A group of chemists has introduced an innovative technique to ease the process of producing piperidines, which are essential building blocks in numerous medications. Their research, published in Science, merges biocatalytic carbon-hydrogen oxidation with radical cross-coupling, presenting a more efficient and budget-friendly method to create intricate, three-dimensional compounds. This breakthrough has the potential to speed up drug discovery and improve the effectiveness of medicinal chemistry.
A group of chemists from Scripps Research and Rice University has introduced an innovative technique to ease the process of producing piperidines, which are essential building blocks in numerous medications. Their research, published in Science, merges biocatalytic carbon-hydrogen oxidation with radical cross-coupling, presenting a more efficient and budget-friendly method to create intricate, three-dimensional compounds. This breakthrough has the potential to speed up drug discovery and improve the effectiveness of medicinal chemistry.
Today’s medicinal chemists are increasingly challenged when trying to target intricate molecules for complex biological tasks. While established methods exist for making flat, two-dimensional molecules like pyridines, creating their three-dimensional equivalents, such as piperidines, has proven more difficult.
To tackle this issue, the research team devised a two-step process to modify piperidines, critical components in numerous drugs. The initial stage utilizes biocatalytic carbon-hydrogen oxidation, a technique where enzymes add a hydroxyl group to specific areas of piperidine structures. This approach is reminiscent of a popular chemical method known as electrophilic aromatic substitution, effective for flat molecules like pyridines, but adapted here for three-dimensional configurations.
In the subsequent stage, the newly modified piperidines participate in a radical cross-coupling process using nickel electrocatalysis. This methodology efficiently forms new carbon-carbon bonds by linking diverse molecular fragments without unnecessary extra steps, such as applying protective groups during the synthesis or utilizing expensive palladium catalysts. This two-step approach significantly streamlines the development of intricate piperidines.
“We’ve essentially developed a modular technique to simplify the synthesis of piperidines, similar to how palladium cross-coupling transformed pyridine chemistry years ago,” remarked Hans Renata, a co-author of the study and associate professor of chemistry at Rice. “This serves as a powerful tool to explore new molecular structures for drug discovery.”
The research validated the efficient synthesis of several high-value piperidines found in natural products and pharmaceuticals, including neurokinin receptor antagonists, anticancer drugs, and antibiotics. The method cut down multistep procedures from 7-17 stages to merely 2-5, greatly boosting efficiency and reducing costs.
This progress is crucial for both medicinal and process chemists. By providing a versatile approach to rapidly obtain complex 3D molecules, the technique minimizes dependency on costly precious metals like palladium and simplifies historically challenging synthesis routes. For pharmaceutical development, this translates to quicker access to life-saving drugs, decreased production expenses, and a more sustainable method for creating drug candidates.
“This research showcases the potential of fusing enzymatic transformations for selective carbon-hydrogen oxidation with modern cross-couplings to unveil new molecular avenues for drug discovery,” stated Renata.
“By merging biocatalytic oxidation with radical cross-coupling, we are granting access to molecules that were previously seen as out of reach or too costly,” noted Yu Kawamata, a co-author and investigator in the Department of Chemistry at Scripps Research.
This new technique paves the way for innovative drug design and synthesis, particularly as the industry transitions to three-dimensional molecular structures to improve drug specificity and effectiveness. Patients and healthcare systems stand to gain from quicker, more efficient pathways to essential medications, potentially lowering costs and broadening access to new treatments.
Alongside Renata and Kawamata, Phil Baran, a professor in the Department of Chemistry at Scripps Research, also contributed as a co-corresponding author. Jiayan He, a postdoctoral associate at Scripps Research, and Kenta Yokoi, a postdoctoral researcher at Rice, were the main authors of the paper. Breanna Wixted, a student in Renata’s lab at Rice under a National Science Foundation Research Experiences for Undergraduates grant, and Benxiang Zhang, a postdoctoral researcher at Scripps Research, also made contributions.
The National Institutes of Health (GM-118176 and GM-128895), the Welch Foundation (C2159), the Naito Foundation fellowship, and the NSF REU grant 2150216 provided financial support for this research.
