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271
(dd, J ¼ 7.4, 1.3 Hz, 1H, H-7), 9.08 (s, 1H, OH); 13C NMR: 16.1 (C-4),
26.9 (CH3), 31.2 (C-3), 81.9 (C-2),112.3 (C-4a),114.6 (C-10a),122.9 (C-
7), 126.1 (C-9), 131.0 (C-6a), 132.1 (C-8), 155.8 (C-10), 164.0 (C-10b),
165.7 (C-10b), 178.1 (C-5), 180.5 (C-6); IR (KBr): 2971, 2929, 2843,
1693,1634,1589,1552,1279 cm-1; HRMS-ESI m/z [M þ H]þ calcd for
C16H17O4: 273.1121, found: 273.1127.
178.4 (C-5), 179.3 (C-6); IR (KBr): 3351, 2978, 1646, 1602, 1394 cmꢀ1
;
HRMS-ESI m/z [M þ H]þ calcd for C15H15O4: 259.0965, found:
4.1.1.7. 3,4-Dihydro-8-methoxy-2,2-dimethyl-2H-benzo[g]chromene-
5,10-dione (8-methoxy-a-lapachone, 5a). Compound 5a (2.8 mg,
259.0972.
25%) was obtained as yellow crystals from 7-methoxylapachol (5)
(11 mg, 0.04 mmol) following the general procedure for cyclization
reactions with methanesulfonic acid (Table 1, entry 18): Rf ¼ 0.53
(hexanes/EtOAc, 7:3); mp: 155e156 ꢁC; 1H NMR: 1.43 (s, 6H, CH3),
1.81 (t, J ¼ 6.6 Hz, 2H, H-3), 2.60 (t, J ¼ 6.6 Hz, 2H, H-4), 3.93 (s, 3H,
CH3O), 7.15 (dd, J ¼ 8.6, 2.7 Hz, 1H, H-7), 7.52 (d, J ¼ 2.7 Hz, 1H, H-9),
8.00 (d, J ¼ 8.6 Hz,1H, H-6); 13C NMR: 16.7 (C-4), 26.5 (CH3), 31.4 (C-
3), 55.9 (CH3O), 77.9 (C-2), 109.9 (C-9), 120.0 (C-4a), 120.0 (C-7),
125.5 (C-5a), 128.3 (C-6), 133.0 (C-9a), 154.3 (C-10a), 163.4 (C-8),
4.1.1.3. 3,4-Dihydro-9-hydroxy-2,2-dimethyl-2H-benzo[g]chromene-
5,10-dione (9-hydroxy-a-lapachone, 3a). Compound 3a (94.8 mg,
46%) was obtained as yellow needles from 8-hydroxylapachol (3)
(20 mg, 0.08 mmol) following the general procedure for cyclization
reactions with methanesulfonic acid (Table 1, entry 10): Rf ¼ 0.45
(hexanes/EtOAc, 8:2); mp: 115e116 ꢁC (from methanol) (lit. [47]
114.5e115 ꢁC); 1H NMR: 1.44 (s, 6H, CH3), 1.82 (t, J ¼ 6.6 Hz, 2H,
H-3), 2.61 (t, J ¼ 6.6 Hz, 2H, H-4), 7.19 (dd, J ¼ 8.2, 1.4 Hz, 1H, H-8),
7.58 (td, J ¼ 7.5, 0.5 Hz, 1H, H-7), 7.62 (dd, J ¼ 7.4, 1.4 Hz, 1H, H-6),
11.85 (d, J ¼ 0.4 Hz, 1H, OH); 13C NMR: 16.8 (C-4), 26.5 (CH3), 31.3
(C-3), 78.4 (C-2), 114.2 (C-9a), 118.7 (C-6), 121.1 (C-4a), 123.5 (C-8),
132.1 (C-5a),136.6 (C-7),154.1 (C-10a),161.6 (C-9),183.5 (C-5),184.9
(C-10); IR (KBr): 2971, 2931, 1638, 1610 cmꢀ1; HRMS-ESI m/z
[M þ H]þ calcd for C15H15O4: 259.0965, found: 259.0957.
180.0 (C-10), 183.8 (C-5); IR (KBr): 2966, 1673, 1597, 1335 cmꢀ1
;
HRMS-ESI m/z [M þ H]þ calcd for C16H17O4: 273.1121, found:
273.1122.
4.1.1.8. 3,4-Dihydro-8-methoxy-2,2-dimethyl-2H-benzo[h]chromene-
5,6-dione (8-methoxy-b-lapachone, 5b). Compound 5b (8.4 mg, 62%)
was obtained as red crystals from 7-methoxylapachol (5) (13 mg,
0.05 mmol) as described in the general procedure for cyclization
reactions using methanesulfonic acid (Table 1, entry 18): Rf ¼ 0.29
(hexanes/EtOAc, 7:3); mp: 166e167 ꢁC (lit. [24] 162e163 ꢁC); 1H
NMR: 1.46 (s, 6H, CH3),1.84 (t, J ¼ 6.7 Hz, 2H, H-3), 2.54 (t, J ¼ 6.7 Hz,
2H, H-4), 3.90 (s, 3H, CH3O), 7.12 (dd, J ¼ 8.6, 2.8 Hz, 1H, H-9), 7.55
(d, J ¼ 2.8 Hz, 1H, H-7), 7.72 (d, J ¼ 8.5 Hz, 1H, H-10); 13C NMR: 16.0
(C-4), 26.8 (CH3), 31.7 (C-3), 55.8 (CH3O), 79.2 (C-2), 110.6 (C-4a),
112.5 (C-7), 121.0 (C-9), 125.4 (C-10a), 125.9 (C-10), 131.7 (C-6a),
161.6 (C-8), 162.8 (C-10b), 178.2 (C-5), 179.9 (C-6); IR (KBr): 2975,
2935,1693,1634,1601,1594 cmꢀ1; HRMS-ESI m/z [M þ H]þ calcd for
C16H17O4: 273.1121, found: 273.1118.
4.1.1.4. 3,4-Dihydro-7-hydroxy-2,2-dimethyl-2H-benzo[h]chromene-
5,6-dione (7-hydroxy-b-lapachone, 3b). Compound 3b (9.6 mg, 93%)
was obtained as reddish orange needles from 8-hydroxylapachol
(3) (10 mg, y 0.04 mmol) following the general procedure for
cyclization reactions with methanesulfonic acid (Table 1, entries
9e10):Rf ¼ 0.37 (Hexane/EtOAc 7:3); mp: 183e184 ꢁC (from
methanol) (lit. [26] 184ꢀ185 ꢁC from methanol); 1H NMR: 1.45 (s,
6H, CH3), 1.84 (t, J ¼ 6.7 Hz, 2H, H-3), 2.55 (t, J ¼ 6.7 Hz, 2H, H-4),
7.05 (dd, J ¼ 8.6, 1.0 Hz, 1H, H-8), 7.35 (dd, J ¼ 7.5, 1.0 Hz, 1H, H-10),
7.53 (ddd, J ¼ 8.5, 7.5, 0.3 Hz, 1H, H-9), 11.98 (s, 1H, OH); 13C NMR:
16.2 (C-4), 26.7 (CH3), 31.5 (C-3), 79.2 (C-2), 112.7 (C-4a), 113.6 (C-
6a), 116.8 (C-10), 121.4 (C-8), 132.4 (C-10a), 137.9 (C-9), 161.5 (C-
10b), 164.3 (C-7), 178.1 (C-5), 183.2 (C-6); IR (KBr): 2969, 1653, 1636,
1585, 1570 cmꢀ1; HRMS-ESI m/z [M þ H]þ calcd for C15H15O4:
259.0965, found: 259.0970; Anal. calcd for C15H14O4: C 69.76, H
5.46, found: C 69.59, H 5.06.
4.1.2. Synthesis of lapachol analogs
4.1.2.1. 2-Hydroxy-5-methoxynaphthalene-1,4-dione (2-hydroxy-5-
methoxy-1,4 naphthoquinone, 8). Compound 8 was obtained as
orange crystals (64% yield) from 5-methoxytetralone (6) following
the procedure described by W. Steglich [48]; mp: 176e177 ꢁC (lit.
[49] 176e177 ꢁC); 1H NMR (500.13 MHz, DMSO-d6): 3.92 (s, 3H,
OCH3), 6.05 (s, 1H, H-3), 7.57 (dd, J ¼ 8.5, 0.9 Hz, 1H, H-8), 7.66 (dd,
J ¼ 7.6, 1.1 Hz, 1H, H-6), 7.77 (dd, J ¼ 8.4, 7.6 Hz, 1H, H-7); 13C NMR
(125.77 MHz, DMSO-d6) 57.2 (CH3O), 114.2 (C-3), 119.5 (C-6), 119.7
(C-4a), 120.7 (C-8), 133.7 (C-8a), 135.2 (C-7), 158.0 (C-2), 159.8 (C-5),
182.6 (C-4),185.1 (C-1); HRMS (ESI): calcd for m/z C11H9O4 [M þ H]þ
205.0495; found 205.0494.
4.1.1.5. 3,4-Dihydro-6-methoxy-2,2-dimethyl-2H-benzo[g]chromene-
5,10-dione (6-methoxy-a-lapachone, 4a). Compound 4a (11 mg,
100%) was obtained as yellow crystals from 5-methoxylapachol (4)
(11 mg, 0.04 mmol) following the general procedure for cyclization
reactions with sulfuric acid (Table 1, entry 11): Rf ¼ 0.63 (CH2Cl2/
MeOH, 4:0.1); mp: 145e146 ꢁC; 1H NMR: 1.41 (s, 6H, CH3), 1.79 (t,
J ¼ 6.6 Hz, 2H, H-3), 2.59 (t, J ¼ 6.6 Hz, 2H, H-4), 3.99 (s, 3H, CH3O),
7.27 (dd, J ¼ 8.5, 0.9 Hz, 1H, H-7), 7.60 (dd, J ¼ 8.4, 7.6 Hz, 1H, H-8),
7.77 (dd, J ¼ 7.6, 1.1 Hz, 1H, H-9); 13C NMR: 16.9 (C-4), 26.4 (CH3),
31.6 (C-3), 56.5 (CH3O), 77.5 (C-2), 118.2 (C-7), 119.3 (C-9), 119.5 (C-
5a), 121.9 (C-4a), 133.4 (C-9a),133.8 (C-8), 152.8 (C-10a),159.2 (C-6),
180.2 (C-10), 184.1 (C-5); IR (KBr): 3002, 2981, 2928, 2837, 1668,
1640, 1625, 1582, 1276 cmꢀ1; HRMS-ESI m/z [M þ H]þ calcd for
C16H17O4: 273.1121, found: 273.1129.
4.1.2.2. 2-Hydroxy-7-methoxynaphthalene-1,4-dione (2-hydroxy-7-
methoxy-1,4-naphthoquinone, 9). Compound 9 was obtained as
red crystals (90% yield) from 7-methoxytetralone (7), following the
general procedure described by Thomson and Baillie [21]; mp:
216e217 ꢁC (lit. [50] 216 ꢁC); 1H NMR (200.13 MHz, DMSO-d6): 3.95
(s, 3H, OCH3), 6.12 (s,1H, H-3), 7.37 (dd, J ¼ 8.4, 2.6 Hz,1H, H-6), 7.44
(d, J ¼ 2.6 Hz, 1H, H-8), 7.91 (d, J ¼ 8.4 Hz, 1H, H-5), 11.61 (s, 1H, OH);
13C NMR (50.32 MHz, DMSO-d6): 56.9 (CH3O), 110.9 (C-8), 111.8 (C-
3), 121.0 (C-6), 126.1 (C-4a), 128.8 (C-5), 133.3 (C-8a), 160.1 (C-2),
163.9 (C-7), 182.2 (C-1), 185.0 (C-4); HRMS (ESI): calcd for m/z
C11H8NaO4 [M þ Na]þ 227.0320; found 227.0322.
4.1.1.6. 3,4-Dihydro-10-methoxy-2,2-dimethyl-2H-benzo[h]chromene-
5,6-dione (10-methoxy-b-lapachone, 4b). Compound 4b (0.9 mg,
7.9%) was obtained as red crystals from 5-methoxylapachol (4)
(11 mg, 0.04 mmol) following the general procedure for cyclization
reactions with methanesulfonic acid (Table 1, entries 15e17):
1
Rf ¼ 0.50 (CH2Cl2/MeOH, 4:0.1); mp: 102e103 ꢁC; H NMR: 1.46 (s,
4.1.2.3. 2-Hydroxy-5-methoxy-3-(3-methylbut-2-enyl)naphthalene-
1,4-dione (5-methoxylapachol, 4). Compound 4 was obtained as
yellow crystals (26% yield) from 8 following the procedure previ-
ously described previously [17] for the synthesis of 5-
6H, CH3),1.83 (t, J ¼ 6.7 Hz, 2H, H-3), 2.57 (t, J ¼ 6.8 Hz, 2H, H-4), 3.90
(s, 3H, CH3O), 7.23 (dd, J ¼ 8.5, 1.2 Hz, 1H, H-9), 7.44 (dd, J ¼ 8.4,
7.5 Hz, 1H, H-8), 7.75 (dd, J ¼ 7.5, 1.2 Hz, 1H, H-7); 13C NMR: 16.5 (C-
4), 26.7 (CH3), 31.2 (C-3), 57.1 (CH3O), 79.0 (C-2), 112.1 (C-4a), 120.2
(C-10a),121.4 (C-9), 122.4 (C-7),131.7 (C-8),132.2 (C-6a), 157.9 (C-10),
hydroxylapachol (2). Rf
¼
0.46 (hexanes/EtOAc, 6:4); mp: