Enantioselective Synthesis of Isoquinuclidine Analogs by Synergistic Copper/Amine‐Catalyzed Sequential [3 + 3]/[4 + 2] Cycloaddition

Abstract

ABSTRACT The development of efficient and concise methods for the construction of chiral three‐dimensional isoquinuclidine (2‐azabicyclo[2.2.2]octane) analogs from readily available flat molecules would be highly valuable for drug discovery. Although the [4+2] cycloaddition of 1,2‐dihydropyridines (1,2‐DHPs) with alkenes has been extensively studied for the synthesis of isoquinuclidine analogs, 3,4‐dihydropyridines (3,4‐DHPs), a potentially useful class of azadienes, have remained largely unexamined in this context, which has seriously restricted the structural type of the isoquinuclidine analogs. Herein, we report a synergistic copper/amine‐catalyzed annulative assembly strategy for the construction of chiral 3,4‐DHPs from readily accessible oximes and enals. The copper catalyst reduces the N─O bond to afford a nucleophilic species, and the amine catalyst activates the enals via iminium activation. The in situ formed 3,4‐DHPs can undergo enantioselective [4+2] cycloaddition for the synthesis of a series of chiral isoquinuclidine analogs. In these reactions, 2‐ tert ‐butylhydroquinone was exploited as a mild reductant to reduce in situ formed Cu(II) species, thus suppressing oxidative aromatization of 3,4‐DHPs and oxidative decomposition of amine catalyst. This method displays broad substrate scope and good functional group compatibility, and affords the products containing four stereocenters with up to two vicinal quaternary carbon centers in generally good yields with excellent diastereoselectivity and good enantioselectivity.