Enantioselective Synthesis of C−O Axially Chiral Diaryl Ethers by NHC‐Catalyzed Atroposelective Desymmetrization**

Abstract

Axially chiral diaryl ethers, a distinguished class of atropisomers possessing unique dual C−O axis, hold immense potential for diverse research domains. In contrast to the catalytic enantioselective synthesis of conventional single axis bearing atropisomers, the atroposelective synthesis of axially chiral ethers containing flexible C−O axis remains a significant challenge. Herein, we demonstrate the first N‐heterocyclic carbene (NHC)‐catalyzed synthesis of axially chiral diaryl ethers via atroposelective esterification of dialdehyde‐containing diaryl ethers. Mechanistically, the reaction proceeds via NHC‐catalyzed desymmetrization strategy to afford the corresponding axially chiral diaryl ether atropisomers in good yields and high enantioselectivities under mild conditions. The derivatization of the synthesized product expands the utility of present strategy via access to a library of C−O axially chiral compounds. The temperature dependency and preliminary investigations on the racemization barrier of C−O bonds are also presented.

NHC-Catalyzed Reaction of Aldehydes for C(sp2)–O Bond Formation

“…Catalysts 2024, 14, x FOR PEER REVIEW 6 of 47 transformation is achieved through the NHC-catalyzed desymmetrization of dialdehyde 24 and the further kinetic resolution via the second esterification of the undesired enantiomer of ester 25. The atroposelective esterification of dialdehyde 26 was also studied [79,80]. The NHC-catalyzed desymmetrization of prochiral dialdehyde 26 gave the axially chiral diaryl ether 27 with the excellent enantioselectivity.…”

Evolution in the asymmetric synthesis of biaryl ethers and related atropisomers

“…Biju's group was the first to disclose a straightforward atropselective synthesis of axially chiral dialdehydes with an NHC-catalysed desymmetrization of the 2-aryloxyisophthaladehydes 24 with various aryl alcohols 25 (Scheme 6). 24 This desymmetrization process involves the oxidative generation of acylazolium intermediate 26 from the substrates 24 with the assistance of NHC generated from triazolium salt C-3 and an external oxidant 27 . The resulting intermediate 26 is trapped by suitable alcohol to yield desymmetrized axially chiral biaryl ethers 28 .…”

Synthesis of axially chiral diaryl ethers via NHC-catalyzed atroposelective esterification

“…At the same time, the second enantiodifferentiation step for aldehydes could amplify the stereoinduction ability of the chiral catalyst, which might provide opportunities for challenging chiral induction of flexible dual-axial chirality, in analogy to the Horeau principle. 20 As part of our continued interests in NHC-catalyzed transformations 21 and asymmetric catalysis, 18 g ,22 we now report an asymmetric esterification approach to axially chiral diaryl ethers by chiral NHC-catalyzed desymmetrization of dicarbaldehydes 23 with alcohols/phenols 23 a – c ,24 (Scheme 1e). The over-esterification could act as an additional stereocontrolling filter to improve the enantioselectivity, leading to excellent chiral induction for C–O axially chiral diaryl ethers.…”