Cycloaddition-mediated strategies for synthesis of perhydrobenzo[14,15]-14β-19-norsteroids

Abstract

Methods are described for sequential cycloaddition–fragmentation–recombination and cycloaddition–rearrangement-mediated processes for synthesis of the title compounds. Reaction of methyl vinyl ketone with 3-methoxyestra-1,3,5(10),14,16-pentaen-17-yl acetate 1 gives a cycloadduct 2, which undergoes retroaldol cleavage followed by intramolecular Michael reaction, to generate 3-methoxy-5′,6′-dihydro-15αH-benzo[14,15]-14β-estra-1,3,5(10)-triene-4′(3′H),17-dione 4. Similarly, it is shown that various 16α-alkenyl-14α,17α-ethenoestradiols undergo ready [3,3]-sigmatropic rearrangement to give functional variants of this pentacyclic system. Synthetic routes to novel (perhydrobenzo)[14,15]-14β-analogues of estradiol are described, and aspects of the chemistry of 14β,16β-propano-19-norsteroids derived from alternative intramolecular reaction pathways are outlined.