Concise Enantioselective Synthesis of Oxygenated Steroids via Sequential Copper(II)-Catalyzed Michael Addition/Intramolecular Aldol Cyclization Reactions

A new
scalable enantioselective approach to functionalized oxygenated
steroids is described. This strategy is based on chiral bis­(oxazoline)
copper­(II) complex-catalyzed enantioselective and diastereoselective
Michael reactions of cyclic ketoesters and enones to install vicinal
quaternary and tertiary stereocenters. In addition, the utility of
copper­(II) salts as highly active catalysts for the Michael reactions of traditionally unreactive β,β′-enones and substituted
β,β′-ketoesters that results in unprecedented Michael adducts
containing vicinal all-carbon quaternary centers is also demonstrated.
The Michael adducts subsequently undergo base-promoted diastereoselective
aldol cascade reactions resulting in the natural or unnatural steroid
skeletons. The experimental and computational studies suggest that
the torsional strain effects arising from the presence of the Δ5-unsaturation are key controlling elements for the formation
of the natural cardenolide scaffold. The described method enables
expedient generation of polycyclic molecules including modified steroidal
scaffolds as well as challenging-to-synthesize Hajos–Parrish
and Wieland–Miescher ketones.