Chiral Phosphoric Acid Catalyzed Asymmetric Ugi Reaction by Dynamic Kinetic Resolution of the Primary Multicomponent Adduct

• Published in: Angewandte Chemie International Edition 2016-04, Vol.55 (17), p.5282-5285
• Main Authors: Zhang, Yun, Ao, Yu-Fei, Huang, Zhi-Tang, Wang, De-Xian, Wang, Mei-Xiang, Zhu, Jieping
• Format: Article
• Language: English
• Subjects: asymmetric synthesis; Asymmetry; Catalysis; Chemical industry; Enantiomers; Forming; kinetic resolution; multicomponent reaction; organocatalysis; Phosphoric acid; reaction mechanisms; Synthesis
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201600751

Reaction of isonitriles with 3‐(arylamino)isobenzofuran‐1(3H)‐ones in the presence of a catalytic amount of an octahydro (R)‐binol‐derived chiral phosphoric acid afforded 3‐oxo‐2‐arylisoindoline‐1‐carboxamides in high yields with good to high enantioselectivities. An enantioselective Ugi four‐center three‐component reaction of 2‐formylbenzoic acids, anilines, and isonitriles was subsequently developed for the synthesis of the same heterocycle. Mechanistic studies indicate that the enantioselectivity results from the dynamic kinetic resolution of the primary Ugi adduct, rather than from the C−C bond‐forming process. The resulting heterocycle products are of significant medicinal importance. Ugi for real: Reaction of isonitriles (A) with 3‐(arylamino)isobenzofuran‐1(3H)‐ones (B) in the presence of a catalytic amount of chiral phosphoric acid (CPA) afforded 3‐oxo‐2‐arylisoindoline‐1‐carboxamides (C) in high yields with good to high enantioselectivities. An enantioselective Ugi multicomponent reaction of D, E, and A was subsequently developed for the synthesis of the same heterocycle C.