Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China.
Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
Nat Commun. 2020 Mar 23;11(1):1511. doi: 10.1038/s41467-020-15345-2.
Enantioselective α-aminomethylation of carbonyl compounds constitutes a powerful protocol for introducing aminomethyl groups to simple organic molecules. However, current strategies rely on nucleophile-based enantioselective activation with inherently activated substrates only, and enantioselective protocol based on the activation of in situ-generated unstable formaldimines remains elusive, probably owing to their unstable nature and the lack of steric environment for efficient stereocontrols. Here, based on a rhodium/chiral phosphoric acid cooperative catalysis, we achieved an enantioselective three-component reaction of α-diazo ketones with alcohols and 1,3,5-triazines. A dual hydrogen bonding between the chiral phosphoric acid catalyst and two distinct active intermediates was proposed to be crucial for the efficient electrophile-based enantiocontrol. A series of chiral β-amino-α-hydroxy ketones including those derived from simple aliphatic alcohols, allylic alcohol, propargyl alcohol, complicated natural alcohols and water could all be prepared in high efficiency and enantioselectivity.
手性羰基化合物的对映选择性α-氨甲基化反应是将氨甲基基团引入简单有机分子的有效方法。然而，目前的策略依赖于基于亲核试剂的对映选择性活化，仅适用于固有活化的底物，而基于原位生成的不稳定甲亚胺的对映选择性反应仍然难以捉摸，这可能是由于其不稳定的性质和缺乏有效的立体控制的空间环境。在这里，基于铑/手性磷酸协同催化，我们实现了α-重氮酮与醇和 1,3,5-三嗪的对映选择性三组分反应。手性磷酸催化剂与两个不同的活性中间体之间的双重氢键被认为对于基于亲电试剂的对映选择性控制至关重要。一系列手性β-氨基-α-羟基酮，包括那些衍生自简单脂肪醇、烯丙醇、炔丙醇、复杂天然醇和水的化合物，都可以以高效率和对映选择性制备。
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