6533b83afe1ef96bd12a78f4
RESEARCH PRODUCT
Total Synthesis of (-)-C/D-cis-Dehydro-3-O-methyl-estradiols
Udo NubbemeyerNora M. KaluzaDieter Schollmeyersubject
chemistry.chemical_classificationAnnulation010405 organic chemistryStereochemistryOrganic ChemistryGrignard reactionEnantioselective synthesisConvergent synthesisTotal synthesis010402 general chemistry01 natural sciencesAldehyde0104 chemical scienceschemistry.chemical_compoundchemistryTetraloneStereoselectivityPhysical and Theoretical Chemistrydescription
A convergent synthesis of (–)-dehydro-3-O-methyl-C/D-cis-estradiol started from stereochemically defined substituted optically active 3-(2-arylethyl)-γ-butyrolactones. Regioselective bromination of the anisyl moiety, reductive ring opening of the iodolactone, and protecting-group changes led to a Weinreb amide. This then underwent an intramolecular Grignard reaction closing the B-ring to give a tetralone with defined configuration. Introduction of C-11 through an allyl Grignard addition and subsequent ring-closing metathesis gave a tetrahydro phenanthrene derivative. Oxidation of the side-chain alcohol resulted in the key aldehyde group, and a final samarium-diiodide-mediated reductive D-ring annulation resulted in the generation of the target dehydro-C/D-cis-estradiol derivatives with high stereoselectivity. Structure elucidation was carried out using NOEDS (nuclear Overhauser enhanced differential spectroscopy) analysis on the one hand, and conversion into known 3-O-methyl-13β-estradiols by double-bond hydrogenation on the other. Further efforts to use this estradiol synthetic strategy to generate more complex steroidal natural products and pharmaceutically interesting compounds are in progress.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2015-11-25 | European Journal of Organic Chemistry |