摘要/Abstract

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.
关键词: 不对称去对称化, 铜催化, 碳氮偶联, 对映选择性, 不对称合成
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


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