5446
R. I. Higuchi et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5442–5446
Seethala, R.; Fura, A.; Krystek, S. R.; An, Y.; Malley, M.
F.; Sack, J. S.; Salvati, M. E.; Grover, G. J.; Ostrowski, J.;
1 h, then poured into water, neutralized with 6 M NaOH,
extracted with EtOAc, and then washed with saturated
NaHCO3 to afford 14 (CH2Cl2/MeOH). Compound 14 (1
equiv) in toluene (0.1–0.2 M) was added to ( )-BINAP (4–
10 mol %), Pd2(dba)3 (2–5 mol%), and t-BuONa (1.4
equiv). The solution was heated at 90–100 °C for 6–24 h,
poured into cold saturated NH4Cl, and extracted with
EtOAc. Compound 15 (R2 = Et) was prepared in 63%
yield (hexanes:EtOAc). 1H NMR (400 MHz, CDCl3) d
7.36 (d, 1H, J = 8.8), 7.18 (s, 1H), 7.03 (d, 1H, J = 8.8),
5.47 (septet, 1H, J = 6.2), 4.36 (dd, 1H, J = 10.6, 2.9), 3.87
(dd, 1H, J = 10.4, 7.5), 3.83 (br s, 1H), 3.48–3.40 (m, 1H),
1.63–1.53 (m, 2H), 1.38 (d, 6H, J = 6.2), 1.06 (t, 3H,
J = 7.4). Compound 18h was prepared in 67% yield from
Hamann, L. G. J. Med.Chem. 2006, 49, 7596.
8. (a) Zhang, X.; Allan, G. F.; Sbriscia, T.; Linton, O.;
Lundeen, S. G.; Sui, Z. Bioorg. Med. Chem. Lett. 2006, 16,
5763; (b) Hanada, K.; Furuya, K.; Yamamoto, N.;
Nejishima, H.; Ichikawa, K.; Nakamura, T.; Miyakawa,
M.; Amano, S.; Sumita, Y.; Oguro, N. Biol. Pharm. Bull.
2003, 26, 1563.
9. Van Oeveren, A.; Motamedi, M.; Mani, N. S.; Marschke,
K. B.; Lopez, F. J.; Schrader, W. T.; Negro-Vilar, A.; Zhi,
L. J. Med. Chem. 2006, 49, 6143.
´
10. Higuchi, R. I.; Arienti, K. L.; Lopez, F. J.; Mani, N. S.;
Caferro, T. R.; Long, O. Y.; Jones, T. K.; Mais, D. E.;
Edwards, J. P.; Zhi, L.; Schrader, W. T.; Negro-Vilar, A.;
Marschke, K. B. J. Med. Chem. 2007, 50, 2486.
11. Kelly, T. R.; Field, J. A.; Li, Q. Tetrahedron Lett. 1988,
29, 3545.
12. Fujisaki, S.; Eguchi, H.; Omura, A.; Okamoto, A.;
Okamotoo, A.; Nishida, A. Bull. Chem. Soc. Jpn. 1993,
66, 1576.
15
(R2 = Et),
and
CF3CHOH(OEt)
(0.028 mL,
0.235 mmol).10 1H NMR (400 MHz, CDCl3) d 12.47 (br
s, 1H), 7.15 (s, 1H), 7.14 (d, 1H, J = 8.9), 7.02 (d, 1H,
J = 8.9), 4.38 (d, 1H, J = 10.9), 3.98 (dd, 1H, J = 10.8, 2.4)
3.93–3.65 (m, 2H), 3.27–3.22 (m, 1H), 1.68–1.51(m, 2H),
0.98 (t, 3H, J = 7.5).
16. Hamann, L. G.; Higuchi, R. I.; Zhi, L.; Edwards, J. P.;
Wang, X.-N.; Marschke, K. B.; Kong, J. W.; Farmer, L.
J.; Jones, T. K. J. Med. Chem. 1998, 41, 623.
17. Wang, F.; Liu, X.; Li, H.; Liang, K.; Miner, J. N.; Hong,
M.; Kallel, E. A.; Van Oeveren, A.; Zhi, L.; Jiang, T. Acta
Crystallgr., Sect. F 2006, F62, 1067.
13. Cherney, R. J.; Wang, L. J. Org. Chem. 1996, 61, 2544.
14. Wagaw, S.; Rennels, R. A.; Buchwald, S. L. J. Am. Chem.
Soc. 1997, 119, 8451.
15. Representative procedures. All reaction mixtures were
washed with brine, dried over MgSO4, and purified by
flash chromatography. Compound 13: Diisopropyl azodi-
carboxylate (1.6 equiv) was added to 11 (1 equiv), 12 (1.6
equiv), PPh3 (1.6 equiv), and N-methylmorpholine (10
equiv) in THF (0.1–0.2 M) at 0 °C, and after 5 min, the
reaction mixture was stirred at rt for 2–16 h. The solution
was poured into water, neutralized with 1.0 M HCl,
extracted with EtOAc, and then washed with of 0.1 M
HCl. Compound 13 (R2 = Et) was prepared in 74% yield
18. Calculations were performed using the Tripos forcefield
and Gasteiger-Huckel, and 18h was docked using the
¨
X-ray cocrystal structure of AR-lbd and 4 as a template.
Structures were refined using a simulated annealing
protocol as described in SYBYL 7.0, Tripos Inc., 1699
South Hanley Rd., St. Louis, MO 63144, USA.
19. Herschberger, L. G.; Shipley, E. G.; Meyer, R. K. Proc.
Soc. Exp. Biol. Med. 1953, 83, 175.
20. Chang, W. Y.; Hill, R. W.; Burnett, K. R.; Hein, H.;
Haakmeester, C.; Van Oeveren, A.; Zhi, L.; Marschke, K.
1
(hexanes:EtOAc). H NMR (400 MHz, CDCl3) d 7.80 (d,
1H, J = 8.9), 7.55 (d, 1H, J = 8.9), 7.29 (s, 1H), 5.52
(septet, 1H, J = 6.3), 4.80 (br s, 1H), 4.06–3.90 (m, 3H),
1.91–1.81 (m, 1H), 1.71–1.59 (m, 1H), 1.46 (s, 9H), 1.41 (d,
6H, J = 6.2), 1.01 (t, 3H, J = 7.4). Compound 15. Com-
pound 13 in 1:1 CH2Cl2/TFA (0.1 M) was stirred at rt for
´
B.; Negro-Vilar, A. Lopez, F. J. Abstract of Papers, The
Endocrine Society’s 89th Annual Meeting, Toronto,
Canada, June 2–5, 2007; Endocrine Society: Chevy Chase,
MD.