Wang Qingyun, Wu Shuquan, Zou Juan, Liang Xuyang, Mou Chengli, Zheng Pengcheng, Chi Yonggui Robin
National Key Laboratory of Green Pesticide, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University, Guiyang, 550025, China.
Center for Industrial Catalysis and Cleaning Process Development, School of Chemical Engineering, Guizhou Minzu University, Guiyang, 550025, China.
Nat Commun. 2023 Aug 12;14(1):4878. doi: 10.1038/s41467-023-40645-8.
A carbene-catalyzed asymmetric access to chiral β-cyano carboxylic esters is disclosed. The reaction proceeds between β,β-disubstituted enals and aromatic thiols involving enantioselective protonation of enal β-carbon. Two main factors contribute to the success of this reaction. One involves in situ ultrafast addition of the aromatic thiol substrates to the carbon-carbon double bond of the enal substrate. This reaction converts almost all enal substrate to a Thiol-click Intermediate, significantly reducing aromatic thiol substrates concentration and suppressing the homo-coupling reaction of enals. Another factor is an in situ release of enal substrate from the Thiol-click Intermediate for the desired reaction to proceed effectively. The optically enriched β-cyano carboxylic esters from our method can be readily transformed to medicines that include γ-aminobutyric acids derivatives such as Rolipram. In addition to synthetic utilities, our control of reaction outcomes via in situ substrate modulation and release can likely inspire future reaction development.
公开了一种通过卡宾催化不对称合成手性β-氰基羧酸酯的方法。该反应在β,β-二取代烯醛和芳族硫醇之间进行，涉及烯醛β-碳的对映选择性质子化。该反应成功的两个主要因素如下。一个因素是芳族硫醇底物原位快速加成到烯醛底物的碳-碳双键上。该反应几乎将所有烯醛底物转化为硫醇点击中间体，显著降低了芳族硫醇底物的浓度并抑制了烯醛的均偶联反应。另一个因素是硫醇点击中间体原位释放烯醛底物，以使所需反应有效进行。通过我们的方法得到的光学富集的β-氰基羧酸酯可以很容易地转化为药物，包括γ-氨基丁酸衍生物如咯利普兰。除了合成应用外，我们通过原位底物调节和释放对反应结果的控制可能会激发未来反应的发展。
