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

Methods are described for sequential cycloaddition-fragmentation-recombinat ion 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 r etroaldol cleavage followed by intramolecular Michael reaction, to generate 3-methoxy-5',6'-dihydro-15 alphaH-benzo[14,15]-14 beta -estra-1,3,5(10)-tr iene-4'(3' H),17-dione 4. Similarly, it is shown that various 16 alpha -alk enyl-14 alpha ,17 alpha -etheno-estradiols undergo ready [3,3]-sigmatropic rearrangement to give functional variants of this pentacyclic system. Synth etic routes to novel (perhydrobenzo)[14,15]-14 beta -analogues of estradiol are described, and aspects of the chemistry of 14 beta ,16 beta -propano-1 9-norsteroids derived from alternative intramolecular reaction pathways are outlined.