Molecules 2019, 24, 3938
9 of 13
2
4
.00–2.11 (4H, m, H-10, H-14), 2.12–2.21 (4H, m, H-11, H-13), 3.71 (1H, m, H-9), 3.99 (3H, s, 6-OMe),
.03 (3H, s, 7-OMe), 7.28 (1H, s, H-5), 7.52 (1H, d, J = 5.7 Hz, H-4), 7.54 (1H, s, H-8), 8.19 (1H, d, J = 5.7
13
3
2
Hz, H-3); C NMR (200 MHz, CD OD)
δ
C
29.6 (2C, d, J = 10.3 Hz, C-10, C-14), 34.8 (2C, dd, J
=
CF
3
CF
2
5.5, 22.6 Hz, C-11, C-13), 40.2 (C-9), 56.46 (6-OMe), 56.54 (7-OMe), 104.2 (C-8), 106.9 (C-5), 119.9 (C-4),
1
1
1
23.3 (C-8a), 124.5 (dd, J = 242.0, 239.2 Hz, C-12), 135.2 (C-4a), 140.9 (C-3), 152.0 (C-7), 154.5 (C-6),
CF
62.3 (C-1); (+)-LRESIMS m/z (rel. int.) 308 (100) [M + H] ; (+)-HRESIMS m/z 308.1454 [M + H] (calcd
+
+
for C H F NO , 308.1457).
17
20
2
2
3
.3. Generation of the Papaverine Library (TFA-Addition Method): Compounds 6–8 and 10
Papaverine hydrochloride (1a, 37.5 mg, 0.1 mmol) was dissolved in CH Cl /H O or DMSO/H O
2
2
2
2
(
µ
2.5:1, 100
µ
L:40
µ
L) before the addition of the sulfinate reagent (85.6–198.9 mg, 0.6 mmol) and TFA (7.7
◦
L, 0.1 mmol) at room temperature. The mixture was cooled to 0 C before TBHP (40
µL, 0.6 mmol)
was slowly added, after which time, the stirred mixture slowly warmed to room temperature over 16 h.
Crude reaction products was dried under N and pre-adsorbed to NH -bonded silica ( 1 g) overnight
before being subjected to identical NH semi-preparative HPLC conditions, which are described above.
≈
2
2
2
This method generated compound
6 using the CH Cl /H O solvent system, while compounds 7, 8,
2 2 2
and 10 were generated using the DMSO/H O mixture.
2
3
.3.1. Compound 6
Colorless gum (1.0 mg, 3%); UV (MeOH) λmax (log ε) 240 (4.15), 273 (3.36), 327 (3.08) nm; IR (UATR)
−1 1
νmax 3458, 2981, 1747, 1705, 1278, 1199, 1165, 1078, 1026, 975, 712 cm ; H NMR (800 MHz, CD OD)
3
δ
3.72 (3H, s, 12-OMe), 3.76 (3H, s, 13-OMe), 3.87 (3H, s, 7-OMe), 3.98 (3H, s, 6-OMe), 4.57 (2H, s,
H
H-9), 6.78 (1H, dd, J = 8.3, 2.0 Hz, H-15), 6.83 (1H, d, J = 8.3 Hz, H-14), 6.84 (1H, t, J = 55.7 Hz, H-16),
.93 (1H, d, J = 2.0 Hz, H-11), 7.37 (1H, s, H-5), 7.48 (1H, s, H-8), 7.88 (1H, s, H-4); 1 C NMR (200 MHz,
3
6
CD OD) δ 42.0 (C-9), 56.4 (12-OMe), 56.45 (13-OMe), 56.49 (7-OMe), 56.6 (6-OMe), 107.4 (C-5), 105.8
3
C
1
3
(
(
1
C-8), 113.2 (C-14), 113.6 (C-11), 115.6 (t, J = 238.0 Hz, C-16), 117.4 (t, J = 4.8 Hz, C-4), 121.9
CF CF
C-15), 125.0 (C-8a), 133.4 (C-10), 135.0 (C-4a), 144.9 (t, J = 24.3 Hz, C-3), 149.2 (C-13), 150.6 (C-12),
52.6 (C-7), 154.9 (C-6), 160.1 (C-1); (+)-LRESIMS m/z (rel. int.) 390 (100) [M + H] ; (+)-HRESIMS m/z
90.1506 [M + H] (calcd for C H F NO , 390.1511).
2
CF
+
+
3
21
22
2
4
3
.3.2. Compound 7
Colorless gum (1.5 mg, 4%); UV (MeOH) λmax (log
νmax 3413, 2986, 1756, 1718, 1279, 1198, 1170, 1078, 1025, 973, 712 cm
.22 (1H, sept, J = 6.9 Hz, H-16), 3.72 (3H, s, 12-OMe), 3.76 (3H, s, 13-OMe), 3.84 (1H, s, 7-OMe), 3.96 (3H,
ε
) 239 (3.72), 276 (3.00), 328 (2.83) nm; IR (UATR)
−
1
;
δ 1.40 (6H, d, J = 6.9 Hz, H-17),
H
3
s, 6-OMe), 4.53 (1H, s, H-9), 6.78 (1H, dd, J = 8.5, 2.2 Hz, H-15), 6.83 (1H, d, J = 8.5 Hz, H-14), 6.91 (1H,
d, J = 2.2 Hz, H-11), 7.21 (1H, s, H-5), 7.44 (1H, s, H-4), 7.37 (1H, s, H-8); 13C NMR (200 MHz, CD OD)
3
δ
23.2 (2C, C-17), 36.6 (C-16), 41.7 (C-9), 56.31 (6-OMe), 56.33 (7-OMe), 56.4 (12-OMe), 56.5 (13-OMe),
C
1
1
05.4 (C-8), 106.5 (C-5), 113.1 (C-14), 113.4 (C-11), 115.3 (C-4), 121.8 (C-15), 123.0 (C-8a), 133.7 (C-10),
36.2 (C-4a), 149.0 (C-13), 159.3 (C-3), 151.0 (C-12), 151.8 (C-7), 154.4 (C-6), 158.7 (C-1); (+)-LRESIMS m/z
+
+
(rel. int.) 382 (100) [M + H] ; (+)-HRESIMS m/z 382.2024 [M + H] (calcd for C H NO , 382.2013).
23 28 4
3
.3.3. Compound 8
Colorless gum (1.3 mg, 4%); UV (MeOH) λmax (log ε) 241 (3.90), 326 (2.94) nm; IR (UATR) νmax
−
456, 2981, 1745, 1705, 1279, 1199, 1167, 1079, 1026, 978, 712 cm ; H NMR (800 MHz, CD OD) δ 3.72
3 H
1 1
3
(
7
3H, s, 13-OMe), 3.84 (3H, s, 7-OMe), 3.96 (3H, s, 6-OMe), 4.52 (2H, s, H-9), 7.15 (2H, m, H-11, H-15),
.26 (1H, s, H-5), 7.39 (1H, s, H-8), 6.81 (2H, m, H-12, H-14), 7.58 (1H, d, J = 5.7 Hz, H-4), 8.20 (1H, d, J
5.7 Hz, H-3); 13C NMR (200 MHz, CD OD)
41.6 (C-9), 55.6 (13-OMe), 56.3 (7-OMe), 56.5 (6-OMe),
=
δ
C
3
105.6 (C-8), 106.6 (C-5), 120.5 (C-4), 124.2 (C-8a), 130.4 (2C, C-11, C-15), 115.0 (2C, C-12, C-14), 135.5
(
C-4a), 132.7 (C-10), 140.5 (C-3), 151.7 (C-7), 154.6 (C-6), 159.7 (C-1), 159.3 (C-13); (+)-LRESIMS m/z (rel.
+
+
int.) 310 (100) [M + H] ; (+)-HRESIMS m/z 310.1436 [M + H] (calcd for C H NO , 310.1438).
19
20
3