Researchers demonstrate the asymmetric synthesis of quinazolin-4-one derivatives possessing isotopic atropisomerism based on carbon isotope discrimination. The synthesized molecules exhibited high rotational stability and stereochemical purity.
Newswise — In chemistry, a molecule or ion is considered chiral if it cannot be mirrored by any mix of rotations, translations, or shape alterations. A chiral molecule or ion exists in two enantiomeric forms, which are mirror images of one another. They are commonly known as 'right-handed' or 'left-handed' based on their absolute arrangement. Enantiomers demonstrate comparable physical and chemical traits, except when interacting with polarized light and reacting with other chiral substances, respectively.
In recent times, the scientific community has shown significant interest in isotopically chiral compounds, which rely on the differentiation of isotopes of an element. These compounds have captured attention in various fields such as structural and synthetic organic chemistry, medicinal chemistry, and fundamental reaction mechanisms. This is due to their unique properties and potential applications. Numerous isotopic molecules with optical activity, featuring an asymmetric carbon, have been successfully synthesized through hydrogen/deuterium (H/D) discrimination. However, the synthesis, detection, and characterization of isotopic atropisomers, which are stereoisomers resulting from restricted rotation around single bonds with a substantial steric strain barrier, pose significant challenges. So far, only a small number of such molecules based on H/D discrimination have been reported.
A research group, headed by Professor Osamu Kitagawa from the Department of Applied Chemistry at the Faculty of Engineering, Shibaura Institute of Technology in Japan, has recently accomplished a significant milestone. They have successfully showcased the asymmetric synthesis of isotopic atropisomers by exploiting the differentiation of carbon isotopes. The details of their achievement were published online in The Journal of Organic Chemistry on June 10, 2023. The research paper includes contributions from Ryunosuke Senda and Yuka Watanabe, who are graduate students at the Department of Applied Chemistry, Shibaura Institute of Technology.
Building upon their previous research (J. Org. Chem. 2022, 87, 13501) concerning the synthesis of CH3/CD3-atropisomeric quinazolin-4-one derivatives, the team of researchers has achieved another breakthrough. They have successfully prepared both enantiomers of 2-ethyl quinazolin-4-one with isotopic atropisomerism, specifically N-C axial chirality, by utilizing ortho-12CH3/13CH3 discrimination. The accomplishment was made possible through an asymmetric synthesis approach involving Suzuki-Miyaura cross-coupling. Professor Kitagawa highlights that the synthesized isotopic atropisomers, which were based on 12C/13C discrimination, are cryptochiral compounds that do not exhibit optical rotation.
In order to confirm the presence of isotopic atropisomerism in the aforementioned compounds, the researchers proceeded to synthesize diastereomeric 3-aryl quinazolin-4-one derivatives that possessed both an asymmetric carbon atom and isotopic atropisomerism. By employing 1H and 13C nuclear magnetic resonance (NMR) spectroscopy, the diastereomers could be clearly differentiated, thus confirming the existence of isotopic atropisomerism. Notably, these diastereomers exhibited remarkable levels of enantiomeric and diastereomeric stereochemical purity, as well as rotational stability. As a result, the diastereomeric 3-aryl quinazolin-4-ones represent a highly effective framework for validating various types of isotopic atropisomers.
The groundbreaking discoveries made through this research are poised to significantly enhance our foundational comprehension of isotopic atropisomers, offering valuable insights for the fields of organic and medicinal chemistry. The identification of the first isotopic atropisomers relying on 12C/13C discrimination is expected to ignite academic interest and inspire researchers to embark on similar investigations in the realm of fundamental organic chemistry. Professor Kitagawa expresses optimism about the potential impact of this work, highlighting its capacity to stimulate further exploration in the scientific community.
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