Organocatalytic, Asymmetric Eliminative [4+2] Cycloaddition of Allylidene Malononitriles with Enals: Rapid Entry to Cyclohexadiene Embedding Linear and Angular Polycycles

Six-membered carbocycles, as well as five- and seven membered rings, are common motifs in nature and they can be found in many terpenoid, polyketide, and shikimate derived monocyclic and polycyclic molecular architectures.1 A direct aminocatalytic synthesis has been developed for the chemo-, regio-, diastereo-, and enantioselective construction of densely substituted polycyclic carbaldehydes containing fused cyclohexadiene rings2. 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 bisvinylogous Michael/Michael/retro-Michael reaction cascade. The utility of the malononitrile moiety as traceless activating group of the dicyano nucleophilic substrates is demonstrated. 1) P. M. Dewick in Medicinal Natural Products. A Biosynthetic Approach, 2nd ed., Wiley, Chichester, 2002 2) N. Brindani, G. Rassu, L. Dell'Amico, V. Zambrano, L. Pinna, C. Curti, A. Sartori, L. Battistini, G. Casiraghi, G. Pelosi, D. Greco, F. Zanardi Angew. Chem. Int. Ed. 2015, 54, 7386 -7390