Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences , and ‡School of Chemistry and Chemical Engineering , Chongqing University , Chongqing 401331 , China.
College of Chemistry and Molecular Engineering , Zhengzhou University , Zhengzhou 450001 , China.
J Am Chem Soc. 2019 Jan 16;141(2):961-971. doi: 10.1021/jacs.8b10939. Epub 2018 Dec 31.
A novel chiral phosphine-urea bifunctional ligand has been developed for Cu-catalyzed asymmetric 1,3-dipolar cycloaddition of iminoesters with methacrylonitrile, a long-standing challenging substrate in asymmetric catalysis. Distortion-interaction energy analysis based on density functional theory (DFT) calculations reveals that the distortion energy plays an important role in the observed enantioselectivity, which can be attributed to the steric effect between the phosphine ligand and the dipole reactant. DFT calculations also indicate that nucleophilic addition is the enantioselectivity-determining step and hydrogen bonding between the urea moiety and methacrylonitrile assists in control of the diastereo- and enantioselectivity. By a combination of metal catalysis and organocatalysis, excellent diastereo- and enantioselectivities (up to 99:1 diastereomeric ratio, 99% enantiomeric excess) as well as good yields are achieved. A wide range of substitution patterns of both iminoester and acrylonitrile is tolerated by this catalyst system, providing access to a series of highly substituted chiral cyanopyrrolidines with up to two quaternary stereogenic centers. The synthetic utility is demonstrated by enantioselective synthesis of antitumor agent ETP69 with a pivotal nitrile pharmacophore and an all-carbon quaternary stereogenic center.
一种新型的手性膦脲双功能配体已被开发用于铜催化的亚胺酯与丙烯腈的不对称 1,3-偶极环加成反应，这是不对称催化中一个长期具有挑战性的底物。基于密度泛函理论（DFT）计算的扭曲相互作用能分析表明，扭曲能在观察到的对映选择性中起着重要作用，这可以归因于膦配体和偶极反应物之间的空间位阻效应。DFT 计算还表明，亲核加成是对映选择性决定步骤，脲部分和丙烯腈之间的氢键有助于控制非对映和对映选择性。通过金属催化和有机催化的结合，实现了优异的非对映和对映选择性（高达 99:1 的非对映体比例，99%的对映体过量）以及良好的产率。该催化剂体系对亚胺酯和丙烯腈的广泛取代模式具有耐受性，为一系列具有高达两个季碳手性中心的高度取代的手性氰基吡咯烷提供了途径。通过具有关键的腈药效团和全碳季碳手性中心的抗肿瘤剂 ETP69 的对映选择性合成证明了其合成实用性。
