铜催化不对称去对称化分子内烯基C-N偶联反应

Copper(I)-Catalyzed Asymmetric Desymmetric Intramolecular Alkenyl C-N Coupling Reaction

不对称去对称化是不对称合成中常用的有效策略.基于去对称化反应,可以利用简单转化区分两个相同的官能团,从而实现高效的手性合成.本工作基于我们前期在分子内不对称去对称化芳基C—N偶联反应的基础,发展了铜催化2-(3-碘烯丙基)-丙二酰胺的分子内不对称去对称化烯基C—N偶联反应.以良好的收率和中等的对映选择性获得了一系列手性2-氧代-1,2,3,4-四氢吡啶-3-酰胺产物.

Enantioselective desymmetrization is a powerful strategy in asymmetric synthesis.By differentiating two identi-cal 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 cou pling 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 desym metrization strategies,we have developed a variety of copper-catalyzed enantioselective aryl carbon-heteroatom bond cou pling 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 cou-pling 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 cou-pling 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 in N,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 enantioselectivi ties.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.