Organocatalytic, Asymmetric Eliminative [4+2] Cycloaddition of Allylidene Malononitriles with Enals

A direct aminocatalytic synthesis has been developed for the chemo-, regio-, diastereo-, and enantioselective construction of densely substituted polycyclic carbaldehydes containing fused cyclohexadiene rings. The chemistry utilizes, for the first time, remotely enolizable ?-extended allylidenemalononitriles as electron-rich 1,3-diene precursors in a direct eliminative [4+2] cycloaddition with both aromatic and aliphatic ?,?-unsaturated aldehydes. The generality of the process is demonstrated by approaching 6,6-, 5,6-, 7,6-, 6,6,6-, and 6,5,6-fused ring systems, as well as biorelevant steroid-like 6,6,6,6,5- and 6,6,6,5,6-rings. A stepwise reaction mechanism for the key [4+2] addition is proposed as a domino bis-vinylogous Michael/Michael/retro-Michael reaction cascade. The utility of the malononitrile moiety as traceless activating group of the dicyano nucleophilic substrates is demonstrated. Without a trace: The covalent activation of ?,?-unsaturated aldehydes with malononitrile produced remotely enolizable ?-extended allylidene malononitriles. Their amine-catalyzed eliminative [4+2] cycloaddition to aromatic and aliphatic enals enabled the construction of cyclohexadiene-containing polycycles with outstanding diastereo- and enantioselectivities. The essential role of the malononitrile handle as a traceless activating moiety was demonstrated.