Enantioselective desymmetrization is a powerful strategy in asymmetric synthesis. By differentiating two identical enantiotopic functional groups through simple transformations, asymmetric desymmetrizations provide efficient protocols for the synthesis of chiral compounds from easily available starting materials. The strategy has been successfully applied in a broad range of organocatalytic and transition metal-catalyzed asymmetric reactions. Copper-catalyzed coupling reactions are one of the most important methods for the construction of aryl or alkenyl carbon-heteroatom bonds. But the asymmetric coupling reactions remain a great challenge. It may be because that the bonds are generally formed between sp²-hybrized carbon and heteroatoms like N or O, and no chiral carbon centers were involved in the bond formation process. By utilizing desymmetrization strategies, we have developed a variety of copper-catalyzed enantioselective aryl carbon-heteroatom bond coupling reactions. However, the research on copper-catalyzed asymmetric alkenyl C-heteroatom coupling is rarely reported, and only one example of enantioselective copper-catalyzed alkenyl C—O bond coupling was achieved recently by Liu and co-workers via the desymmetrization strategy. In a previous work, we reported a desymmetric intramolecular aryl C—N coupling reaction of 2-(2-iodobenzyl)malonamides for the synthesis of chiral 2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamides. During the course, we believed that such a desymmetrization strategy should also be applicable to alkenyl C—N bond coupling reactions. To explore this idea, in this work, an enantioselective alkenyl C—N coupling is developed. It is a copper- catalyzed intramolecular desymmetric reaction with 2-(3-iodoallyl)malonamides as the substrates. Under the catalysis of 10 mol% CuI and 15 mol% of chiral diamine ligand, the reactions of 2-(3-iodoallyl)malonamides proceeded smoothly at room temperature inN,N-dimethylformamide (DMF), with K₃PO₄ as the base. It afforded the desired 2-oxo-1,2,3,4-tetrahydro- pyridine-3-carboxamide products bearing quaternary stereogenic carbon centers in high yields and moderate enantioselectivities. An example of double alkenyl C—N coupling for the synthesis of chiral 2,8-diazaspiro[5.5]undeca-3,9-diene-1,7-dione spirocyclic product was also demonstrated. Although the enantioselectivity is unsatisfactory, the reactions expanded the scope of copper-catalyzed asymmetric C—N coupling from aryl to alkenyl C—N coupling. It may find further applications in the synthesis of chiral heterocycles.

Key words: asymmetric desymmetrization, copper-catalysis, C—N coupling, enantioselectivity, asymmetric synthesis