pubs.acs.org/joc
side effects in numerous studies, which is a remarkable
advantage for a potential chemotherapeutic agent.5
A Short, Economical Synthesis of
2-Methoxyestradiol, an Anticancer Agent in
Clinical Trials†
The commercial and research interest in 2 is obvious from
the many reports on its synthesis, mostly starting from 1. The
shortest reported synthesis requires only two steps: halo-
genation of C-2, followed by a catalyzed substitution of the
halide with methoxide.6 However, the first step suffers poor
selectivity between C-2 and C-4, and the complete separation
of 2-halo- and 4-haloestradiols is very difficult to achieve.
A much more selective method involves the use of organoir-
idium complex to direct the methoxylation process; thus,
2 was obtained from 1 in three steps with a good yield,
although a stoichiometric amount of iridium complex is
required.7 More recently, oxidation of 2-substituted estra-
diol with peroxide has proven successful in the prepara-
tion of 2 with high selectivity; however, five or more steps
were needed to convert 1 into 2.8 We wish to report an
improved synthesis of 2 from 1 by directly introducing
a methoxy group onto C-2, using similar MOM-directed
C-2 lithiation chemistry followed by oxidation with cumyl
methyl peroxide.9
Yuqing Hou,* Cal Y. Meyers, and Mercy Akomeah§
Meyers Institute for Interdisciplinary Research in
Organic and Medicinal Chemistry, and Department of
Chemistry and Biochemistry, MC 4409, Southern Illinois
University, Carbondale, Illinois 62901
§Summer Undergraduate Researcher from Wartburg
College, Waverly, Iowa 50677 †This paper was presented at
the Midwest ACS Regional Meeting, Quincy, IL 2006.
Received May 22, 2009
Although it had been known that alkyl peroxides could
alkoxylate carbanions,10 this methodology has not been
widely used; a search on SciFinder Scholar showed only a
handful of references for this type of reaction.11 Interest-
ingly, Kochi et al.10c carried out a detailed mechanistic study
more than three decades ago and concluded that, in the case
of sterically encumbered dialkyl peroxides, these reactions
went through electron-transfer mechanisms. The limited
usage of this methodology might therefore be attributed to
the explosiveness of these alkyl peroxides, particularly
the low molecular weight analogues such as dimethyl
peroxide.10a It has been reported that cumyl methyl peroxide
2-Methoxyestradiol, a natural metabolite of estradiol and
potential therapeutic agent for many types of cancers, has
been synthesized successfully in three steps, starting from
estradiol and cumyl methyl peroxide.
Estradiol (1), the major female hormone in humans, is
primarily oxidized into 2-hydroxyestradiol by P450 enzymes
in the liver and converted into 2-methoxyestradiol (2)
through the action of catechol-O-methyl transferase.1 Re-
cently, it was reported that 2 binds to the colchicine binding
site, inhibiting the polymerization of tubulin and, thereby,
cell division.2 Thus, 2 inhibits the growth of new blood
vessels, i.e., it is antiangiogenic, leading to the possibility
that 2 may be useful in treating cancers by inhibiting the
formation of new blood vessels around cancer tissues, there-
by cutting off the nutrition supply to the cancer cells. This
strategy has proven practical by the FDA’s approval of the
first antiangiogenic drug for the treatment of advanced-stage
colorectal cancer with Avastin (bevacizumab), introduced by
Genentech.3 Currently, 2 has been granted an “orphan drug”
status by the FDA, and is in clinical trials for many types of
cancers, including breast and prostate cancers, by Entremed,
Inc., in association with leading medical institutions in the
United States under the trade name Panzem.4 Unlike many
other chemotherapeutic agents for cancer, 2 has shown few
(5) Pribluda, V. S.; Gubish, E. R. Jr.; LaVallee, T. M.; Treston, A.;
Swartz, G. M.; Green, S. J. Cancer Metastasis Rev. 2000, 19, 173–179.
(6) (a) Luo, G.; Chen, S.; Kuang, T.; Yao, Y.; Zhao, H. Sichuan Daxue
Xuebao, Ziran Kexueban 1990, 27, 106–8. (b) Luo, G.; Chen, S.; Zhan, H.
Youji Huaxue 1989, 9, 266–9. (c) Numazawa, M.; Ogura, Y.; Kimura, K.;
Nagaoka, M. J. Chem. Res., Synop. 1985, 348–9. (d) Numazawa, M.; Ogura,
Y. J. Chem. Soc., Chem. Commun. 1983, 533–4. (e) Rao, P. N.; Burdett, J. E.
Jr. Synthesis 1977, 168–9. (f) Chen, S. H.; Luo, G. R.; Wu, X. S.; Chen, M.;
Zhao, H. M. Steroids 1986, 47, 63–6.
(7) Le Bras, J.; Rager, M. N.; Besace, Y.; Amouri, H.; Vaissermann
J. Organomet. 1997, 16, 1765–1771.
(8) (a) Rao, P. N.; Cessac, J. W. Steroids 2002, 67, 1065–1070. (b) Rao, P.
N.; Cessac, J. W.; Tinley, T. L.; Mooberry, S. L. Steroids 2002, 67, 1079–
1089. (c) Wang, Z.; Cushman, M. Synth. Commun. 1998, 28, 4431–4437. (d)
Paaren, H. E.; Duff, S. R. U.S. Patent, 6448419, 2002. (e) He, H.-M.; Cushman, M.
Bioorg. Med. Chem. Lett. 1994, 4, 1725–1728. (f) Cushman, M.; He, H.-M.;
Katzenellenbogen, J. A.; Lin, C. M.; Hamel, E. J. Med. Chem. 1995, 38, 2041–
€ € €
2049. (g) Kiuru, P.; Wahala, K. Steroids 2003, 68, 373–375. (h) Mun, J.; Voll, R.
J.; Goodman, M. M. J. Labelled Compd. Radiopharm. 2006, 49, 1117–1124.
(9) Dussault, P. H.; Lee, H.-J.; Liu, X. J. Chem. Soc., Perkin Trans. 1
2000, 3006–3013.
(10) (a) Baramki, G. A.; Chang, H. S.; Edward, J. T. Can. J. Chem. 1962,
40, 441–444. (b) Jarvie, A. W. P.; Skelton, D. J. Organomet. Chem. 1971, 30,
145–150. (c) Nugent, W. A.; Bertini, F.; Kochi, J. K. J. Am. Chem. Soc. 1974,
96, 4945–4954. (d) Campbell, T. W.; Burney, W.; Jacobs, T. L. J. Am. Chem.
Soc. 1950, 72, 2735–2736. (e) Okubo, M.; Saito, H.; Tomiyoshi, T. Bull.
Chem. Soc. Jpn. 1974, 47, 1289–1290.
(1) Lakhani, N. J.; Sarkar, M. A.; Venitz, J.; Figg, W. D. Pharmacotherapy
2003, 23, 165–172.
(2) Kamath, K.; Okouneva, T.; Larson, G.; Panda, D.; Wilson, L.;
Jordan, M. A. Mol. Cancer Ther. 2006, 5, 2225–2233.
(3) Sparano, J. A.; Gray, R.; Giantonio, B.; O’Dwyer, P.; Comis, R. L.
Clin. Cancer Res. 2004, 10, 1206–1211.
(11) For representative reactions between carbanions and alkyl peroxy
esters, diaroyl peroxides, or disilyl peroxide, see: (a) Lawesson, S.-O.; Yang,
N. C. J. Am. Chem. Soc. 1959, 81, 4230–4233. (b) Okubo, M.; Maruyama, K.;
Osugi, J. Bull. Chem. Soc. Jpn. 1971, 44, 1365–1368. (c) Camici, L.; Dembech,
P.; Ricci, A.; Seconi, G.; Taddei, M. Tetrahedron 1988, 44, 4197–206.
6362 J. Org. Chem. 2009, 74, 6362–6364
Published on Web 07/17/2009
DOI: 10.1021/jo901086s
r
2009 American Chemical Society