Abstract
The construction of axially chiral N-heterobiaryls is of great interest as a result of their occurrence in organocatalysts, chiral ligands, natural products, and biologically active molecules. Despite remarkable achievements in this area, strategies for the preparation of new classes of axially chiral N-heterobiaryls remain to be further explored. Herein, we report the enantioselective synthesis of axially chiral arylquinolizones through an intramolecular atroposelective cycloisomerization. The reaction proceeds via the Brønsted acid-enhanced dearomatization of pyridine by a copper catalyst that allows for the formation of the desired products in excellent yields and enantioselectivities. The utility of this methodology is illustrated by a synthesis on gram scale production and transformation of the products into chiral thiourea catalysts. Mechanistic studies demonstrate that Brønsted acid plays a significant role in promoting the reactivity of the reaction, while both the steric and electronic effects of aryl substituents in substrate play a role in controlling the stereoselectivity.
Highlights
The construction of axially chiral N-heterobiaryls is of great interest as a result of their occurrence in organocatalysts, chiral ligands, natural products, and biologically active molecules
As part of our continuing efforts in axially chiral compounds[26,49,50,51], we envisioned that catalytic asymmetric dearomatization (CADA) of nucleophilic pyridines might be used for the atroposelective cycloisomerization to axially chiral arylquinolizones
We evaluated the reaction conditions by using 1a as the model substrate for the synthesis of axially chiral arylquinolizones
Summary
The construction of axially chiral N-heterobiaryls is of great interest as a result of their occurrence in organocatalysts, chiral ligands, natural products, and biologically active molecules. As part of our continuing efforts in axially chiral compounds[26,49,50,51], we envisioned that CADA of nucleophilic pyridines might be used for the atroposelective cycloisomerization to axially chiral arylquinolizones If successful, it would represent the first example of their facile construction from readily prepared alkyne starting materials. At the outset of our studies, we anticipated that several challenges that may arise during our efforts to develop this cycloisomerization process: (1) The sp[2] nitrogen lone pair of the pyridine directed outward the ring skeleton which is well directed to have overlap with vacant metal orbital in producing an σ bonding interaction This may cause pyridine to be a good ligand, resulting in poisoning and deactivation of the metal catalyst. We report a Brønsted acid-enhanced copper-catalyzed atroposelective cycloisomerization to access axially chiral arylquinolizones via dearomatization of pyridines 1 (Fig. 1e)
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