Brief Articles
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 24 4291
receptor ligands and prospects for combinatorial synthesis of
estrogens. Chem. Biol. 1999, 6, 205-219.
is more planar than is the naphthol. In some related
ligands it is thought that ligand “thickness” in this
portion of the receptor contributes to high affinity
binding.28,29
(13) Brzozowski, A. M.; Pike, A. C. W.; Dauter, Z.; Hubbard, R. E.;
Bonn, T.; Engstro¨m, O.; O¨ hman, L.; Greene, G. L.; Gustafsson,
J .-Å.; Carlquist, M. Molecular basis of agonism and antagonism
in the oestrogen receptor. Nature 1997, 389, 753-758.
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J . H. N.; van Gunsteren, W. F. Simulations of the Estrogen
Receptor Ligand-Binding Domain: Affinity of Natural Ligands
and Xenoestrogens. J . Med. Chem. 2000, 43, 4594-4605.
(15) Lednicer, D.; Lyster, S. C.; Aspergren, B. D.; Duncan, G. W.
Mammalian Antifertility Agents. III. 1-Aryl-2-phenyl-1,2,3,4-
tetrahydro-1-naphthols, 1-Aryl-2-phenyl-3,4-dihydronaphtha-
lenes, and Their Derivatives. J . Med. Chem. 1966, 9, 172-176.
(16) Vuik, C. P. J .; ul Hasan, M.; Holloway, C. E. Carbon-13 T1 Study
of Aldehydes and Aldehyde Oximes. J . Chem. Soc., Perkin 2
1979, 1214-1218 and references therein.
Con clu sion
In this investigation we demonstrate that the six-
member ring formed by the intramolecular hydrogen
bond in the salicylaldoxime 1 appears to be an effective
stereoelectronic replacement of the aromatic A-ring of
typical estrogen ligands and that the hydroxyl group of
the oxime in compound 1 seems to effectively mimic the
fundamental role played by the hydroxyl of the phenolic
A-ring in the interaction with the estrogen receptor. It
is not difficult to see that salicylaldoxime 1 represents
the first and simplest member of what might prove to
be a large class of novel estrogen receptor ligands, other
members of which could be accessed by modifying the
aromatic substituents in positions 3 and 4. Investiga-
tions along these lines are underway.
(17) Photochemical preparation of compound 8 had been previously
described in: Zimmerman, H. E.; Lamers, P. H. Photochemistry
of Some Extended π-Systems: Type A and Aryl Rearrangements
of Systems with Extended Conjugation Related to Cyclohexa-
dienones and Cyclohexenones. Mechanistic and Exploratory
Organic Photochemistry. J . Org. Chem. 1989, 54, 5788-5804.
We found it more convenient to prepare compound 8 by DDQ-
aromatization followed by BBr3-demethylation of 1,2-diphenyl-
6-methoxy-3,4-dihydronaphthalene, reported in ref 15.
(18) Hoffman, W. F.; Woltersdorf, O. W.; Novello, F. C.; Cragoe, E.
J ., J r.; Spinger, J . P.; Sherman Watson, L.; Fanelli, G. M., J r.
Acylaryloxyacetic Acid Diuretics. 3. 2,3-Dihydro-5-acyl-2-benzo-
furancarboxylic Acids, a New Class of Uricosuric Diuretics. J .
Med. Chem. 1981, 24, 865-873.
(19) Guillaumet, G.; Hretani, M.; Coudert, G. Synthe`se de dioxino-
coumarines angulaires. J . Heterocycl. Chem. 1989, 26, 193-197.
(20) Demuth, M.; Ritterskamp, P.; Weigt, E.; Schaffner, K. Total
Synthesis of (-)-Coriolin. J . Am. Chem. Soc. 1986, 108, 4149-
4154. Note: we found that yields are considerably improved by
using at least 2.3 equiv of sodium periodate, since 1 equiv is
consummated for the initial osmium-catalyzed dihydroxylation,
and another equivalent is needed for the oxidative cleavage of
the C-C bond of the diol formed in the first step.
Su p p or tin g In for m a tion Ava ila ble: Characterization
data of compounds 1-3 and 5-7 and experimental details.
This material is available free of charge via the internet at
http://pubs.acs.org.
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