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(0.46 mL) and the mixture was heated to 90 ꢁC. A 1:5
(d, J = 1.4 Hz, 2H), 7.14 (d, J = 1.8 Hz, 2H), 3.91 (s, 2H,
CH2), 3.80 (s, 6H, OCH3); 13C NMR (Acetone-d6,
100 MHz) d 173.00 (CO2H), 152.28, 149.67, 132.54,
121.84, 119.30, 112.95, (Carom), 56.55 (CH3), 41.16 (CH2);
LRMS m/z 348 (M+); HRMS calcd for C17H16O8 348.0845
(M+), found 348.0842.
mixture of sulfuric acid and glacial acetic acid (27 lL) was
then added and stirred at 90–96 ꢁC for 3 h. The reaction
mixture was cooled to rt, poured into water, and extracted
with EtOAc. Organic extracts were combined, washed
with water, and the solvent was removed. Column
chromatography of the resulting oil afforded dimethyl
Compound 9: mp 248 ꢁC (dec); 1H NMR (Acetone-d6,
200 MHz) d 11.36 (br s, 2H, exchangeable with D2O), 7.61
(d, J = 2.2 Hz, 2H), 7.29 (d, J = 2.2 Hz, 2H), 7.24–7.13 (m,
10H), 3.95 (s, 4H, CH2), 3.85 (s, 2H, CH2); 13C NMR
(Acetone-d6, 100 MHz) d 173.12 (CO2H), 159.51, 141.56,
138.16, 132.59, 130.67, 129.72, 129.19, 129.10, 126.82,
112.68 (Carom), 44.35, 35.89 (CH2); LRMS m/z 468 (M+);
HRMS calcd for C29H24O6 468.1573(M+), found 468.1574.
1
ester of 8 as a white solid (306 mg): mp 150–153 ꢁC; H
NMR (CDCl3, 200 MHz) d 11.16 (s, 2H), 7.68 (d,
J = 2.4 Hz, 2H), 7.57–7.51 (m, 4H), 7.46–7.29 (m, 8H),
3.95 (s, 6H, CH3), 3.93 (s, 2H, CH2). Hydrolysis of the
ester (200 mg) in hot 1,4-dioxane (1.0 mL) and 10% NaOH
(2.0 mL) gave 8 as a white solid (185 mg): mp 261 ꢁC (dec);
1H NMR (Acetone-d6, 200 MHz) d 11.54 (s, 2H, exchange-
able with D2O), 7.86 (d, J = 2.6 Hz, 2H), 7.60–7.54 (m, 6H),
7.44–7.27 (m, 6H), 4.07 (s, 2H, CH2); 13C NMR (Acetone-
d6, 100 MHz) d 173.24 (CO2H), 158.89, 138.31, 138.27,
133.10, 131.09, 130.39, 130.26, 128.93, 128.12, 113.32
(Carom), 40.25 (CH2); LRMS m/z 440 (M+); HRMS calcd
for C27H20O6 440.1260 (M+), found 440.1262.
1
Compound 10: mp >300 ꢁC (dec); H NMR (Acetone-d6,
200 MHz) d 12.03 (s, 2H), 7.97 (d, J = 2.2 Hz, 2H), 7.79 (d,
J = 2.2 Hz, 2H), 7.60 (d, J = 1.6 Hz, 2H), 7.11 (d,
J = 3.4 Hz, 2H), 6.57 (m, 2H), 4.10 (s, 2H); 13C NMR
(Acetone-d6, 100 MHz) d 173.69 (CO2H), 158.07, 150.49,
143.20, 133.49, 133.05, 130.31, 121.17, 114.04, 113.29,
112.18, 40.93 (CH2); LRMS m/z 420 (M+); HRMS calcd
for C23H16O8 420.0845 (M+), found 420.0840.
13. Compounds 3–8 and 9–10 were synthesized starting from
appropriate 3-substituted methyl salicylate derivatives in
the similar conditions as for the synthesis of 8. For example,
9 was synthesized starting from methyl 3-benzylsalicylate.
Compound 4: mp 284 ꢁC (dec); 1H NMR (200 MHz,
Acetone-d6) d 11.58 (s, 2H, OH), 7.78 (d, J = 2.2 Hz, 2H),
7.60 (d, J = 2.2 Hz, 2H), 3.99 (s, 2H, CH2).
14. Massa, M. A.; Spangler, D. P.; Durley, R. C.; Hickory, B.
S.; Connolly, D. T.; Witherbee, B. J.; Smith, M. E.;
Sikorski, J. A. Bioorg. Med.Chem. Lett. 2001, 11, 1625.
15. Burke, T. R., Jr.; Zhang, Z.-Y. Biopolymers 1998, 47,
225.
16. Shrestha, S.; Lee, K. H.; Cho, H. Bull. Korean Chem. Soc.
2004, 25, 1303.
17. Vena¨la¨inen, J. I.; Juvonen, R. O.; Garcia-Horsman, J. A.;
Compound 5: mp 283–285 ꢁC (dec); 1H NMR (Acetone-d6,
200 MHz) d 11.39 (br s, 2H), 7.82 (d, J = 2.2 Hz, 2H), 7.76
(d, J = 2.2 Hz, 2H), 3.99 (s, 2H); 13C NMR (Acetone-d6,
100 MHz) d 172.12 (COOH), 157.99, 140.37, 134.07, 130.71,
114.36, 111.50, 39.32 (CH2).
´
Wallen, E. A. A.; Christiaans, J. A. M.; Jarho, E. M.;
Gynther, J.; Ma¨nnisto¨, P. T. Biochem. J. 2004, 382, 1003.
18. Johnson, T. O.; Ermolieff, J.; Jirousek, M. R. Nat. Rev.
Drug Discov. 2002, 1, 696.
19. Andersen, H. S.; Olsen, O. H.; Iversen, L. F.; Sørensen, A.
L. P.; Mortensen, S. B.; Christensen, M. S.; Branner, S.;
Hansen, T. K.; Lau, J. F.; Jeppesen, L.; Moran, E. J.; Su,
J.; Bakir, F.; Judge, L.; Shahbaz, M.; Collins, T.; Vo, T.;
Newman, M. J.; Ripka, W. C.; Møller, N. P. H. J. Med.
Chem. 2002, 45, 4443.
Compound 6: mp 268 ꢁC (dec), rep 296–298 ꢁC; 1H NMR
(DMSO-d6, 200 MHz) d 11.47 (br s, 2H, exchangeable with
D2O), 7.46 (s, 2H), 7.25 (s, 2H), 3.77 (s, 2H, CH2), 2.14 (s,
6H, CH3); 13C NMR (DMSO-d6, 100 MHz) d 173.09
(CO2H), 158.73, 137.52, 131.99, 127.81, 126.36, 112.33,
(Carom), 40.75 (CH2), 16.01 (CH3).
Compound 7: mp 239 ꢁC (dec); 1H NMR (Acetone-d6,
200 MHz) d 11.20 (br s, 2H, exchangeable with D2O), 7.35