Activation and Regioselective Ortho-Functionalization of the A-Ring of β-Estradiol Promoted by “Cp*Ir”:  An Efficient Organometallic Procedure for the Synthesis of 2-Methoxyestradiol

5,6,7,8-Tetrahydro-2-naphthol (3) and β-estradiol (1) gave η6-arene complexes using [Cp*Ir(solvent)3][BF4]2 (4) prepared in situ; subsequent O-deprotonation with NEt3 produced the corresponding complexes [Cp*Ir(oxo-η5-dienyl)][BF4] (5 and 6a,b). In the case of the complexed hormone, the Cp*Ir moiety coordinates the A-ring either α (metal down, 6a) or β (metal up, 6b) relative to the methyl group at C(13). The X-ray molecular structure of the α-isomer 6a was determined. These (oxo-η5-dienyl)iridium derivatives 5 and 6a react with NaOMe in methanol at −40 °C to give respectively the novel iridium cyclohexadienone complexes [Cp*Ir(methoxy-η4-dienone)] (7a and 8a) in 95 and 91% yields, respectively, with nucleophilic attack occurring exclusively at the ortho-position relative to the CO function. The novel iridium cyclohexadienone compound of the complexed steroid 8a can be oxidized easily by iodine to produce 2-methoxyestradiol (2) in 60% overall yield from β-estradiol. This efficient organometallic procedure is preferable to the classical organic procedure, which requires five steps and affords 2 in less than 5% yield.