Organocatalyzed Asymmetric Intermolecular Annulation of Nucleophilic Imines with High-Temperature-Dependent Enantioselectivity

Reactions involving imines have been extensively studied with the bulk of the research centered on their reactivity toward nucleophiles. In contrast, the nucleophilic character of imine nitrogen and its capacity to initiate reactions remain largely unexplored. Herein, we report an organocatalyzed, intermolecular enantioselective annulation between cyclic α,β-unsaturated imines and <i>in situ</i> generated 8-methylene-2-ones derived from 1-ethynyl-2-naphthols. Leveraging nucleophilic attack by the imine nitrogen and subsequent intramolecular Friedel-Crafts reaction, cyclic α-amino acid derivatives were successfully furnished in high yields with excellent enantioselectivities. This newly established methodology exhibits broad functional group compatibility and is operationally straightforward. Notably, elevated temperatures resulted in simultaneous improvements in enantioselectivity, an unusual effect that was rationalized by the temperature-promoted dissociation of the catalyst dimer into the catalytically competent monomer. Computational studies further elucidated the temperature-dependent reaction efficiency and the key stereodetermining interactions.