1820
Z. Lu et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1817–1820
A.; Toler, S. M.; Pan, L. C.; Cook, E. R.; Dibrino, J. N.;
Chidsey-Frink, K. L.; Hada, W. A.; Inthavongsay, J.; Mullins,
M. A.; Nickerson, D. F.; Ng, O.; Pirie, C. M.; Rose, C. R.;
Tess, D. A.; Wright, A. S.; Zawistoski, M. P.; DaSilva-Jar-
dine, P. A.; Thompson, D. D. 222nd ACS National Meeting,
Chicago, IL, Aug. 23–27, 1999. (g) Chen, M.-H.; Pollard, P. P.;
Cheng, K.; Wei, L.; Chan, W. W.-S.; Butler, B.; Jacks, T. M.;
Smith, R. G.; Patchett, A. A. Bioorg. Med. Chem. Lett. 1999,
9, 1261. (a) For recent reviews on GHS, see: Ghigo, E.; Arvat,
E.; Broglio, F.; Giordano, R.; Gianotti, L.; Muccioli, G.;
Papotti, M.; Graziani, A.; Bisi, G.; Deghenghi, R.; Camanni,
F. Horm. Res. 1999, 51, 9. (b) Nargund, R. P.; Patchett, A. A.;
Bach, M. A.; Murphy, M. G.; Smith, R. G. J. Med. Chem.
1998, 41, 3103. (c) Nargund, R. P.; Van der Ploeg, L. H. T. In
Annual Reports in Medicinal Chemistry; Bristol, J. A., Ed.;
Academic: San Diego, 1997; Vol. 32, p 221 and references
cited therein. (d) DeVita, R. J.; Wyvratt, M. J. Drugs Future
1996, 21, 273.
2. (a) Shoen, W. R.; Pisano, J. M.; Prendergast, K.; Wyvratt,
M. J.; Fisher, M. H.; Cheng, K.; Chan, W.-S.; Butler, B.;
Smith, R. G.; Ball, R. G. J. Med. Chem. 1994, 37, 897. (b) For
more recent work in this area, see: DeVita, R. J.; Bochis, R.;
Frontier, A. J.; Kotliar, A.; Fisher, M. H.; Shoen, W. R.;
Wyvratt, M. J.; Cheng, K.; Chan, W.-S.; Butler, B.; Jacks,
T. M.; Hickey, G. J.; Schleim, K. D.; Leung, K.; Chen, Z.;
Chiu, S.-H. L.; Feeney, W. P.; Cunningham, P. K.; Smith,
R. G. J. Med. Chem. 1998, 41, 1716.
4. Tata, J. R.; Lu, Z.; Jacks, T. M.; Schleim, K. D.; Cheng,
K.; Wei, L.; Chan, W.-S.; Butler, B.; Tsou, N.; Leung, K.;
Chiu, S.-H. L.; Hickey, G. J.; Smith, R. G.; Patchett, A. A.
Bioorg. Med. Chem. Lett. 1997, 7, 2319.
5. Yang, L.; Morriello, G.; Leung, K.; Jacks, T. M.; Cheng,
K.; Schleim, K. D.; Smith, R. G.; Patchett, A. A. Bioorg. Med.
Chem. Lett. 1999, 9, 1761.
6. Barakat, K. J.; Cheng, K.; Chan, W.-S.; Butler, B.; Jacks,
T. M.; Schleim, K. D.; Hora, D. F., Jr.; Hickey, G. J.; Smith,
R. G.; Patchett, A. A.; Nurgund, R. P. Bioorg. Med. Chem.
Lett. 1998, 8, 1431.
7. For resolution of 22a and 22b by flash column and recrys-
tallization: A solution of compound 21 (0.67 g, 1.87 mmol) in
MeOH (20 mL) was charged with 10% Pd/C and hydrogen at
1 atm for 20 h. The mixture was filtered through Celite to give
22 as a colorless oil (0.65 g, 97%) after removal of the solvent.
A flash column was carried out using 1:9 EtOAc/hexane as the
elute togive 0.184 g of 22a (faster component), 0.047 g of 22b
(slower component) and 0.35 g of the mixture. More 22a (0.1
g) was obtained by recrystallization in hexane/EtOAc at 0 ꢁC
and using 22a as a seed crystal. The mother liquid was then
subjected to a second flash column (1:9 EtOAc/hexane) to
isolate pure 22b (0.17 g). 1H NMR (400 MHz, CDCl3): 22a
7.74 (d, J=7.94 Hz, 1H), 7.40 (t, J=7.94 Hz, 1H), 7.31 (d,
J=7.77 Hz, 1H), 7.22 (t, J=7.77 Hz, 1H), 4.35 (m, 2H), 4.22
(m, 2H), 4.08 (m, 1H), 2.50 (m, 2H), 2.00 (m, 2H), 1.80 (m,
2H), 1.70 (m, 2H), 1.50 (s, 9H), 1.35 (t, J=7.1 Hz, 3H); 22b
7.60 (d, J=7.94 Hz, 1H), 7.38 (t, J=7.93 Hz, 1H), 7.31 (d,
J=7.7 Hz, 1H), 7.18 (t, J=7.7 Hz, 1H), 4.32 (m, 2H), 4.22 (m,
2H), 3.25 (m, 1H), 2.50 (m, 2H), 2.06 (m, 2H), 1.62 (m, 2H),
1.48 (s, 9H), 1.35 (t, J=7.1 Hz, 3H), 1.28 (m, 2H).
3. Patchett, A. A.; Nargund, R. P.; Tata, J. R.; Chen, M. H.;
Barakat, K. J.; Johnston, D. B. R.; Cheng, K.; Chan, W.-S.;
Butler, J. B.; Hickey, G. J.; Jacks, T. M.; Schleim, K.; Pong,
S.-S.; Chaung, L.-Y. P.; Chen, H. Y.; Frazier, E.; Leung,
K. H.; Chiu, S.-H.; Smith, R. G. Proc. Natl. Acad. Sci. U.S.A.
1995, 92, 7001.
8. Cheng, K.; Chan, W.-S.; Barreto, A.; Convey, E. M.;
Smith, R. G. Endocrinology 1989, 124, 2791.