TETRAHEDRON LETTERS Tetrahedron Letters 44 (2003) 2749–2751 Pergamon Modification of the Cp ring in the ferrocifen precursor and its influence on the recognition by the estrogen receptor Konrad Kowalski, a,b Anne Vessie `res, a Siden Top, a Ge ´rard Jaouen a, * and Janusz Zakrzewski b a Ecole Nationale Supe ´rieure de Chimie de Paris, 11 rue Pierre et Marie Curie, 75231 Paris Cedex 05, France b Department of Organic Chemistry, University of Lo ´dz ´ , 90 -136 Lo ´dz ´ , Narutowicza 68, Poland Received 18 December 2002; accepted 28 January 2003 Abstract—A synthetic pathway giving access to diphenyl ethylene organometallic derivatives possessing the ferrocifen precursor skeleton modified in the Cp ring is described. It relies on reaction of the ( 5 -propionylcyclopentadienyl) ( 6 -benzene)iron(II) salt 7 with substituted cyclopentadienyl anions or their heteroanalogs followed by the McMurry coupling reaction with 4,4-dihydroxy- benzophenone. Using this approach pentamethylcyclopentadienyl and 3,4-dimethylphospholyl analogs of ferrocifen precursor (10 and 11) have been synthesized. Even with the presence of the bulky and containing phosphorus  5 -ligands these compounds are still recognized by the two subtypes of estrogen receptor(ER and ER). © 2003 Elsevier Science Ltd. All rights reserved. 1. Introduction Ferrocifen 1 and hydroxyferrocifen 2 are the ferrocenyl analogs of tamoxifen 3, a drug currently used in the Chart 2. Chart 1. treatment of hormone-dependent breast cancers via its active metabolite, 4-hydroxytamoxifen 4, 1 which is con- sidered as the archetypal SERM (Selective Estrogen Receptor Modulator) (Chart 1). The replacement of the phenyl ring by the ferrocenyl moiety brought about novel pharmacological properties for 2. For example it has been shown that 2 displays an in vitro antiproliferative effect on both hormono depen- dent (MCF7) and independent (MDA-MB231) breast cancer cell lines whereas its phenyl counterpart 4 is active only against hormono dependent cell line. 2 It has also been shown that 5, a complex deprived of the dimethylamino side chain generally assumed to be responsible for the antiestrogenic effect also displays an antiproliferative activity on MCF7 cells (Chart 2). 3 So far, the mechanism behind these promising and intriguing properties has not been elucidated. This situ- ation prompted us to start a systematic study on the Keywords : ferrocene; phosphaferrocene; estrogen receptor; SERM. * Corresponding author. Tel.: 33 1 43 26 95 55; fax: 33 1 43 26 00 61; e-mail: jaouen@ext.jussieu.fr 0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0040-4039(03)00284-3