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Atropisomers: Synthesis, Analysis, and Applications
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Accounts of Chemical Research

Cite this: Acc. Chem. Res. 2023, 56, 3, 187–188
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https://doi.org/10.1021/acs.accounts.2c00765
Published February 7, 2023

Copyright © Published 2023 by American Chemical Society. This publication is available under these Terms of Use.

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Copyright © Published 2023 by American Chemical Society

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Guest Editorial for the Accounts of Chemical Research special issue “Atropisomers: Synthesis, Analysis, and Applications”.

A modern course of stereochemistry might shock Louis Pasteur, Jacobus Henricus van’t Hoff, Joseph Lebel, Lord Kelvin, Charlotte Finch Roberts, and many other pioneers of the field. The tetrahedral nature of carbon notwithstanding, axial and planar chirality, chiral supramolecular assemblies, conformational isomerism, and in particular atropisomerism arising from hindered rotation about a chemical bond have all expanded the field and stimulated an expansive range of investigations ranging from fundamental questions about properties to the development of new ideas and methods for synthesis. The recent and explosive literature addressing atropisomerism in particular has been hard to miss. Naturally occurring molecules that exhibit atropisomerism have a prominent place in the development of the field, as these have stimulated explorations of not only physical organic issues about structure and stability but also new concepts for reaction development. Imaginative design and synthesis of new molecules that exhibit atropisomerism have been no less special in expanding the field. The bridges between chemistry, biology, and physics also feature prominently in the ongoing development of the field, as atropisomeric compounds find applications in medicinal chemistry and materials science. Similarly, small molecule-based catalysis and biocatalysis are rushed to the forefront to confront state-of-the-art challenges in the synthesis of stable single atropisomers. Successes in these campaigns enable a whole new set of studies of the functions of these products as they engage chiral partners in many contexts. Accordingly, we are delighted to present this Special Issue of Accounts of Chemical Research, “Atropisomers: Synthesis, Analysis, and Applications.”

Several Accounts within this special issue address synthetic efforts toward single atropisomers wherein the barrier of rotation is sufficiently high to allow isolation, characterization, and further use. The vast majority of these efforts focus on generation of compounds where the atropisomerism derives from a C–C biaryl bond with 2-fold rotational isomerism, although there are other systems with higher-fold rotational isomerism. Other bonds, such as C–N bonds, can also give rise to similar features. The groups at either end of the atropisomeric bond may be aryls, heteroaryls, alkenes, amides, and even, in select instances, sp3-hybridized centers. Many synthetic methods begin with the atropisomeric bond already formed and employ desymmetrization, kinetic resolution, or dynamic kinetic resolution processes to generate enantioenriched products through a range of chemistries including functional group modification and cyclization. Another common approach is to forge the atropisomeric bond by union of two fragments in a redox-neutral (e.g., Suzuki, C–H activation), oxidative, or reductive coupling manner. Many novel approaches have appeared over the past few years including use of strain-release to break C–C bonds and C–H activation, and this special issue highlights the rich potential of the field.

From the perspective of the pharmaceutical industry, atropisomerism has historically been viewed as a latent threat, potentially leading to synthesis, development, and regulatory challenges associated with the interconversion rate between atropisomeric pairs of biologically active molecules. Considering the pharmacological benefits of preorganizing sigma bonds and limiting the number of accessible conformations of drug molecules, reports of synthetic bioactive molecules bearing configurationally stable axes of atropisomerism have been increasing significantly over the past decade. Modern asymmetric synthesis, catalysis, and biocatalysis, as well as innovative purification and crystallization methods have made atropisomeric drugs more accessible. Sotorasib, the first FDA-approved KRASG12C inhibitor, is a remarkable fully synthetic drug marketed as a single and stable atropisomer. While it is presently a rare, if not unique, example of a synthetic drug with a configurationally stable atropisomeric stereogenic element, several promising drug candidates are being evaluated in various clinical trials (e.g., zunsemetinib, MRTX-1719, RP-6309), and the number of such compounds seems certain to increase in the near future.

Atropisomerism has transitioned from a phenomenon of fundamental interest in chemistry to a design principle in various functional and translational settings. Review articles of a decade ago spelled out the advantages of designing this aspect of dynamic stereochemistry out of target molecules to avoid complexity. Today, atropisomerism is designed in: into target molecules to enhance target selectivity in medicinal chemistry, to create observable dynamics in physical organic contexts, and to test hypotheses about molecular structure and function. As is so often the case, these ambitions in design required advances in synthesis and analysis. In this special issue of Accounts of Chemical Research, leading research groups share their latest results in pushing forward the frontiers for the utility, analysis, and generation of atropisomeric organic structures.

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This article is cited by 24 publications.

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  3. Longhui Yu, Yuuya Nagata, Hugh Nakamura. Atroposelective Total Synthesis of Cihunamide B. Journal of the American Chemical Society 2024, 146 (4) , 2549-2555. https://doi.org/10.1021/jacs.3c11016
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  5. Mohamed S. H. Salem, Shinobu Takizawa. Introduction. 2024, 1-20. https://doi.org/10.1002/9783527844258.ch1
  6. Wei Tan, Xin‐Yue Wu, Feng Shi. Catalytic Atroposelective Construction of Furan‐Based Axially Chiral Scaffolds. ChemCatChem 2024, 16 (21) https://doi.org/10.1002/cctc.202401022
  7. Meng Zhang, Xiaoqun Yang, Xiaolin Peng, Xiangyang Li, Zhichao Jin. Asymmetric construction of axial and planar chirality with N-heterocyclic carbene (NHC) organocatalysis. Science China Chemistry 2024, 56 https://doi.org/10.1007/s11426-024-2363-4
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  10. Xin‐Qi Zhu, Hai‐Yu Yang, Long‐Wu Ye. Chiral Brønsted Acid‐Catalyzed Asymmetric Reaction via Vinylidene Ortho ‐Quinone Methides. Chemistry – A European Journal 2024, 30 (49) https://doi.org/10.1002/chem.202402247
  11. Hiroshige Ogawa, Hugh Nakamura. Atroposelective total synthesis of strecintide 839. Tetrahedron Chem 2024, 11 , 100084. https://doi.org/10.1016/j.tchem.2024.100084
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  15. Jing‐Yi Wang, Cong‐Hui Gao, Cheng Ma, Xin‐Yue Wu, Shao‐Fei Ni, Wei Tan, Feng Shi. Design and Catalytic Asymmetric Synthesis of Furan‐Indole Compounds Bearing both Axial and Central Chirality. Angewandte Chemie 2024, 136 (8) https://doi.org/10.1002/ange.202316454
  16. Jing‐Yi Wang, Cong‐Hui Gao, Cheng Ma, Xin‐Yue Wu, Shao‐Fei Ni, Wei Tan, Feng Shi. Design and Catalytic Asymmetric Synthesis of Furan‐Indole Compounds Bearing both Axial and Central Chirality. Angewandte Chemie International Edition 2024, 63 (8) https://doi.org/10.1002/anie.202316454
  17. Hong‐Hao Zhang, Tian‐Zhen Li, Si‐Jia Liu, Feng Shi. Catalytic Asymmetric Synthesis of Atropisomers Bearing Multiple Chiral Elements: An Emerging Field. Angewandte Chemie 2024, 136 (3) https://doi.org/10.1002/ange.202311053
  18. Hong‐Hao Zhang, Tian‐Zhen Li, Si‐Jia Liu, Feng Shi. Catalytic Asymmetric Synthesis of Atropisomers Bearing Multiple Chiral Elements: An Emerging Field. Angewandte Chemie International Edition 2024, 63 (3) https://doi.org/10.1002/anie.202311053
  19. Xin‐Qi Zhu, Yu‐Chao Li, Long‐Wu Ye. Enantioselective Reaction of Diynes and Multiynes for the Synthesis of Axially Chiral Compounds. Asian Journal of Organic Chemistry 2024, 13 (1) https://doi.org/10.1002/ajoc.202300554
  20. Hiroshige Ogawa, Hugh Nakamura. Atroposelective Total Synthesis of Strecintide 839. 2024https://doi.org/10.2139/ssrn.4854570
  21. Lucas Mele, Rachida Babouri, Jean‐Luc Pirat, Eder Tomás‐Mendivil, David Martin, Tahar Ayad, David Virieux. Beyond the Limits of Atropochirality: Design of Highly Conformationally Restrained Biaryls with Bridgehead Phosphine Oxide. Chemistry – A European Journal 2023, 29 (42) https://doi.org/10.1002/chem.202300452
  22. Hajar A. Ali, Mohamed A. Ismail, Abd El-Aziz S. Fouda, Eslam A. Ghaith. A fruitful century for the scalable synthesis and reactions of biphenyl derivatives: applications and biological aspects. RSC Advances 2023, 13 (27) , 18262-18305. https://doi.org/10.1039/D3RA03531J
  23. Wei-Yun Cai, Qian-Ni Ding, Ling Zhou, Jie Chen. Asymmetric Synthesis of Axially Chiral Molecules via Organocatalytic Cycloaddition and Cyclization Reactions. Molecules 2023, 28 (11) , 4306. https://doi.org/10.3390/molecules28114306
  24. Huai‐Ri Sun, Atif Sharif, Jie Chen, Ling Zhou. Atroposelective Synthesis of Heterobiaryls through Ring Formation. Chemistry – A European Journal 2023, 29 (27) https://doi.org/10.1002/chem.202300183
  25. Fen Huang, Ling-Fei Tao, Jiyong Liu, Linghui Qian, Jia-Yu Liao. Diastereo- and enantioselective synthesis of biaryl aldehydes bearing both axial and central chirality. Chemical Communications 2023, 59 (30) , 4487-4490. https://doi.org/10.1039/D3CC00708A
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Cite this: Acc. Chem. Res. 2023, 56, 3, 187–188
Click to copy citationCitation copied!
https://doi.org/10.1021/acs.accounts.2c00765
Published February 7, 2023

Copyright © Published 2023 by American Chemical Society. This publication is available under these Terms of Use.

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