5566
T. I. Richardson et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5563–5566
Krishnan, V. J. Med. Chem. 2006, 49, 6155; (b) Richard-
son, T. I.; Norman, B. H.; Lugar, C. W.; Jones, S. A.;
Wang, Y.; Durbin, J. D.; Krishnan, V.; Dodge, J. A.
Bioorg. Med. Chem. Lett. 2007, 17, 3570; (c) WO
2003044006.
His-475. The difluoromethylene group of the C-ring is
pointed toward Ile 373, while the methymethoxy group
is pointed toward Met-336.
In conclusion, we were able to increase the binding selec-
tivity of the benzopyran scaffold by combining modifica-
tions of the C- and A-rings of benzopyran 1a.
Fluorination of the C-ring gave a compound with 19-
fold selectivity, while addition of a methoxymethyl
group to the A-ring gave a compound with 43-fold
selectivity. The combination of these two modifications
gave a compound that was equipotent at ERb and
83-fold selective for ERb over ERa. The cocrystal
structures of this A/C-ring analog 4a in ERb demon-
strated similar binding orientations compared to the
C-ring modified, A-ring modified, and unfunctionalized
benzopyrans.
6. (a) Richardson, T. I.; Dodge, J. A.; Durst, G. L.; Pfeifer,
L. A.; Shah, J.; Wang, Y.; Durbin, J. D.; Krishnan, V.;
Norman, B. H. Bioorg. Med. Chem. Lett. 2007, 17, 4824;
(b) WO 2004094400..
7. (a) Norman, B. H.; Richardson, T. I.; Dodge, J. A.;
Pfeifer, L. A.; Durst, G. L.; Wang, Y.; Durbin, J. D.;
Krishnan, V.; Dinn, S. R.; Shengquan, L.; Reilly, J. E.;
Ryter, K. T. Bioorg. Med. Chem. Lett. 2007, 17, 5082; (b)
WO 2004094401.
8. Experimental details have been described in WO
2006044176.
9. (a) 3-Bromo-2-hydroxy-5-methoxy-benzaldehyde was pre-
pared according to Rubenstein, L. J. Chem. Soc. 1925,
127, 1998; see also (b) Swenton, J. S.; Raynolds, P. W. J.
Am. Chem. Soc. 1978, 100, 6188.
10. Trost, B. M.; Chan, D. M. T. J. Am. Chem. Soc. 1979, 101,
6429; for a review of transition metal-mediated cycload-
dition reactions, see Lautens, M.; Klute, W.; Tam, W.
Chem. Rev. 1996, 96, 49; an asymmetric version of this
reaction, not available to us at the time, of our work has
recently been reported by Trost, B. M.; Stambuli, J. P.;
Silverman, S. M.; Schwo¨rer, U. J. Am. Chem. Soc. 2006,
128, 13329.
11. (a) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992,
33, 6299; (b) Comins, D. L.; Dehghani, A.; Foti, C. J.;
Joseph, S. P. Org. Syn. 1997, 74, 77.
12. (a)Metal-Catalyzed Cross-Coupling Reactions; de Meijere,
A., Diederich, F., Eds., 2 ed.; John Wiley & Sons: New
York, 2004; (b)Handbook of Organopalladium Chemistry
for Organic Synthesis; Negishi, E., Ed.; John Wiley &
Sons: New York, 2002.
References and notes
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13. Diethylaminosulfur trifluoride (NEt2SF3) Singh, R. P.;
Shreeve, J. M. Synthesis 2002, 2561.
14. The X-ray data for 4a bound to ERb (Fig. 2) have been
deposited into the Protein Data Bank with accession code
2QTU.
5. (a) Norman, B. H.; Dodge, J. A.; Richardson, T. I.;
Borromeo, P. S.; Lugar, C. W.; Jones, S. A.; Chen, K.;
Wang, Y.; Durst, G. L.; Barr, R. J.; Montrose-Rafizadeh,
C.; Osborne, H. E.; Amos, R. M.; Guo, S.; Boodhoo, A.;