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

Abstract

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.

General Synthesis, First Crystal Structure, and Reactivity of Stable o-Quinone Methide Complexes of Cp*Ir

“…Recently we have described a general procedure for nucleophilic phenol functionalization , promoted by the Cp*Ir moiety, which allows efficient functionalization of tetralols and steroids ).…”

Ir-Mediated Nucleophilic Ortho-Functionalization of Phenols: Syntheses, Structures, Scope, and Limitation

“…We recently discovered that oxo-η 5 -dienyl complexes can be used as precursors to promote nucleophilic phenol functionalization . In fact such complexes are attacked smoothly with a nucleophile such as a phosphine or methoxide MeO - specifically at the ortho-position, leading to only a single dienone iridium complex.…”

“…Our method (Scheme ) has been shown also to be efficient for ortho-functionalization of complex organic molecules such as tetralols and steroids. For instance 2-methoxyestradiol is obtained from β-estradiol in 60% yield and only in three steps,7b compared to the conventional organic procedure, which affords the same compound in 5% overall yield and via five steps (Scheme ). 2-Methoxyestradiol is an anticancer agent and possesses important physiological properties …”

Steroids: reactions and partial synthesis

“…A number of estra-1,4-quinones have been synthesized and aspects of their chemistry including nucleophilic addition at C-2 to give 26, have been examined. 69,70 Organometallic routes based on cyclopentadienyl iridium complexes of estradiol, have been devised 71 for the synthesis of 2-methoxyestradiol. On the other hand the nucleophilic addition to the 3,17-di-O-methylestradiol manganese tricarbonyl complex 27 takes place at C-1.…”