3396
F. Herna´ndez et al. / Tetrahedron: Asymmetry 12 (2001) 3387–3398
(m, 5H, Ph), 5.41 (t, 1H, J=5.6 Hz, H-4), 4.02 (dd, 1H,
J=3.5 and 8.5 Hz, H-1), 3.45 (2dd, 2H, J=5.6 and 13.5
Hz, CH2ꢀPh), 1.16 (m, 1H, J=6.7 and 8.5 Hz,
CH(CH3)2), 0.94 (d, 3H, J=6.7 Hz, CH3), 0.84 (d, 3H,
J=6.7 Hz, CH3); lC (62.5 MHz, CDCl3) 167.7, 161.1,
149.3, 146.8, 136.0, 134.8, 129.9, 128.7, 127.3, 127.1,
126.7, 120.1, 61.9, 57.5, 38.1, 35.1, 20.0, 19.0.
C21H21N3O2 requires: C, 72.60; H, 6.09; N, 12.09.
Found: C, 72.73; H, 6.04; N, 12.10%.
(d, 3H, J=7.0 Hz, CH3); lC (62.5 MHz, CDCl3) 168.2,
162.4 (d, J=247 Hz), 160.6, 149.6, 146.8, 134.8, 131.2
(d, J=8.0 Hz), 130.5 (d, J=3.3 Hz), 127.3, 127.1,
126.8, 119.9, 115.6 (d, J=21.3 Hz), 58.1, 56.8, 36.3,
29.7, 18.9, 14.8. C21H20FN3O2 requires: C, 69.03; H,
5.52; N, 11.50. Found: C, 68.98; H, 5.78; N, 11.35%.
4.11.2.10. (1S,4S)-4-(p-Fluorobenzyl)-1-isopropyl-2,4-
dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione
19e.
Compound 19e was obtained as an oil; yield 8%; lH
(250 MHz, CDCl3) 8.30 (dd, 1H, J=1.4 and 8.0 Hz,
H-7), 7.79 (ddd, 1H, J=1.4, 7.2 and 8.4 Hz, H-9), 7.65
(dd, 1H, J=1.1 and 8.4 Hz, H-10), 7.52 (ddd, 1H,
J=1.1, 7.2 and 8.0 Hz, H-8), 7.17 (m, 2H, Ar), 6.93 (m,
2H, Ar), 6.73 (d, 1H, J=3.7 Hz, N-H), 5.37 (dd, 1H,
J=4.5 and 6.9 Hz, H-4), 4.11 (dd, 1H, J=3.7 and 8.1
Hz, H-1), 3.44 (dd, 1H, J=4.5 and 13.9 Hz, CH2ꢀAr),
3.36 (dd, 1H, J=6.9 and 13.9 Hz, CH2ꢀAr), 1.54 (m,
1H, J=6.8 and 8.1 Hz, CH(CH3)2), 1.01 (d, 3H, J=6.8
Hz, CH3), 0.87 (d, 3H, J=6.8 Hz, CH3).
4.11.2.7. (1S,4R)-1-Isopropyl-4-(p-methylbenzyl)-2,4-
dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione
18d.
Mp: 75–77°C; yield 57%; [h]2D5=−340.0 (c 0.11; CHCl3);
wmax (NaCl) 3199, 3076, 2961, 2926, 1730, 1683, 1599,
1570 cm−1; lH (250 MHz, CDCl3) 8.33 (dd, 1H, J=1.4
and 8.1 Hz, H-7), 7.77 (ddd, 1H, J=1.4, 7.1 and 8.4
Hz, H-9), 7.61 (dd, 1H, J=1.1 and 8.4 Hz, H-10), 7.51
(ddd, 1H, J=1.1, 7.1 and 8.1 Hz, H-8), 6.96 (d, 2H,
J=7.9 Hz, H-3% and H-5%), 6.78 (d, 2H, J=7.9 Hz, H-2%
and H-6%), 5.99 (s, 1H, N-H), 5.61 (t, 1H, J=4.2 Hz,
H-4), 3.42 (dd, 1H, J=4.2 and 13.7 Hz, CH2ꢀAr), 3.40
(dd, 1H, J=4.3 and 13.7 Hz, CH2ꢀAr), 2.76 (m, 1H,
J=2.4 and 7.0 Hz, CH(CH3)2), 2.72 (d, 1H, J=2.4 Hz,
H-1), 2.27 (s, 3H, ArCH3), 0.86 (d, 3H, J=7.0 Hz,
CH3), 0.69 (d, 3H, J=7.0 Hz, CH3); lC (62.5 MHz,
CDCl3) 168.6, 160.9, 150.1, 147.1, 137.4, 134.9, 131.8,
129.8, 129.5, 127.4, 127.2, 127.0, 120.1, 58.0, 57.3, 36.9,
29.6, 21.2, 19.1, 15.0. C22H23N3O2 requires: C, 73.11; H,
6.41; N, 11.63. Found: C, 72.84; H, 6.34; N, 11.57%.
4.11.2.11.
(1S,4R)-4-(N-Boc-3-indolylmethyl)-1-iso-
propyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-
dione 18f. Compound 18f was isolated (EtOAc:toluene,
1:1) as an oil; yield 31%; [h]2D5=−241.4 (c 0.62;
methanol); wmax (NaCl) 1734, 1685, 1601 cm−1; lH (250
MHz, CDCl3) 8.36 (dd, 1H, J=1.5 and 8.0 Hz, H-7),
8.07 (dd, 1H, J=0.8 and 8.3 Hz, H-7%), 7.78 (ddd, 1H,
J=1.5, 7.1 and 8.4 Hz, H-9), 7.57 (dd, 1H, J=1.0 and
8.4 Hz, H-10), 7.54 (ddd, 1H, J=1.0, 7.1 and 8.0 Hz,
H-8), 7.41 (dd, 1H, J=0.8 and 8.0 Hz, H-4%), 7.24 (dt,
1H, J=0.8 and 8.0 Hz, H-6%), 7.01 (dt, 1H, J=0.8 and
8.0 Hz, H-5%), 6.96 (s, 1H, H-2%), 6.19 (s, 1H, N-H), 5.67
(‘t’, 1H, J=5.4 Hz, H-4), 3.63 (dd, 1H, J=5.4 and 14.9
Hz, CH2ꢀAr), 3.57 (dd, 1H, J=5.4 and 14.9 Hz,
CH2ꢀAr), 3.20 (d, 1H, J=2.2 Hz, H-1), 2.73 (m, 1H,
J=2.2 and 6.9 Hz, CH(CH3)2), 1.49 (s, 9H, 3CH3), 0.79
(d, 3H, J=7.2 Hz, CH3), 0.69 (d, 3H, J=6.7 Hz, CH3);
lC (62.5 MHz, CDCl3) 168.8, 160.8, 149.7, 149.1, 146.9,
135.2, 134.6, 129.7, 127.1, 127.0, 126.7, 124.9, 124.7,
122.7, 120.0, 118.7, 115.0, 113.8, 86.3, 58.3, 56.0, 29.9,
27.9, 26.8, 18.8, 14.7. C28H30N4O4 requires: C, 69.05; H,
6.16; N, 11.50. Found: C, 69.45; H, 6.02; N, 11.24%.
4.11.2.8. (1S,4S)-1-Isopropyl-4-(p-methylbenzyl)-2,4-
dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione
19d.
Compound 19d was isolated as an oil; yield 10%;
[h]2D5=+161.7 (c 0.06; CHCl3); wmax (NaCl) 3208, 3064,
2958, 2928, 1682, 1597, 1472 cm−1; lH (250 MHz,
CDCl3) 8.31 (dd, 1H, J=1.4 and 8.1 Hz, H-7), 7.77
(ddd, 1H, J=1.4, 7.1 and 8.4 Hz, H-9), 7.63 (dd, 1H,
J=1.2 and 8.4 Hz, H-10), 7.51 (ddd, 1H, J=1.2, 7.1
and 8.1 Hz, H-8), 7.03 (m, 4H, Ar), 6.88 (d, 1H, J=3.8
Hz, N-H), 5.34 (dd, 1H, J=4.9 and 6.3 Hz, H-4), 4.03
(dd, 1H, J=3.8 and 8.5 Hz, H-1), 3.45 (dd, H, J=4.9
and 14.0 Hz, CH2ꢀAr), 3.38 (dd, H, J=6.3 and 14.0
Hz, CH2ꢀAr), 2.26 (s, 3H, ArCH3), 1.23 (m, 1H, J=6.6
Hz, CH(CH3)2), 0.94 (d, 3H, J=6.6 Hz, CH3), 0.83 (d,
3H, J=6.6 Hz, CH3); lC (62.5 MHz, CDCl3) 167.2,
161.0, 149.2, 146.7, 136.9, 134.7, 132.8, 129.6, 129.2,
127.0, 126.7, 120.1, 61.9, 57.6, 37.6, 34.8, 21.0, 19.8,
18.8. C22H23N3O2 requires: C, 73.11; H, 6.41; N, 11.63.
Found: C, 73.04; H, 6.39; N, 11.47%.
4.11.2.12.
(1S,4S)-4-(N-Boc-3-indolylmethyl)-1-iso-
propyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-
dione 19f. Compound 19f was isolated (EtOAc:toluene,
1:1) as an oil; yield 46%; [h]2D5=+173.5 (c 0.62;
methanol); wmax (NaCl) 3344 1735, 1684, 1595 cm−1; lH
(250 MHz, CDCl3) 8.33 (dd, 1H, J=1.5 and 8.0 Hz,
H-7), 8.05 (dd, 1H, J=0.8 and 8.2 Hz, H-7%), 7.78 (ddd,
1H, J=1.5, 7.2 and 8.4 Hz, H-9), 7.62 (dd, 1H, J=1.1
and 8.4 Hz, H-10), 7.60 (d, 1H, J=3.7 Hz, N-H), 7.51
(ddd, 1H, J=1.1, 7.2 and 8.0 Hz, H-8), 7.30 (s, 1H,
H-2%), 7.23 (dt, 1H, J=0.8 and 8.0 Hz, H6%), 7.12 (dt,
1H, J=0.8 and 8.2 Hz, H-5%), 5.50 (dd, 1H, J=4.2 and
7.4 Hz, H-4), 4.02 (dd, 1H, J=3.7 and 8.3 Hz, H-1),
3.61 (dd, 1H, J=4.2 and 14.5 Hz, CH2ꢀAr), 3.51 (dd,
1H, J=4.2 and 14.5 Hz, CH2ꢀAr), 1.55 (s, 9H, 3CH3),
1.45 (m, 1H, J=6.7 and 8.3 Hz, CH(CH3)2), 0.89 (d,
3H, J=6.7 Hz, CH3), 0.68 (d, 3H, J=6.7 Hz, CH3); lC
(62.5 MHz, CDCl3) 167.6, 161.1, 149.3, 149.1, 146.7,
135.1, 134.7, 130.4, 127.0, 126.6, 124.5, 122.7, 120.0,
4.11.2.9. (1S,4R)-4-(p-Fluorobenzyl)-1-isopropyl-2,4-
dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione
18e.
Mp: 188–190°C; yield 48%; [h]2D5=−478.3 (c 0.06;
CHCl3); wmax (NaCl) 3200, 2967, 2921, 2857, 1684,
1601, 1508 cm−1; lH (250 MHz, CDCl3) 8.31 (dd, 1H,
J=1.3 and 8.1 Hz, H-7), 7.78 (ddd, 1H, J=1.3, 7.1 and
8.3 Hz, H-9), 7.61 (dd, 1H, J=1.1 and 8.3 Hz, H-10),
7.51 (ddd, 1H, J=1.1, 7.1 and 8.1 Hz, H-8), 6.85 (m,
4H, Ar), 6.33 (s, 1H, N-H), 5.61 (dd, 1H, J=4.3 and
4.6 Hz, H-4), 3.45 (dd, 1H, J=4.6 and 14.6 Hz,
CH2ꢀAr), 3.39 (dd, 1H, J=4.3 and 14.6 Hz, CH2ꢀAr),
2.96 (d, 1H, J=2.3 Hz, H-1), 2.81 (m, 1H, J=2.3 and
7.0 Hz, CH(CH3)2), 0.93 (d, 3H, J=7.0 Hz, CH3), 0.71