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

Switchable
reaction patterns of β-substituted cyclic enones
via amine-based dienamine activation are reported. While γ-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 Diels–Alder cycloaddition pathway.