Stereodivergence in Amine-Catalyzed Regioselective [4+2] Cycloadditions of β-Substituted Cyclic Enones and Polyconjugated Malononitriles

Switchable reaction patterns of beta-substituted cyclic enones via amine-based dienamine activation are reported. While gamma-regioselective vinylogous Michael addition was observed with alkylidenemalononitriles, a completely different [4 + 2] cycloaddition was obtained with allylidene- or alkynylidenemalononitrile substrates, affording densely substituted bicyclo[2.2.2]octanes or analogous architectures with moderate to excellent diastereo- and enantioselectivity by the catalysis of primary amines from natural quinidine or quinine. Importantly, high diastereodivergence was achieved through unusual hydrogen-bonding interactions of multifunctional primary-amine catalytic systems. Endo cycloadducts were efficiently produced using a combination of 9-amino-9-deoxyepiquinidine and salicylic acid, while exo variants were obtained using 6'-hydroxy-9-amino-9-deoxyepiquinidine. Moreover, we successfully isolated the Michael addition intermediates in some cases, indicating that the above [4 + 2] reaction via dienamine catalysis may proceed by a stepwise Michael-Michael cascade rather than by a concerted Diets-Alder cycloaddition pathway.