Breakthrough in beta-lactam synthesis using nickel catalysts

Led by Director Chang Sukbuk, scientists from the Center for Catalytic Hydrocarbon Functions within the Institute for Basic Science (IBS) have made significant progress in the synthesis of beta-lactam scaffolds, structural components frequently found in basic antibiotics such as penicillin and antibiotics. The carbapenems. This achievement overcomes challenges in beta-lactam synthesis to promise simplified pathways for drug development.

The primary chemical structure of which penicillin is made is a four-membered cyclic amide scaffold called β-lactam, which is also frequently found in other major antibiotics such as carbapenems and cephalosporins. The high value potential of β-lactam has been recognized in modern science due to its importance to pharmaceutical products, which has led to many efforts to manufacture it using readily available chemical raw materials.

In 2019, the IBS group revealed a catalytic reaction that allowed access to γ-lactams, which are five-membered amide structures that differ in ring size from β-lactams. They were able to achieve high selectivity by using iridium chiral catalysts; However, the same approach cannot be applied to the synthesis of the four-membered variant, β-lactam.

Indeed, one of the major hurdles in accessing β-lactams was the formation of superior γ-lactams. Overcoming this critical problem of regional selectivity, while simultaneously achieving high reversible selectivity, remains a major challenge for beta-lactam synthesis. In addition, the use of expensive rare earth minerals can present limitations in many aspects.

To address these challenges, the IBS research team created a new catalytic reaction using nickel, a transition metal that is more abundant naturally. Their work has been published in stimulate nature.

They first tackled the challenge of suppressing the formation of five-membered γ-lactams by harnessing the catalytic properties of nickel hydride (NiH) species and its alkyne substrate dioxazolone. High selectivity towards the desired formation of β-lactam scaffolds is achieved under this new catalytic system, as NiH species react more favorably with the dioxazolone model than with the alkyne to induce selective nitrogen-carbon bond formation via a nickelamide intermediate.

The selective formation of β-lactams is also made possible by combination with chiral linkers, which can be applied to the synthesis of biologically related compounds.

The IBS researchers also demonstrated the value of their findings by simplifying the synthesis of a number of beta-lactams that previously required more complex processes. Moreover, the beta-lactams produced are valued at high market values ​​of up to 700 times compared to the primary raw material, and the fact that this can be achieved using a low-cost nickel catalyst makes this process highly economically desirable.

What makes this development notable is its immediate applicability. By using this method, the team proposed more efficient and simplified formulation strategies for specific drugs and natural substances. Moreover, they have accomplished the synthesis of novel compounds that could be potential drug candidates by activating complex chemical structures at a late stage.

Director Zhang commented, “Through this study, we were able to easily synthesize chiral beta-lactams, which are the backbone of major antibiotics such as penicillin and carbapenems, from cheap nickel catalysts and chemical raw materials. Discovering new pathways for the manufacture of high-value materials such as chiral beta-lactams is an important achievement It can significantly shorten the drug discovery phase.”