Catalytic Enantioselective Synthesis of Axially Chiral Diaryl Ethers Via Asymmetric Povarov Reaction Enabled Desymmetrization

• Published in: Advanced science Vol. 11; no. 35; pp. e2403125 - n/a
• Main Authors: Ye, Zidan, Xie, Wansen, Liu, Wei, Zhou, Changyu, Yang, Xiaoyu
• Format: Journal Article
• Language: English
• Published: Germany John Wiley & Sons, Inc 01-09-2024; John Wiley and Sons Inc; Wiley
• Subjects: asymmetric catalysis; atropisomerism; desymmetrization; diaryl ethers; Investigations; Povarov reaction; Protocol; Povarov reaction; desymmetrization; asymmetric catalysis; atropisomerism; diaryl ethers
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202403125

Axially chiral diaryl ethers represent a distinct class of atropisomers, characterized by a unique dual C─O axes system, which have been found in a variety of natural products, pharmaceuticals, and ligands. However, the catalytic enantioselective synthesis of these atropoisomers poses significant challenges, due to the difficulty in controlling both chiral C─O axes, and their more flexible conformations. Herein, an efficient protocol for catalytic enantioselective synthesis of axially chiral diaryl ethers is presented using organocatalyzed asymmetric Povarov reaction‐enabled desymmetrization, followed by aromatizations. This method yields a wide range of novel quinoline‐based diaryl ether atropoisomers in good yields and high enantioselectivities. Notably, various aromatization protocols are developed, resulting in a diverse set of polysubstituted quinoline‐containing diaryl ether atropisomers. Thermal racemization studies suggested excellent configurational stabilities for these novel diaryl ether atropisomers (with racemization barriers up to 38.1 kcal mol−1). Moreover, this research demonstrates for the first time that diaryl ether atropisomers lacking the bulky t‐Bu group can still maintain a stable configuration, challenging the prior knowledge in the field. The fruitful derivatizations of the functional group‐rich chiral products further underscore the value of this method.
An efficient and stereoselective protocol is developed for the catalytic enantioselective synthesis of axially chiral diaryl ethers, a unique class of atropisomers characterized by a dual C─O axes system. This method leverages organocatalyzed asymmetric Povarov reaction‐enabled desymmetrization, followed by various aromatization protocols, which resulted in a diverse array of novel polysubstituted quinoline‐containing diaryl ether atropisomers with high enantioselectivities.