New synthetic technology reduces drug development time and cost

A team of chemists from the Scripps Research Institute and Rice University has unveiled a new method that simplifies the synthesis of piperidine, a key structural component of many pharmaceuticals. The study, published in the journal Science, combines biocatalytic carbon-hydrogen oxidation with radical cross-coupling, providing an efficient and cost-effective approach for creating complex three-dimensional molecules . This innovation could help accelerate drug discovery and increase the efficiency of medicinal chemistry.

Modern medicinal chemists face increasing challenges when targeting complex molecules to address difficult biological targets. While traditional methods for synthesizing flat two-dimensional molecules such as pyridine are well established, synthetic strategies for three-dimensional molecules such as piperidine are much more elusive.

To fill this gap, the research team introduced a two-step process to modify piperidine, which is important in many pharmaceutical products. The first step uses biocatalytic carbon-hydrogen oxidation. This is how the enzyme selectively adds hydroxyl groups to specific sites on the piperidine molecule. This process is similar to a common chemical technique called electrophilic aromatic substitution that works on planar molecules like pyridine, but here it is applied to 3D structures.

In the second step, these newly functionalized piperidines undergo radical cross-coupling with a nickel electrocatalyst. This approach connects different molecular fragments without requiring additional steps such as adding protecting groups to protect parts of the molecule during synthesis or using expensive noble metal catalysts such as palladium. This effectively forms new carbon-carbon bonds. This two-step process greatly simplifies the complex method of piperidine construction.

“We essentially developed a modular approach to simplifying piperidine synthesis, which was developed several decades ago using palladium cross-coupling. just as it revolutionized pyridine chemistry.” “This is a powerful tool to unlock new molecular spaces for drug discovery.”

This study demonstrated the efficient synthesis of a number of high-value piperidines used in natural products and pharmaceuticals, such as neurokinin receptor antagonists, anticancer drugs, and antibiotics. This approach reduced a multi-step process from 7-17 steps to just 2-5 steps, significantly increasing efficiency and cost.

This achievement is important for both medicinal and process chemists. This method provides a generalizable strategy to rapidly access complex 3D molecules, reducing dependence on expensive noble metals such as palladium and simplifying traditional and difficult synthetic routes. For drug development, this means faster access to life-saving medicines, lower production costs, and a sustainable approach to the synthesis of drug candidates.

“This study demonstrates the power of combining enzymatic conversion for selective carbon-hydrogen oxidation with advanced cross-coupling to unlock new molecular space for drug discovery,” Renata said.

“The combination of biocatalytic oxidation and radical cross-coupling allows access to molecules previously considered inaccessible or prohibitively expensive,” said co-author and author of The Scripps Research Institute said Hiroshi Kawamata, a laboratory researcher in the Department of Chemistry.

This method opens new possibilities for drug design and synthesis, especially as the industry moves toward 3D molecular structures to enhance drug specificity and performance. Patients and health systems could also benefit from faster and more efficient routes to critical drugs, potentially reducing costs and increasing access to new treatments.