Xu Changming, Zhang Long, Luo Sanzhong
Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences , Beijing 100190, China.
J Org Chem. 2014 Dec 5;79(23):11517-26. doi: 10.1021/jo502152w. Epub 2014 Nov 14.
α-Branched ketones remain a challenging type of substrates in aminocatalysis due to their congested structures as well as the associated difficulties in controlling chemo- and stereoselectivity. In this work, we have explored asymmetric aminocatalysis with α-substituted β-ketoesters. A simple chiral primary amine catalyst was identified to enable unprecedentedly effective catalysis of β-ketoesters in α-hydrazination and Robinson annulation reaction with good yields and high enantioselectivities. Stoichiometric experiments with preformed enamine ester intermediates revealed their enamine-catalytic nature as well as the critical roles of acidic additives in facilitating catalytic turnovers and in tuning the chemo- and stereoselectivity. With the identical catalytic system, the two reactions demonstrated opposite chiral inductions in terms of the absolute configurations of the newly formed stereogenic centers. Investigations into this intriguing issue by DFT have revealed divergent stereocontrol modes. For α-hydrazination, H-bonding-directed facial attack determines the stereoselectivity, whereas a steric model is applied to the Robinson annulation where dual activations of both β-ketoester and vinyl ketone/aldehyde are involved.
由于α-支链酮结构拥挤，以及在控制化学选择性和立体选择性方面存在相关困难，它们在氨基催化中仍然是一类具有挑战性的底物。在这项工作中，我们探索了用α-取代的β-酮酯进行不对称氨基催化。我们发现一种简单的手性伯胺催化剂能够以前所未有的效率催化β-酮酯的α-肼化反应和罗宾逊缩环反应，产率高且对映选择性好。对预先形成的烯胺酯中间体进行的化学计量实验揭示了它们的烯胺催化性质，以及酸性添加剂在促进催化周转和调节化学选择性和立体选择性方面的关键作用。在相同的催化体系下，这两个反应在新形成的立体中心的绝对构型方面表现出相反的手性诱导。通过密度泛函理论（DFT）对这个有趣问题的研究揭示了不同的立体控制模式。对于α-肼化反应，氢键导向的面进攻决定了立体选择性，而对于涉及β-酮酯和乙烯基酮/醛双重活化的罗宾逊缩环反应，则应用了空间模型。
