The utilization of enones as latent enolates enables regioselective enolate formation from chemically robust presursors. In this communication, we report a catalytic Michael cycloisomerization of bis(enones) under Morita-Baylis-Hillman conditions. Upon exposure to 10 mol % tributylphosphine, bis(enone) substrates afford both five- and six-membered ring products. Notably, unsymmetrical bis(enones) possessing sufficient steric or electronic bias yield single isomeric products.

In the presence of phenylsilane and 5 mol % cobalt(II) bis(2,2,6,6-tetramethylheptane-3,5-dionate), aryl-substituted monoenone monoaldehydes and bis(enones) undergo reductive cyclization to afford syn-aldol and anti-Michael products, respectively. For both aldol and Michael cycloreductions, five- and six-membered ring formation occurs in good yield with high levels of diastereoselectivity. Cycloreduction of monoenone monoaldehyde 1a in the presence of d(3)-phenylsilane reveals incorporation of a single deuterium at the enone beta-position as an equimolar mixture of epimers, inferring rapid isomerization of the kinetically formed cobalt enolate prior to cyclization. The deuterated product was characterized by single-crystal neutron diffraction analysis. For bis(enone) substrates, modulation of the silane source enables partitioning of the competitive Michael cycloreduction and [2 + 2] cycloaddition manifolds. A study of para-substituted acetophenone-derived bis(enones) reveals that substrate electronic features also direct partitioning of cycloreduction and cycloaddition manifolds. Further mechanistic insight is obtained through examination of the effects of enone geometry on product stereochemistry and electrochemical studies involving cathodic reduction of bis(enone) substrates. The collective experiments reveal competitive enone reduction pathways. Enone hydrometalation produces metallo-enolates en route to aldol and Michael cycloreduction products, that is, products derived from coupling at the alpha-position of the enone. Electron-transfer-mediated enone reduction produces metallo-oxy-pi-allyls en route to [2 + 2] cycloadducts and, under Ni catalysis, homoaldol cycloreduction products, that is, products derived from coupling at the beta-position of the enone. The convergent outcome of the metal-catalyzed and electrochemically induced transformations suggests the proposed oxy-pi-allyl intermediates embody character consistent with the mesomeric metal-complexed anion radicals.

Catalytic tandem conjugate addition-enolate trapping represents an effective strategy for the design of catalytic transformations that enable formation of multiple COC bonds. Recently, using enantioselective rhodium-catalyzed conjugate addition methodology, we developed a catalytic tandem conjugate addition-aldol cyclization of keto-enones. Here, we report related desymmetrizations and parallel kinetic resolutions involving the use of diones as terminal electrophiles. The Rh-enolate generated on enone carbometallation effectively discriminates among four diastereotopic -faces of the appendant dione, ultimately providing products that embody four contiguous stereocenters, including two adjacent quaternary centers, with quantitative diastereoselection and high levels of enantiomeric excess. This methodology allows concise entry to optically enriched seco-B ring steroids possessing a 14-hydroxy cis-fused C-D ring junction, as found in naturally occurring cardiotonic steroids derived from digitalis.

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