<br>金鸡纳生物碱氯环化催化剂的结构-对映选择性关系 (SER) 研究,The Journal of Organic Chemistry

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金鸡纳生物碱氯环化催化剂的结构-对映选择性关系 (SER) 研究
The Journal of Organic Chemistry ( IF 3.3 ) Pub Date : 2023-02-16 , DOI: 10.1021/acs.joc.3c00084
Sarah E Luderer ₁ , Behrad Masoudi ₁ , Aritra Sarkar ₁ , Calvin Grant ₁ , Arvind Jaganathan ₁ , James E Jackson ₁ , Babak Borhan ₁

Affiliation

研究金鸡纳生物碱二聚体的各种结构元素，以在三种不同的卤环化反应中建立结构-对映选择性关系 (SER)。 1,1-二取代链烯酸、1,1-二取代链烯酰胺和反式-1,2-二取代链烯酰胺的氯环化 SER 显示出对接头刚性和极性、生物碱结构方面以及存在的不同敏感性。两个或仅一个生物碱侧基限定催化剂袋。通过对甲氧基化模型进行 DFT 计算，探究了连接基-醚连接的构象刚性，发现了包含哒嗪环的芳烃系统中醚平面外旋转的特别高的障碍。这些连接基也存在于具有最高对映诱导作用的催化剂中。 SER 结果的多样性表明，三个明显相似的测试反应可能通过显着不同的机制进行。基于这些发现，设计、合成和评估了 (DHQD) ₂ PYDZ 的精简类似物，称为“(trunc) ₂ PYDZ”，在三个测试反应中显示出适度但相当大的不对称诱导，具有最佳性能1,1-二取代烯酰胺环化。这是首次努力找出有效立体控制和反应促进所必需的因素，为新型选择性有机催化剂的简化设计和系统改进提供了指导。

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Structure–Enantioselectivity Relationship (SER) Study of Cinchona Alkaloid Chlorocyclization Catalysts

Various structural elements of the Cinchona alkaloid dimers are interrogated to establish a structure–enantioselectivity relationship (SER) in three different halocyclization reactions. SER for chlorocyclizations of a 1,1-disubstituted alkenoic acid, a 1,1-disubstituted alkeneamide, and a trans-1,2-disubstituted alkeneamide showed variable sensitivities to linker rigidity and polarity, aspects of the alkaloid structure, and the presence of two or only one alkaloid side group defining the catalyst pocket. The conformational rigidity of the linker–ether connections was probed via DFT calculations on the methoxylated models, uncovering especially high barriers to ether rotation out of plane in the arene systems that include the pyridazine ring. These linkers are also found in the catalysts with the highest enantioinduction. The diversity of the SER results suggested that the three apparently analogous test reactions may proceed by significantly different mechanisms. Based on these findings, a stripped-down analogue of (DHQD)₂PYDZ, termed “(trunc)₂PYDZ”, was designed, synthesized, and evaluated, showing modest but considerable asymmetric induction in the three test reactions, with the best performance on the 1,1-disubstituted alkeneamide cyclization. This first effort to map out the factors essential to effective stereocontrol and reaction promotion offers guidance for the simplified design and systematic refinement of new, selective organocatalysts.

更新日期：2023-02-16

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