In the field of chemistry, a molecule or ion is considered chiral if it cannot be overlapped with its mirror image through any combination of translations, rotations, or conformational changes. Chiral molecules have two forms known as enantiomers, which are mirror images of each other. These enantiomers are often referred to as “right-handed” or “left-handed” based on their absolute configuration. While enantiomers share similar physical and chemical properties, they differ when it comes to interacting with polarized light and reacting with other chiral compounds.
In recent years, there has been significant interest in isotopically chiral compounds. These compounds involve the discrimination of isotopes of an element and have attracted attention in structural and synthetic organic chemistry, medicinal chemistry, and the study of fundamental reaction mechanisms. Many optically active isotopic molecules with an asymmetric carbon have been synthesized using hydrogen/deuterium (H/D) discrimination.
However, the synthesis, detection, and characterization of isotopic atropisomers are particularly challenging. Isotopic atropisomers are stereoisomers that result from hindered rotation around single bonds. In these molecules, the steric strain barrier to rotation is high enough to allow for the isolation of conformers. So far, only a few such molecules based on H/D discrimination have been reported.
Recently, a team of researchers led by Professor Osamu Kitagawa from the Department of Applied Chemistry at the Faculty of Engineering at the Shibaura Institute of Technology in Japan achieved the asymmetric synthesis of isotopic atropisomers based on carbon isotope discrimination. Their work was published online in The Journal of Organic Chemistry. The research was co-authored by graduate students Ryunosuke Senda and Yuka Watanabe from the Department of Applied Chemistry at Shibaura Institute of Technology.
Inspired by their previous work on the synthesis of CH3/CD3-atropisomeric quinazolin-4-one derivative, the team successfully prepared both enantiomers of 2-ethyl quinazolin-4-one with isotopic atropisomerism (N–C axial chirality) based on ortho-12CH3/13CH3 discrimination.
They achieved this by using an asymmetric synthesis method involving Suzuki–Miyaura cross-coupling. Professor Kitagawa noted that the synthesized isotopic atropisomers based on 12C/13C discrimination were cryptochiral compounds that did not exhibit optical rotation.
Since the existence of isotopic atropisomerism in the above-mentioned molecules could not be verified, the researchers went on to synthesize diastereomeric 3-aryl quinazolin-4-one derivatives with both an asymmetric carbon atom and isotopic atropisomerism. The diastereomers could be clearly distinguished, and the presence of isotopic atropisomerism could be confirmed using 1H and 13C nuclear magnetic resonance.
The diastereomers also demonstrated high enantiomeric and diastereomeric stereochemical purity as well as rotational stability. Therefore, diastereomeric 3-aryl quinazolin-4-ones provide an excellent framework for verifying diverse isotopic atropisomers.
Overall, the novel findings of this research will enhance our fundamental understanding of isotopic atropisomers and have positive implications in organic and medicinal chemistry. Professor Kitagawa believes that this work, which reports the first isotopic atropisomers based on 12C/13C discrimination, could inspire researchers to conduct similar studies in the field of fundamental organic chemistry.
Source: Shibaura Institute of Technology