The rich diversity of organic compounds is a result of the remarkable ability of carbon atoms to connect and form bonds with different molecules. Variations in these bonding arrangements, as well as the types of atoms and functional groups involved, result in the formation of isomers. They are a type of compounds that share the same molecular formula but exhibit distinct three-dimensional shapes and properties.

Atropisomers are a type of isomers that are formed when bulky substituents or functional groups get attached to a single bond and experience restricted rotation about the bond. This restriction leads to molecules with a distinct spatial arrangement of atoms and functional groups. Atropisomers are often encountered in compounds containing aromatic rings. Notably, compounds formed as a result of restricted rotation around an N−C single bond between the aromatic ring and the functional group are used as chiral ligands and chiral building blocks to create specific stereoisomers with chiral carbon centers. They often find use in various chemical and pharmaceutical applications. However, maintaining axial chirality around the N−C bond is challenging to attain, and this results in a limited number of synthesizable N−C axially chiral compounds.

In a recent study, researchers have now demonstrated that the Pauson–Khand reaction—a chemical reaction for synthesizing molecules containing cyclopentenones—when applied to atropisomeric substrates, can produce new derivatives containing a chiral carbon. The study was made available online on 2 October 2023 and published in the journal Organic Letters on 13 October 2023. It was led by Professor Osamu Kitagawa from the Department of Applied Chemistry at Shibaura Institute of Technology, Japan along with graduate students Ryohei Kasahara and Tatsuya Toyoda. Possibly the first demonstration of this kind, this breakthrough significantly expands the scope of synthesizing such compounds.

“Although Pauson–Khand reaction is a widely used reaction for the synthesis of many organic compounds, the reaction with atropisomeric substrates had not been explored yet. Out of academic curiosity, we decided to explore the Pauson–Khand reaction with atropisomeric substrates,” says Prof. Kitagawa, while talking about the study.

To this end, the researchers applied an intramolecular version of the reaction to enantioenriched atropisomeric sulfonamides for synthesizing chiral nitrogen-containing tricyclic compounds. They observed that conducting Pauson–Khand reactions on enantioenriched atropisomeric sulfonamides (78–89% ee) containing various substituents in the presence of a Co₂(CO)₈ complex led to the formation of products with enantiomeric excesses ranging from 78% to 89%. These findings suggest that the Pauson–Khand reaction can effectively transfer chirality from the starting materials to the reaction products with a high degree of selectivity.

“The reaction with enantioenriched N–C axially chiral sulfonamide derivatives proceeded with complete chirality transfer from axial chirality (P configuration) to central chirality (R configuration), affording chiral nitrogen-containing tricyclic compounds,” explains Prof. Kitagawa.

Further, a wide range of substrates were compatible with the reaction, including sulfonamides with methyl-, chloro-, and bromo- substituents, as well as aromatic groups. A crucial factor for the success of this approach was the presence of the Co₂(CO)₈ complex, which forms an intermediate with the substrate. The specific arrangement of carbon and cobalt atoms within this intermediate controls how alkenes attach to it, promoting the formation of specific enantiomers.

In summary, this level of control over chirality is of significant importance in chemical synthesis and has practical applications in various fields, particularly for the synthesis of pharmaceutical compounds. “With the reaction products possessing a nitrogen-containing tricyclic structure, the reaction can be used for novel applications, such as for the synthesis of natural products and bioactive compounds,” concludes Prof. Kitagawa.

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Reference

DOI: https://doi.org/10.1021/acs.orglett.3c02893

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 is a Professor at the Shibaura Institute of Technology in Japan. He 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. Dr. Kitagawa was working as an Assistant, Lecturer, and Associate Professor there before moving to Shibaura Institute of Technology in 2008. His research interests include the chemistry of novel stereoisomeric molecules and development of novel synthetic organic reactions. He has authored around 100 research articles, which have received more than 4,100 citations.

Modern humans left Africa some 60,000 years ago in the event known as “Out-of-Africa”. In Asia, they coincided with the Denisovans, and that encounter may have led to confrontations and collaborations, but also various crossbreeding. In fact, even today modern humans retain genetic variants of Denisovan origin in our genome, which are testimony to those initial interactions.

Now, a team led by the Institute of Evolutionary Biology (IBE), a joint centre of the Spanish National Research Council (CSIC) and Pompeu Fabra University (UPF), and by the UPF Department of Medicine and Life Sciences (MELIS), has identified one of the most widespread traces of the genetic heritage of the extinct Denisovans in modern humans. The teams of Elena Bosch, IBE principal investigator, and of Rubén Vicente, MELIS-UPF principal investigator, have discovered that this genetic adaptation helped ancestral populations of sapiens to adapt to the cold.

The variant observed, involved in zinc regulation and with a role in cellular metabolism, could also have predisposed modern humans to psychiatric disorders such as depression or schizophrenia.

Genetic variation in zinc regulation may have meant an evolutionary advantage

How adaptation has shaped current genetic diversity in human populations is a matter of great interest in evolutionary genetics.

Arising from this question, Elena Bosch’s team identified an adaptive variant among current human populations in a region of our genome that bears great similarity to the genome of an extinct ancestral population: the Denisovans.

“Through genomic analysis, we noted that the genetic variant observed came from our interbreeding with archaic humans in the past, possibly the Denisovans”, says Ana Roca-Umbert, co-first author of the study. The team has ruled out Neanderthal heritage, since these populations do not have this mutation.

“Apparently, the change was beneficial and proved a selective advantage for humans. As a consequence, this variation in the SLC30A9 gene was selected and has reached current populations”, adds Jorge Garcia-Calleja, co-first author of the study.

The Evolutionary Population Genetics Laboratory, directed by Bosch, wished to find out what changes are brought about by this genetic variation of Denisovan origin at the cellular level. “We discovered that this mutation surely had implications for the transport of zinc within the cell, and so we contacted Vicente’s team”, recalls Elena Bosch, IBE principal investigator and co-leader of the study.

Zinc regulation: key to adapting to the cold

“Elena contacted me because her team had observed a change in an amino acid in a zinc transporter, which was very different between the populations of Africa and Asia today. From there, we started asking ourselves questions and looking for answers”, Rubén Vicente comments. His team, in the Biophysics of the Immune System group at the Laboratory of Molecular Physiology, undertook the technical challenge of studying the movement of intracellular zinc. 

Zinc, an essential trace element for human health, is an important messenger that transfers both information from the outside to the inside of cells and between different cellular compartments. A lack of zinc causes growth, neurological and immune disorders, although “its regulation is still poorly studied due to the lack of molecular tools to follow the flow of zinc”.

Vicente’s laboratory identified that the observed variant causes a new zinc balance within the cell, promoting a change in metabolism. By altering the endoplasmic reticulum and mitochondria of the cells, this variation causes a possible metabolic advantage to cope with a hostile climate. “The observed phenotype leads us to think of a possible adaptation to the cold”, Vicente asserts.

The Denisovan genetic heritage could affect the mental health of European and Asian populations

Zinc transport is also involved in nervous system excitability, and plays a role in people’s mental equilibrium and health.

The team points out that the variant found in this zinc transporter, which is expressed in all tissues of the body, is associated with a greater predisposition to suffering from some psychiatric diseases. These include anorexia nervosa, hyperactivity disorder, autism spectrum disorder, bipolar disorder, depression, obsessive compulsive disorder, and schizophrenia.

“In the future, expanding this study to animal models could shed light on this predisposition to suffering from mental illnesses”, Vicente notes.

The genetic variant has left a global mark, except in Africa

Although the variant was established in Asia as a result of interbreeding between Denisovans and sapiens, it also spread to European and native American populations. In fact, it is found in populations all over the planet, although, in the case of African populations, it is much less frequent. 

The team points out that it is probably the Denisovan genetic adaptation to have the greatest geographical scope discovered to date. “For example, a variant in the EPAS1 gene inherited from the Denisovans allows adapting to life at altitude, but is found only in Tibetans. However, in our case, the impact extends to all populations outside Africa”, Bosch concludes.