Formylation of Estrogens

Abstract

Reimer-Tiemann formylations of oestradiol and oestrone were investigated and, whilst substitution was effected under certain conditions to give mixtures of 2- and 4-formyloestrogens, yields were very low and the method was unsuitable for preparative purposes. Regioselective methods were developed and 2-formyloestradiol was conveniently prepared from oestradiol by formylation of the lithio derivative of the bis(methoxymethyl) ether and removal of the rotecting groups with hydrochloric acid. 4-Formyloestradiol was prepared by a sequence of reactions starting with the methoxyethyl ether of 4-bromooestradiol, then metal-halogen interconversion, formylation with N-methylformanilide, and removal of the protecting group. A number of related derivatives, including 2-formyloestriol, were prepared.

Anti-cancer activities of novel D-ring modified 2-substituted estrogen-3-O-sulfamates

“…In earlier studies on the synthesis of 2-substituted estrones we had adopted and further developed the ortholithiation of 3-O-methoxymethyl functionalised estrogens first reported by Pert and Ridley [35] to install various functional groups selectively at the 2-position of estradiol. Application of this strategy to the 17-deoxy estrone series required 3-O-methoxymethyl 17-deoxy estrone (8), a molecule readily available by reaction of 17-deoxy estrone [32] with chloromethylmethyl ether under basic conditions, as starting material.…”

ortho-Formylation of oxygenated phenols

“…2ME2 was prepared in five steps and 6% overall yield. 128 Some years later the same group reported a similar, but improved, synthetic pathway changing the protection group and formylation chemistry as described by Pert 131 and Brueggemeier, 132 selectively formylating the 2-position of 3,17E-bis(MOM) protected estradiol ( Figure 22, path b). Furthermore, the authors improved the Baeyer-Villiger oxidation conditions which resulted in a five step synthesis with 63% overall yield of 2ME2.…”

“…Reaction conditions and yields of reported formylations of estradiol are summarised in By using a heteroatom facilitated ortho-lithiation process and DMF, Ridley and co-workers were able to regioselectively formylate the 2-position of 3,17E-bis(methoxymethoxy) estradiol. 131 The groups of Peters and Cushman have formylated estradiol under Duff reaction conditions (HMT, acidic cond. ), but a mixture of the 2-and 4-regioisomeres was obtained.…”

A- and D-Ring Structural Modifications of an Androsterone Derivative Inhibiting 17β-Hydroxysteroid Dehydrogenase Type 3: Chemical Synthesis and Structure–Activity Relationships

“…Finally, compound 33 was readily prepared via a reductive amination between the amine A and 2-formyl-estrone (32), readily obtained from estrone. 43 In NMR spectra, the new methylene group formed at C2 appears at δ H = 3.61−3.69 and δ C = 57.8 ppm. Interestingly, the OH attached at C3 is shifted downfield to δ H = 10.23 ppm, suggesting an intramolecular H-bond with the tertiary amine in the piperazine moiety, which may be favored since a sixmembered ring is formed.…”