quinazolin-
4,7(3H,5H)-dione (1l)
Light yellow solid; mp 107–108 ꢀC; 1H NMR (400 MHz, CDCl3)
d
3.17–3.21 (m, CH2, 2H), 3.39 (dd, J¼13.8, 9.6 Hz, CH2, 1H), 3.55–
1H); 13C NMR (100 MHz, CDCl3)
d
21.9, 23.0, 25.0, 40.7, 45.1, 54.2,
3.59 (m, CH2Ph, CH2, 3H), 6.17 (br s, NH, 1H), 6.57 (dd, J¼9.2, 5.2 Hz,
COCH, 1H), 7.03–7.04 (m, ArH, 2H), 7.04–7.11 (m, ArH, 3H), 7.40 (t,
J¼7.6 Hz, ArH, 1H), 7.56 (d, J¼8.0 Hz, ArH, 1H), 7.71 (t, J¼8.4 Hz, ArH,
120.4, 127.0, 127.3, 134.8, 147.1, 148.2, 160.4, 169.8; FAB-HRMS m/z
[MþH]þ calcd for C15H18N3O2 272.1399, found 272.1392.
1H), 8.05 (d, J¼8.0 Hz, ArH, 1H); 13C NMR (100 MHz, CDCl3)
d 36.1,
4.2.7. (1S,4S)-4-Benzyl-1-methyl-2,4-dihydro-1H-pyrazino[2,1-b]-
40.4, 41.4, 58.7, 119.9, 126.7, 127.1, 127.3, 127.9, 128.6, 129.4, 134.6,
quinazoline-3,6-dione (1g)
135.5, 146.4, 155.2, 161.4, 169.9; FAB-HRMS m/z [MþH]þ calcd for
White solid; mp 145–148 ꢀC; 1H NMR (400 MHz, CDCl3)
d
0.76
C19H18N3O2 320.1399, found 320.1391.
(d, J¼6.8 Hz, CH3, 3H), 3.47 (d, J¼11.4 Hz, CH2Ph, 1H), 3.59 (dd,
J¼5.4, 14.0 Hz, CH2Ph, 1H), 4.52 (q, J¼5.0 Hz, NHCH, 1H), 5.46 (br s,
COCH, 1H), 6.92–6.94 (m, ArH, 2H), 7.19–7.21 (m, ArH, 3H), 7.48 (t,
J¼7.4 Hz, ArH, 1H), 7.62 (d, J¼8.0 Hz, ArH, 1H), 7.76 (t, J¼7.4 Hz, ArH,
1H), 7.96 (s, NH,1H), 8.33 (d, J¼7.8 Hz, ArH,1H); 13C NMR (100 MHz,
Acknowledgements
We thank Ms. Ping-Yu Lin of Academia Sinica (Taiwan, ROC) for
her excellence in mass analyses, and Mr. Chi-Yu Lai and Chris Huang
for their contribution at the early stage of this research. We also
appreciate constructive comments from reviewers. This work was
supported by a multi-year Grant-in-Aid from ANT Technology
(Taipei, Taiwan, ROC) and in part by the National Science Council
(Taiwan, ROC).
CDCl3)
d 22.9, 36.7, 51.8, 56.7, 119.8, 126.7, 126.8, 126.9, 127.5, 128.8,
130.1, 134.8, 135.2, 147.1, 151.1, 160.7, 167.1; FAB-HRMS m/z [MþH]þ
calcd for C19H18N3O2 320.1399, found 320.1398.
4.2.8. (1R,4S)-4-Benzyl-1-methyl-2,4-dihydro-1H-pyrazino[2,1-b]-
quinazoline-3,6-dione (1h)
Light yellow solid; mp 164–168 ꢀC; 1H NMR (400 MHz, CDCl3)
References and notes
d
1.48 (d, J¼6.1 Hz, CH3, 3H), 3.03 (q, J¼6.3 Hz, NHCH, 1H), 3.42 (br s,
CH2Ph, 2H), 5.65 (t, J¼4.6 Hz, COCH, 1H), 6.99 (d, J¼7.2 Hz, ArH, 2H),
7.18–7.29 (m, ArH, NH, 4H), 7.54 (t, J¼7.3 Hz, ArH, 1H), 7.65 (d,
J¼7.8 Hz, ArH,1H), 7.78 (d, J¼7.0 Hz, ArH,1H), 8.34 (d, J¼7.4 Hz, ArH,
1. For reviews, see: (a) Michael, J. P. Nat. Prod. Rep. 2005, 22, 627–646; (b)
Michael, J. P. Nat. Prod. Rep. 2004, 21, 650–668; (c) Avendano, C.; Menendez,
J. C. Curr. Org. Chem. 2003, 7, 149–173; (d) Michael, J. P. Nat. Prod. Rep. 2003,
20, 476–493; (e) Michael, J. P. Nat. Prod. Rep. 2002, 19, 742–760; (f) Michael,
J. P. Nat. Prod. Rep. 2001, 18, 543–559; (g) Michael, J. P. Nat. Prod. Rep. 2000, 17,
603–620.
1H); 13C NMR (100 MHz, CDCl3)
d 18.7, 36.9, 48.9, 57.6, 120.1, 126.8,
127.2,127.4,127.8,128.8,129.7,134.7,135.0,147.0,151.5,160.6,168.8;
FAB-HRMS m/z [MþH]þ calcd for C19H18N3O2 320.1399, found
320.1391.
2. (a) Cagir, A.; Jones, S. H.; Eisenhauer, B. M.; Gao, R.; Hecht, S. M. Bioorg. Med.
Chem. Lett. 2004, 14, 2051–2054; (b) Ma, Z.; Hano, Y.; Nomura, T.; Chen, Y.