Successful synthesis of gamma-lactam rings from hydrocarbons

March 01, 2018

A team of researchers at the Center for Catalytic Hydrocarbon Functionalizations, within the Institute for Basic Science (IBS, South Korea), have designed a novel strategy to synthesize ring-shaped cyclic molecules, highly sought-after by pharmaceutical and chemical industries, and known as gamma-lactams. This study describes how these five-membered rings can be prepared from inexpensive and readily available feedstock hydrocarbons, as well as from complex organic molecules, such as amino acids and steroids. Gamma-lactams find several applications in medicinal, synthetic, and material chemistry. For example, they are included in a large number of pharmaceutically active compounds with antibiotic, anti-inflammatory, and anti-tumoral functions. Published in Science, this research was conducted at the Korea Advanced Institute of Science and Technology (KAIST).

Conversion of hydrocarbons into nitrogen-containing compounds is an important area of research, where the challenge lies in breaking strong carbon-hydrogen (C?H) bonds, and converting them into carbon-nitrogen (C-N) bonds in a controlled fashion. For this reason, hydrocarbons are difficult to use as starting materials, albeit the fact that they exist in large quantities in nature.

Over the last 35 years, chemists have found ways of converting simple hydrocarbons into nitrogen-containing rings, such as indoles or pyrrolidines, but gamma-lactams proved impossible to prepare using the same approaches. IBS researchers hypothesized that such failure was due to alternative chemical pathways that steer the reaction away from the wanted rings: The reaction intermediate (carbonylnitrene) quickly breaks down into unsought products. Using computer models of the desired and undesired reaction pathways, the team found a strategy to completely shut down the latter in order to obtain the longed-for gamma-lactams. For the first time, these four carbons and one nitrogen cyclic molecules were obtained directly from simple feedstock chemicals.

"With this work we offer a brand new solution to a long-standing challenge and demonstrate the power of what we call mechanism-based reaction development," explains Professor BAIK Mu-Hyun, a corresponding author of the study.

Led by professor CHANG Sukbok, IBS researchers designed the winning reaction with the help of computer simulations that analyze the reaction mechanisms and calculate the energy required for the reaction to take place. According to such computer predictions, the reaction could follow three pathways, leading to the formation of either the desired gamma-lactam, an unwanted product (isocyanate), or the degradation of the catalyst caused by the substrate reacting with the catalyst backbone. Combining experimental observations and detailed computer simulations, the team designed an iridium-based catalyst, highly selective for the gamma-lactam formation. In this way, the two undesired pathways were systematically shut down, leaving the formation of the nitrogen-containing ring as the only possible outcome.

Beyond using cheap feedstock hydrocarbons as substrates, the team was also successful in converting amino acids, steroids, and other bio-relevant molecules into gamma-lactams, which might find a variety of applications as plant insecticide, drugs against parasitic worms, or anti-aging agents. This new synthetic technology gives much easier access to these complicated molecules and will enable the development of potential drugs in a much shorter amount of time at a lower cost.

"In this groundbreaking work, we moved away from the existing amination strategy and opened the door to an entirely new way of turning C-H into C-N bonds. Our discovery is a paradigm changing piece of work and it offers a new conceptual foundation for many exciting developments to follow," enthuses professor CHANG.

IBS researchers are now keen on developing less expensive catalyst systems, and expanding the range of products, for example by producing rings with four or six atoms (known as beta-lactam and delta-lactam, respectively). Finally, as explained by the first author of the study, HONG Seung Youn, the team aspires to step up from intramolecular amination reactions to intermolecular ones: "The final goal would be to achieve the direct conversion of unactivated alkanes, such as natural gases like methane or ethane gas, into useful value-added chemicals via intermolecular C-H amination."
-end-


Institute for Basic Science

Related Amino Acids Articles from Brightsurf:

Igniting the synthetic transport of amino acids in living cells
Researchers from ICIQ's Ballester group and IRBBarcelona's Palacín group have published a paper in Chem showing how a synthetic carrier calix[4]pyrrole cavitand can transport amino acids across liposome and cell membranes bringing future therapies a step closer.

Microwaves are useful to combine amino acids with hetero-steroids
Aza-steroids are important class of compounds because of their numerous biological activities.

New study finds two amino acids are the Marie Kondo of molecular liquid phase separation
a team of biologists at the Advanced Science Research Center at The Graduate Center, CUNY (CUNY ASRC) have identified unique roles for the amino acids arginine and lysine in contributing to molecule liquid phase properties and their regulation.

Prediction of protein disorder from amino acid sequence
Structural disorder is vital for proteins' function in diverse biological processes.

A natural amino acid could be a novel treatment for polyglutamine diseases
Researchers from Osaka University, National Center of Neurology and Psychiatry, and Niigata University identified the amino acid arginine as a potential disease-modifying drug for polyglutamine diseases, including familial spinocerebellar ataxia and Huntington disease.

Alzheimer's: Can an amino acid help to restore memories?
Scientists at the Laboratoire des Maladies Neurodégénératives (CNRS/CEA/Université Paris-Saclay) and the Neurocentre Magendie (INSERM/Université de Bordeaux) have just shown that a metabolic pathway plays a determining role in Alzheimer's disease's memory problems.

New study indicates amino acid may be useful in treating ALS
A naturally occurring amino acid is gaining attention as a possible treatment for ALS following a new study published in the Journal of Neuropathology & Experimental Neurology.

Breaking up amino acids with radiation
A new experimental and theoretical study published in EPJ D has shown how the ions formed when electrons collide with one amino acid, glutamine, differ according to the energy of the colliding electrons.

To make amino acids, just add electricity
By finding the right combination of abundantly available starting materials and catalyst, Kyushu University researchers were able to synthesize amino acids with high efficiency through a reaction driven by electricity.

Nanopores can identify the amino acids in proteins, the first step to sequencing
While DNA sequencing is a useful tool for determining what's going on in a cell or a person's body, it only tells part of the story.

Read More: Amino Acids News and Amino Acids Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.