Chemistry of Heterocyclic Compounds 2020, 56(5), 572–577
(174 mg, 0.810 mmol, 1.20 equiv), Pd2(dba)3 (7.9 mg,
in DMF (150 ml), and the resulting slurry was stirred for
15 min at room temperature, then L-Pro-OMe·HCl (9.91 g,
59.821 mmol, 2.00 equiv) was added and stirring was
continued for 16 h. The volatiles were removed in vacuo,
and brine and CH2Cl2 were added to the residue. The
organic phase was separated, and the H2O phase was
extracted with CH2Cl2 (2×100 ml). The combined organic
phase was dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo. THF–H2O–HCl (50:350:1 ml)
solution was added to the obtained material, and the
resulting mixture was stirred overnight at room temperature
and then evaporated. The residue was purified by flash
column chromatography (eluent petroleum ether – EtOAc,
gradient from 9:1 to 0:1), then reversed-phase column
chromatography (eluent H2O–MeOH, gradient from 90:10
to 5:95). Yield 6.33 g (86%), light-yellow solid, mp 164–
167°C, [α]D20 426.50° (c 1.0, MeOH). IR spectrum, ν, cm–1:
1694, 1622, 1440, 850. 1H NMR spectrum, δ, ppm (J, Hz):
8.21 (1H, br. s, NH); 7.96 (1H, d, J = 8.8, H Ar); 6.81 (1H,
dd, J = 8.8, J = 2.4, H Ar); 6.46 (1H, d, J = 2.4, H Ar); 4.11–
4.05 (1H, m, CH); 3.84 (3H, s, OCH3); 3.82–3.73 (1H, m,
CH2); 3.66–3.54 (1H, m, CH2); 2.80–2.67 (1H, m, CH2);
2.10–1.95 (3H, m, CH2). 13C NMR spectrum, δ, ppm:
172.5; 167.8; 164.6; 139.5; 133.2; 120.4; 112.5; 106.4;
58.4; 56.1; 48.3; 27.1; 24.5. Found, m/z: 247.1084 [M+H]+.
C13H15N2O3. Calculated, m/z: 247.1083.
0.034 mmol, 0.05 equiv), Xantphos (58 mg, 0.101 mmol,
0.15 equiv), and Cs2CO3 (308 mg, 0.945 mmol, 1.40 equiv)
were placed in a pressure tube, evacuated and backfilled
with Ar twice, then dioxane (2 ml) was added. The resulting
mixture was stirred overnight at 100°C, then cooled to
room temperature. CH2Cl2 was added, and the mixture was
filtered through syringe filter, filtrate was evaporated, and
the residue was purified by flash column chromatography
(eluent petroleum ether – EtOAc, gradient from 9:1 to 3:7).
Yield 149 mg (55%), white solid, mp 165–168°C,
[α]D20 –140.20° (c 0.1, CHCl3). IR spectrum, ν, cm–1: 1739,
1
1699, 1596, 1515, 1387. H NMR spectrum (rotamers),
δ, ppm (J, Hz): 12.22 (1H, s, NH); 10.76 (1H, s, COH);
8.75 (1H, d, J = 7.8, H Ar), 7.86–7.72 (1H, m, H Ar); 6.25
(1H, s, H Ar); 4.49–4.25 (1H, m, CH); 3.87–3.73 (1H, m,
CH2), 3.70–3.47 (1H, m, CH2); 2.45 (3H, s, CH3); 2.39–
2.22 (1H, m, CH2); 2.20–2.07 (1H, m, CH2); 2.02–1.88
(2H, m, CH2); 1.48 and 1.31 (9H, both s, C(CH3)3).
13C NMR spectrum (rotamers), δ, ppm: 191.8; 173.9;
173.5; 159.0; 156.8; 155.2; 154.1; 152.5; 143.8; 132.4;
132.2; 115.6; 115.3; 114.8; 113.4; 109.0; 80.8; 62.8; 62.4; 47.4;
47.0; 31.7; 31.0; 30.8; 28.4; 24.6; 24.0; 19.1. Found, m/z:
423.1522 [M+Na]+. C21H24NaN2O6. Calculated, m/z:
423.1532.
7-({[(2S)-1-(tert-Butoxycarbonyl)pyrrolidin-2-yl]-
carbonyl}amino)-4-methyl-2-oxo-2H-chromene-8-carb-
oxylic acid (15). 2-Methyl-2-butene (1.3 ml), followed by
solution of NaH2PO4·2H2O (195 mg, 1.249 mmol, 5.00 equiv)
in H2O (2.7 ml), and solution of NaClO2 (80% purity,
110 mg, 0.974 mmol, 3.90 equiv) in H2O (0.7 ml) was
added to a solution of compound 14 (100 mg, 0.250 mmol,
1.00 equiv) in t-BuOH (2.7 ml) and THF (2.7 ml). The
resulting mixture was stirred for 2 h at room temperature,
then diluted with saturated aqueous Na2S2O3, acidified with
10% HCl, and extracted with EtOAc (3×20 ml). The
organic phase was washed with H2O and dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by reversed-phase flash column
chromatography, eluent (H2O + 0.1% AcOH)–MeOH.
(11aS)-8-Hydroxy-2,3-dihydro-1H-pyrrolo[2,1-c][1,4]-
benzodiazepine-5,11(10H,11aH)-dione (18). BBr3 (1 M in
CH2Cl2, 50.8 ml, 50.758 mmol, 5.00 equiv) was added
dropwise to a solution of compound 17 (2.50 g, 10.152 mmol,
1.00 equiv) in CH2Cl2 (150 ml) at 0°C. The resulting
mixture was allowed to warm up to room temperature and
stirred overnight, then cooled with an ice-water bath and
additional BBr3 (1 M in CH2Cl2, 101.5 ml, 101.516 mmol,
10 equiv) was added dropwise. After stirring overnight at
room temperature, the reaction mixture was cooled to 0°C
and cold H2O was carefully added, followed by CH2Cl2.
CH2Cl2 layer was separated and extracted with H2O
(2×100 ml). The combined H2O layer was evaporated and
purified by reversed-phase column chromatography (eluent
H2O–MeOH, gradient from 90:10 to 5:95). Yield 1.70 g
20
Yield 76 mg (73%), colorless wax, [α]D –143.50° (c 0.2,
20
CHCl3). IR spectrum, ν, cm–1: 1703, 1596, 1519, 1396.
1H NMR spectrum (rotamers), δ, ppm: 11.52 and 11.35
(1H, both s, NH); 8.81–8.67 (1H, m, H Ar); 8.31 (1H, br. s,
COOH); 7.80–7.67 (1H, m, H Ar); 6.30 (1H, s, H Ar); 4.49–
4.25 (1H, m, CH); 3.72 (1H, br. s, CH2); 3.65–3.42 (1H, m,
CH2); 2.48 (3H, s, CH3); 2.38–2.11 (2H, m, CH2); 2.05–
1.87 (2H, m, CH2); 1.49 and 1.34 (9H, both s, C(CH3)3).
13C NMR spectrum (rotamers), δ, ppm: 173.0; 167.7;
161.0; 155.3; 154.4; 154.0; 153.6; 153.1; 144.2; 143.6;
129.3; 117.0; 116.5; 115.7; 115.4; 113.0; 112.6; 106.9;
106.3; 81.0; 62.9; 62.3; 47.3; 47.0; 31.6; 30.6; 28.4; 24.6;
24.0; 19.3. Found, m/z: 439.1485 [M+Na]+. C21H24NaN2O7.
Calculated, m/z: 439.1481.
(72%), white solid, mp 239–242°C, [α]D 443.00° (c 0.1,
MeOH). IR spectrum, ν, cm–1: 1681, 1600, 1439, 746.
1H NMR spectrum, δ, ppm (J, Hz): 7.73 (1H, d, J = 8.7,
H Ar); 6.70 (1H, dd, J = 8.7, J = 2.4, H Ar); 6.51 (1H, d,
J = 2.4, H Ar); 4.18–4.12 (1H, m, CH); 3.76–3.65 (1H, m,
CH2); 3.60–3.49 (1H, m, CH2); 2.70–2.61 (1H, m, CH2);
2.12–1.89 (3H, m, CH2). 13C NMR spectrum, δ, ppm:
172.5; 168.0; 162.9; 139.6; 133.3; 119.3; 113.6; 108.0;
58.4; 48.2; 27.0; 24.6. Found, m/z: 233.0931 [M+H]+.
C12H13N2O3. Calculated, m/z: 233.0926.
(11aS)-12-{[2-(Trimethylsilyl)ethoxy]methyl}-8,9,10,10a-
tetrahydro-2H,6H-chromeno[7,6-e]pyrrolo[1,2-a][1,4]-
diazepine-2,6,11(12H)-trione (21). A mixture of compound
18 (1.60 g, 6.900 mmol, 1.00 equiv), 2-hydroxysuccinic
acid (1.85 g, 13.779 mmol, 2.00 equiv), and H2SO4 (2.9 ml)
was stirred for 30 min at room temperature and then
overnight at 120°C. After cooling to room temperature, ice
water was added and the resulting mixture was stirred for
(11aS)-8-Methoxy-2,3-dihydro-1H-pyrrolo[2,1-c][1,4]-
benzodiazepine-5,11(10H,11aH)-dione (17). Et3N (42.0 ml,
299.107 mmol, 10.00 equiv) was added to a stirred solution
of 4-methoxyanthranilic acid (16) (5.00 g, 29.911 mmol,
1.00 equiv) and HBTU (17.01 g, 44.866 mmol, 1.5 equiv)
576