Total Synthesis of (–)‐C/D‐cis‐De­hydro‐3‐O‐methyl‐estradiols

Abstract

AbstractA 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.