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 (<b>3</b>) and β-estradiol (<b>1</b>) gave η<sup>6</sup>-arene complexes using [Cp*Ir(solvent)<sub>3</sub>][BF<sub>4</sub>]<sub>2</sub> (<b>4</b>) prepared <i>in situ</i>; subsequent O-deprotonation with NEt<sub>3</sub> produced the corresponding complexes [Cp*Ir(oxo-η<sup>5</sup>-dienyl)][BF<sub>4</sub>] (<b>5</b> and <b>6a,b</b>). In the case of the complexed hormone, the Cp*Ir moiety coordinates the A-ring either α (metal down, <b>6a</b>) or β (metal up, <b>6b</b>) relative to the methyl group at C(13). The X-ray molecular structure of the α-isomer <b>6a</b> was determined. These (oxo-η<sup>5</sup>-dienyl)iridium derivatives <b>5</b> and <b>6a</b> react with NaOMe in methanol at −40 °C to give respectively the novel iridium cyclohexadienone complexes [Cp*Ir(methoxy-η<sup>4</sup>-dienone)] (<b>7a </b>and<b> 8a</b>) 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 <b>8a</b> can be oxidized easily by iodine to produce 2-methoxyestradiol (<b>2</b>) in 60% overall yield from β-estradiol. This efficient organometallic procedure is preferable to the classical organic procedure, which requires five steps and affords <b>2</b> in less than 5% yield.