Atropisomeric N-aryl quinazoline-4-thiones with isotopic differences at the ortho position

Isotopes are atoms that have the same number of protons but a different number of neutrons. Compounds consisting of stable isotopes have been used as probes in chemistry or molecular biology to study the structure of different molecules. Deuterium (D), an isotope of hydrogen, is a common molecular label used by scientists to understand reaction pathways and drug activity and to identify organ toxicities. Organic compounds “labeled” or tagged with deuterium can also act as excellent solvents for analytical techniques like nuclear magnetic resonance (NMR) spectroscopy.

Deuterated chiral organic compounds—molecules that are non-superimposable mirror images of each other—act as perfect probe molecules for mechanistic studies of various biochemical and synthetic reactions. Over the years, scientists have developed many reactions for the synthesis of optically active chiral deuterated compounds. However, most of them are centrally chiral compounds bearing a chiral carbon, while the synthesis of atropisomeric chiral deuterated compounds has not been reported yet because of “racemization” and  difficulty of detecting the atropisomerism based on H/D discrimination.

To overcome this issue, a team of researchers from Shibaura Institute of Technology (SIT), Japan, led by Professor Osamu Kitagawa synthesized 3-(2-deuteriophenyl)-2-(1-phenylpropan-2-yl)quinazoline-4-thiones. The molecules showed unprecedented isotopic atropisomerism— a form of chirality that arises due to the difference in a bond rotation that arises from steric hindrance. The atropisomerism in the prepared quinazoline-4-one derivatives was due to rotational restriction around an N-Ar(deuterio-phenyl ) bond. As Prof. Kitagawa explains, “We were trying to understand the chemistry of N-C axially chiral compounds which is when we discovered atropisomers based on ortho-H/F discrimination. These were rare compounds where the smallest hydrogen atom and the second smallest fluorine atom were at the ortho position. This gave us an idea about creating isomers based on ortho-H/D discrimination.” The findings of their study are published in Organic Letters.

Optically active 3-(2-deuteriophenyl)-2-(1-phenylpropan-2-yl)quinazoline-4-thione was prepared via highly diastereoselective α-benzylation of a precursor [optically pure 3-(2-bromophenyl)-2-ehyl quinazolin-4-one] followed by thionation with Lawesson’s reagent and then “deuteration” using sodium boro-deutiride. This synthesis was achieved by Kazuya Saito and Shota Miwa, who are graduate students in Kitagawa’s lab.    

The team (mainly Dr. Elsa Caytan at University of Rennes who is co-worker) then analyzed the samples using ¹H- and ²H-NMR, which clearly indicated that the quinazoline-4-thiones existed as a 1:1 mixture of diastereomers based on a chiral carbon atom and atropisomerism due to the rotational restriction around an N-aryl bond. Density functional theory (DFT) calculations, which were performed by Dr. Yuuki Fujimoto (co-worker), also strongly supports the formation of diastereomers. 

This study is the first to detect a class 2 isotopic atropisomer based on the difference in ortho-H/D. The molecules synthesized during this research could also be used for pharmaceutical purposes. “The N aryl quinazolinones and the thione analogs prepared during our study are multifunctional. Not only can they be used as probe molecules but are also of great interest from a medicinal chemistry point of view. Quinazoline-4-thiones are known to have high biological activity. They can be used to develop therapeutic agents with show antibacterial, anti-inflammatory, and anti-cancer properties,” concludes Prof. Kitagawa.

***

Reference

DOI: https://doi.org/10.1021/acs.orglett.1c02723

About Shibaura Institute of Technology (SIT), Japan

Shibaura Institute of Technology (SIT) is a private university with campuses in Tokyo and Saitama. Since the establishment of its predecessor, Tokyo Higher School of Industry and Commerce, in 1927, it has maintained “learning through practice” as its philosophy in the education of engineers. SIT was the only private science and engineering university selected for the Top Global University Project sponsored by the Ministry of Education, Culture, Sports, Science and Technology and will receive support from the ministry for 10 years starting from the 2014 academic year. Its motto, “Nurturing engineers who learn from society and contribute to society,” reflects its mission of fostering scientists and engineers who can contribute to the sustainable growth of the world by exposing their over 8,000 students to culturally diverse environments, where they learn to cope, collaborate, and relate with fellow students from around the world.

Website: https://www.shibaura-it.ac.jp/en/

About Professor Osamu Kitagawa from SIT, Japan

Dr. Osamu Kitagawa received his BS and PhD from the Tokyo University of Pharmacy and Life Science (then called the Tokyo College of Pharmacy) in 1984 and 1989, respectively. He worked as an assistant, a lecturer, and an associate professor at the same university before moving to SIT in 2008. He was promoted to Full Professor in 2010. His research interests include the chemistry of novel stereoisomeric molecules and development of novel synthetic organic reactions. He has authored 100 articles and has received over 3400 citations.