Laboratory of Synthesis and Natural Products, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, EPFL-SB-ISIC-LSPN, BCH5304, CH-1015 Lausanne, Switzerland.
School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China.
J Am Chem Soc. 2021 May 19;143(19):7320-7325. doi: 10.1021/jacs.1c03915. Epub 2021 May 6.
Chiral morpholinone is an important building block in organic synthesis and a pharmacophore in medicinal chemistry. However, catalytic enantioselective methods for the construction of this ,-heterocycle remain scarce. We report herein a chiral phosphoric acid-catalyzed enantioselective synthesis of C3-substituted morpholinones from aryl/alkylglyoxals and 2-(arylamino)ethan-1-ols. The reaction proceeds through a domino [4 + 2] heteroannulation followed by a 1,2-aryl/alkyl shift of the resulting cyclic α-iminium hemiacetals. It represents formally an unprecedented asymmetric aza-benzilic ester rearrangement reaction. A concise synthesis of L-742,694, a neurokinin-1 receptor antagonist, featuring this reaction is documented.
手性吗啉酮是有机合成中的重要构建块，也是药物化学中的药效团。然而，催化对映选择性方法构建这种[C3]-杂环仍然很少。我们在此报告了一种手性磷酸催化的对映选择性合成 C3-取代吗啉酮的方法，该方法由芳基/烷基乙二醛和 2-(芳基氨基)乙醇-1-醇反应得到。该反应通过[4+2]杂芳环加成反应进行，然后是生成的环状α-亚氨基半缩醛的 1,2-芳基/烷基迁移。它代表了一种前所未有的不对称氮杂-安息香酸酯重排反应。本文记录了以该反应为特色的神经激肽-1 受体拮抗剂 L-742,694 的简洁合成。
