Catalytic Asymmetric Synthesis of Axially Chiral Diaryl Ethers through Enantioselective Desymmetrization

Abstract

Axially chiral diaryl ethers are a type of unique atropisomers bearing two potential axes, which have potential applications in a variety of research fields. However, the catalytic enantioselective synthesis of these diaryl ether atropisomers is largely underexplored when compared to the catalytic asymmetric synthesis of biaryl or other types of atropisomers. Herein, we report a highly efficient catalytic asymmetric synthesis of diaryl ether atropisomers through an organocatalyzed enantioselective desymmetrization protocol. The chiral phosphoric acid‐catalyzed asymmetric electrophilic aromatic aminations of the symmetrical 1,3‐benzenediamine type substrates afforded a series of diaryl ether atropisomers in excellent yields and enantioselectivities. The facile construction of heterocycles by the utilizations of the 1,2‐benzenediamine moiety in the products provided access to a variety of structurally diverse and novel azaarene‐containing diaryl ether atropisomers.

Atroposelective Synthesis of Axially Chiral Diaryl Ethers by N-Heterocyclic-Carbene-Catalyzed Sequentially Desymmetric/Kinetic Resolution Process

“…Collectively, both the desymmetric process and the kinetic resolution process play vital roles in the construction of 3aa with excellent enantioselectivity. Based on our control experiments and reported literature, a possible catalytic cycle was proposed as Scheme (3) . First, an active catalyst NHC-cat was formed by the reaction between NHC-1 and Cs 2 CO 3 .…”

“…In 2008, Clayden’s group documented the first enantioselective synthesis of an atropisomeric diaryl ether through dynamic resolution . Thereafter, the Clayden, Zeng and Zhong, and Yang groups realized the atroposelective construction of the axially diaryl ethers via biocatalytic or organocatalytic desymmetrization of prochiral diaryl ethers respectively (Scheme a) . In 2018, Gustafson and co-workers developed a C­(sp 2 )–H alkylation with nitroalkanes to access enantioenriched diaryl ethers with a quaternary ammonium salt (derived from quinine) as the catalyst .…”

Bioactive atropisomers: Unraveling design strategies and synthetic routes for drug discovery

“…Fortunately, many chemists have made significant strides in developing numerous asymmetric synthesis methods to create a diverse range of atropisomers [151][152][153][154][155][156][157][158][159][160][161][162][163][164][165][166][167][168] and these methodologies are continually evolving. Furthermore, some atropisomers, not covered in this review, such as those C▬B bonded, 168 C▬O bonded, 169 C▬S bonded 170 atropisomers, also been successfully synthesized, albeit without their activities being tested. This expands the structural diversity available and provides additional synthetic insights for the development of future atropisomeric drugs.…”

Asymmetric Synthesis of Axially Chiral Molecules via Organocatalytic Cycloaddition and Cyclization Reactions

“…Diaryl ether, another type of nonbiaryls containing C-O-C bonds, was proved by Mislow et al in 1982 [21], but its synthesis was not reported until 1998 by Kinoshita et al [22]. At present, there is still a large room for research on this kind of compounds, and new progresses have been developed for the synthesis of these compounds by using organocatalytic strategies in recent years [23].…”