Exploring the Vinylogous Reactivity of Cyclohexenylidene Malononitriles: Switchable Regioselectivity in the Organocatalytic Asymmetric Addition to Enals Giving Highly Enantioenriched Carbabicyclic Structures

• Published in: Journal of the American Chemical Society 2014-08, Vol.136 (31), p.11107-11114
• Main Authors: Dell’Amico, Luca, Rassu, Gloria, Zambrano, Vincenzo, Sartori, Andrea, Curti, Claudio, Battistini, Lucia, Pelosi, Giorgio, Casiraghi, Giovanni, Zanardi, Franca
• Format: Article
• Language: English
• Subjects: Aldehydes - chemistry; Bridged Bicyclo Compounds - chemistry; Catalysis; Cycloaddition Reaction; Cyclohexenes - chemistry; Methane - analogs & derivatives; Methane - chemistry; Nitriles - chemistry; Spiro Compounds - chemistry; Stereoisomerism; Substrate Specificity
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja5054576

Modulation of the complex reactivity of cyclohexenylidene malononitriles using diverse β-aryl-substituted enals and proper organocatalytic modalities resulted in divergent asymmetric reaction patterns to furnish angularly fused or bridged carbabicyclic frameworks. In particular, use of remotely enolizable dicyanodienes 1, under one-pot sequential amine/NHC catalysis, led to [3 + 2] cycloaddition to afford ε,δ-bonded spiro[4.5]­decanone structures 5. Alternatively, modifying the standard amine catalysis by adding a suitable chemical stimulus (p-nitrophenol cocatalyst) switched the reactivity decidedly toward a domino [4 + 2] cycloaddition to afford γ′,δ-bonded bicyclo[2.2.2]­octane carbaldehydes 8. Products invariably formed in good yields, with rigorous chemo-, regio-, diastereo-, and enantiocontrol. Experimental evidence, including carbon isotope effects measured by 13C NMR, were indicative of the rate (and stereochemistry) determining step of these transformations and suggested a stepwise mechanism for the [4 + 2] cycloadditive pathway.