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

Abstract

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 π‐extended allylidenemalononitriles as electron‐rich 1,3‐diene precursors in a direct eliminative [4+2] cycloaddition with both aromatic and aliphatic α,β‐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.

New Developments of the Principle of Vinylogy as Applied to π-Extended Enolate-Type Donor Systems

“…The following year, Zanardi and co-workers reported the use of allylidene malononitriles of type 1059 ( Scheme 270 , eq 1) as vinylogous donors, whose π-system conjugation propagates the nucleophilic character to the remote ε-position on the cycle. 685 The reaction with both aliphatic and aromatic enals 1060 , catalyzed by prolinol-derived catalyst A4 , provided a series of fused polycycles 1061 in good yields, complete trans -diastereoselectivity, and very high enantioselectivities, via a formal [4 + 2]-eliminative cycloaddition reaction. The authors proposed a plausible mechanism, describing the reaction as a stepwise domino process involving a bis-vinylogous Michael/Michael/retro-Michael organocascade.…”

Turning the Imidazole Core into Three‐Dimensional Ring Systems: Mild Organocatalytic Entry to Enantiopure 6,7‐Dihydrobenzimidazoles

“…Based on the above observations, and also considering precedents on the use of methylenemalononitrile pro‐diene precursors in successful [4+2] cycloadditions, [9c,16a] a plausible catalytic cycle for the present [4+2] cycloaddition between dicyanovinyl substrates 4 and β‐aryl enals 2 is illustrated in Scheme 3. Initial in situ formation of the key IM‐ o QDM dienophile and iminium ion dienophile 2‐cat from the respective precursors 4 and 2 is triggered by the cooperative action of the Et 3 N promoter and silylprolinol catalyst C1 .…”

1,3-Cyclohexadien-1-Als: Synthesis, Reactivity and Bioactivities

“…A formal eliminative (4 + 2) cycloaddition can be performed, starting from a γ-enolizable α,β-unsaturated carbonyl compound (diene) and an enal (dienophile) ( Scheme 33 ) [ 65 ]. The addition of an organocatalyst allows for a diastereoselection in the cycloaddition through the formation of the Schiff-base.…”