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E. Perez Sacau et al. / Bioorg. Med. Chem. 11 (2003) 483–488
487
12,13-Epoxy lapachol acetate (7). 32 mg (0.11 mmol) of
compound (2) was treatedwith 33.3 mg (1.2 equiv) of
MCPBA at 0 ꢂC for 26 h. The solvent was removed
under vacuum and the corresponding residue was puri-
fiedby Sephadex LH-20 column (CHCl 3/MeOH/hex-
under vacuum and the corresponding residue was puri-
fiedby flash chromatography (silica gel, 7:3, hexanes/
EtOAc) to yield12 mg (9%) of compound 10. 1H NMR
(CDCl3, 300 MHz) d: 8.15 (m, 2H), 7.49 (m, 2H), 6.80
(s, 1H), 5.73 (d, J=2.9 Hz, 1H), 4.39 (d, J=2.9 Hz,
1H), 3.92 (s, 3H), 1.80 (s, 3H), 1.47 (s, 3H). 13C NMR
(CDCl3, 75 MHz) d: 149.8 (s), 142.6 (s), 139.8 (s), 137.1
(s), 126.7 (s), 126.4 (d), 126.2 (d), 125.4 (s), 125.1 (s),
124.0 (s), 122.1 (d), 121.7 (d), 120.5 (s), 120.2 (s), 107.9
(s), 100.0 (d), 76.7 (s), 72.3 (d), 68.2 (d), 55.5 (q), 24.3
(q), 23.3 (q). EI HR-MS m/z 503.9880 [calcdfor
C22H18O5Cl4 (M+) 504.1912].
1
anes, 1:1:2) to yield20 mg (60%) of compound 7. H
NMR (CDCl3, 300 MHz) d: 8.10 (m, 2H), 7.74 (m, 2H),
2.90 (m, 2H), 2.75 (m, 1H), 2.39 (s, 3H), 1.39 (s, 3H),
1.28 (s, 3H). 13C NMR (CDCl3, 75 MHz) d: 184.4 (s),
177.9 (s), 167.8 (s), 152.5 (s), 135.6 (s), 134.2 (d), 134.0
(d), 131.9 (s), 130.9 (s), 126.8 (d), 126.7 (d), 61.9 (d),
59.0 (s), 24.5 (t), 24.5 (q), 20.5 (q), 18.9 (q). EI HR-MS
m/z 300.1025 [calcdfor C 17H16O5 (M+) 300.0998]. IR
(CHCl3) nmax 2958, 2930, 1778, 1680, 1639, 1597, 1451,
1424, 1379, 1340, 1333, 1305, 1174, 1153, 1090, 1055,
Preparation of compound 11. 57 mg of 1 in 10 mL of
NaOH solution (5%) were treatedwith 22 mg of
1014, 944, 861, 729 cmꢀ1
.
NH2OH HCl for 2 h. The reaction mixture was acidified
.
with AcOH, andthe resultant solidwas filteredto yield
54 mg of (9) (91%). 1H NMR (MeOD, 300 MHz) d 9.01
(d, J=7.5 Hz, 1H), 8.11 (d, J=7.2 Hz, 1H), 7.63 (m,
2H), 5.21 (m, 1H), 3.23 (d, J=7.0 Hz, 2H), 1.76 (s, 3H),
1.65 (s, 3H). 13C NMR (CDCl3, 75 MHz) d: 184.8 (s),
158.6 (s), 139.5 (s), 132.0 (d), 131.3 (s), 130.9 (s), 130.2
(d), 129.5 (d), 125.9 (d), 121.4 (d), 117.0 (s), 24.5 (t), 21.6
(q), 16.6 (q). EI HR-MS m/z 257.1052 [calcdfor
C15H15O3N (M+) 257.1037]. IR (CHCl3) nmax: 2922,
2852, 2360, 2341, 1809, 1723, 1616, 1591, 1378, 1292,
12,13-Dihydroxy lapachol acetate (8). 54 mg of com-
pound (7) were treatedwith 0.2 mL of dilutedHClO
4
(5%) in a mixture of THF/H2O at 0 ꢂC for 21 h. The
reaction was quenchedwith idlutedNaHCO
organic layer was separatedandthe aqueous phase was
3. The
extractedwith CH Cl2. The combinedorganic extracts
2
were washedwith brine anddriedover MgSO
4. After
solvent removal the residue was purified by flash chro-
matography (silica gel, 7:3, hexanes/EtOAc) to yield55
mg (96%) of compound (8). 1H NMR (CDCl3,
300 MHz) d: 8.09 (m, 2H), 7.73 (m, 2H), 3.56 (dd,
J=9.9 and 2.3 Hz, 1H), 2.83 (dd, J=13.0 and2.3 Hz,
1H), 2.69 (dd, J=13.0 and9.9 Hz, 1H), 2.39 (s, 3H),
1.29 (s, 3H), 1.27 (s, 3H). 13C NMR (CDCl3, 75 MHz) d:
185.4 (s), 177.8 (s), 168.4 (s), 152.2 (s), 137.3 (s), 134.2
(d), 134.0 (d), 131.9 (s), 130.8 (s), 126.8 (d), 126.7 (d),
72.9 (d), 29.1 (s), 27.3 (t), 25.9 (q), 24.0 (q), 20.4 (q). EI
HRMS m/z 318.1122 [calcdfor C 17H18O6 (M+)
318.1103]. IR (CHCl3) nmax 3521, 2977, 1776, 1675,
1639, 1595, 1371, 1340, 1297, 1176, 1072, 1014, 946,
1237, 1204, 951, 771 cmꢀ1
.
Preparation of compound 12. 32 mg of 11 in 3 mL of
CH2Cl2 at 0ꢂC were treatedwith 2 equiv of lutidine and
acetyl chloride (1.8 equiv) for 5 min. The crude was
treatedwith dilutedHCl, the organic layer was washed
with H2O andseparate.d The aqueous layer was
extractedseveral times with CH 2Cl2. The combined
organic extracts were washedwith brine anddriedover
MgSO4. After solvent removal the residue was purified
by chromatography on Sephadex LH-20 to yield 40 mg
of compound(12) (97%). 1H NMR (CDCl3, 300 MHz)
d: (d ,J=7.5 Hz, 1H), 8.26 (d, J=7.4 Hz, 1H), 7.67 (m,
2H), 5.08 (t, J=7.2 Hz, 1H), 3.25 (d, J=7.1 Hz, 2H),
2.38 (s, 6H), 1.75 (s, 3H), 1.66 (s, 3H). 13C NMR
(CDCl3, 75 MHz) d: 183.8 (s), 168.5 (s), 167.4 (s), 152.1
(s), 144.4 (s), 133.9 (s), 133.4 (s), 133.2 (d), 131.9 (d),
131.4 (s), 130.9 (d), 127.7 (d), 126.1 (s), 119.2 (d), 25.7
880, 756, 733 cmꢀ1
.
12-Bromo, 13-hydroxy lapachol acetate (9). 262 mg of
(2) were treatedwith 180 mg of NBS in 10 mL of
tBuOH/H2O 1:1. The reaction mixture was stirredfor 2
h, then the solvent was removedto half of its volume
andthe mixture of the reaction was extractedwith
ether. The combinedorganic extracts were washedwith
brine anddriedover MgSO 4. The product was purified
by flash chromatography (silica gel, 7:3, hexanes/
(q), 23.5 (t), 20.6 (q), 19.7 (q), 17.9 (q). IR (CHCl3) nmax
2915, 2360, 1778, 1633, 1591, 1371, 1290, 1177, 1005,
954, 928, 777 cmꢀ1
:
.
1
EtOAc) to yield330 mg (94 mg) of compound( 9). H
NMR (CDCl3, 300 MHz) d: 8.10 (m, 2H), 7.75 (m, 2H),
4.36 (dd, J=10.7, 3.3 Hz, 1H), 3.28 (dd, J=13.7, 3.3
Hz, 1H), 3.16 (dd, J=13.7, 10.8 Hz, 1H), 2.41 (s, 3H),
1.47 (s, 3H), 1.46 (s, 3H). 13C NMR (CDCl3, 75 MHz) d:
184.5 (s), 177.8 (s), 167.7 (s), 158.4 (s), 136.0 (s), 134.2
(d), 134.0 (d), 131.9 (s), 130.9 (s), 126.8 (d), 126.7 (d),
72.7 (s), 64.2 (d), 28.5 (t), 27.0 (q), 25.2 (q), 20.5 (q). EI
HR-MS m/z 380.0263 [calcdfor C 17H17O5Br (M+)
380.0259]. IR (CHCl3) nmax: 3525, 2980, 1778, 1678,
1640, 1595, 1460, 1427, 1371, 1329, 1298, 1173, 1036,
Preparation of derivatives 13, 14 and 15. 355 mg of 1
were treatedwith 432 mg of MCPBA (1.2 equiv) in 10
mL of dry CH2Cl2 at rt for 24 h. The evolution of the
reaction was followedby TLC, when compound 1 dis-
appearedthe mixture of reaction was treatedwith
NaHCO3 (5%), the organic layer was separatedandthe
aqueous layer was extractedwith CH 2Cl2. The com-
binedorganic extracts were washedwith brine anddried
over MgSO4. The product was purified by flash chro-
matography (silica gel, 4:1, hexanes/EtOAc) to yield102
mg (27%) of compound 13, 214 mg (57%) of compound
14 as a dark yellow solid, and 54 mg (14%) of com-
pound 15. The spectroscopic data were identical to the
reportedfor the same compounds obtainedfrom nat-
ural source.20,21
1016, 948, 732, 701 cmꢀ1
.
Preparation of compound 10. 69 mg (0.28 mmol) of
chloranil in 3 mL of CH3CN were treatedwith 3.3 equiv
of lapachol (1) at rt for 14 h. The solvent was eliminated