New molecule-creation method a ‘powerful tool’ to accelerate drug synthesis and discovery

Modern medicinal chemists face increasing challenges in targeting complex molecules to solve difficult biological targets. Traditional methods for synthesizing flat two-dimensional molecules (such as pyridine) are well established, but strategies for synthesizing 3D molecules (such as piperidine) are more elusive.

To bridge this gap, the team introduced a two-stage process to modify piperidine, which is important in many drugs. The first step uses biocatalytic hydrocarbon oxidation, a method in which enzymes selectively add hydroxyl groups to specific sites on the piperidine molecule. This process is similar to a common chemistry technique called electrophilic aromatic substitution that works on flat molecules such as pyridine, but here it is applied to 3D structures.

In a second step, these newly functionalized piperidines undergo radical cross-coupling under nickel electrocatalysis. This method efficiently forms new carbon-carbon bonds by joining different molecular fragments without requiring additional steps, such as adding protecting groups to protect parts of the molecules during synthesis or using expensive noble metal catalysts such as palladium. ). This two-step process greatly simplifies the construction of complex piperidines.

“We essentially created a modular approach to simplify piperidine synthesis, similar to how palladium cross-coupling revolutionized pyridine chemistry decades ago,” said study co-author Hans Rei, associate professor of chemistry at Rice University. Hans Renata said. “This represents a powerful tool to unlock new molecular space for drug discovery.”

This study demonstrates the simplified synthesis of a variety of high-value piperidines for use in natural products and pharmaceuticals, including neurokinin receptor antagonists, anticancer agents, and antibiotics. This method reduces the multi-step process from 7-17 steps to 2-5 steps, greatly improving efficiency and cost.

This achievement has important implications for both pharmaceutical and process chemists. By providing a versatile strategy for rapid access to complex 3D molecules, this approach reduces reliance on expensive precious metals such as palladium and simplifies traditionally challenging synthetic pathways. For drug development, this means faster access to life-saving medicines, lower production costs, and sustainable methods for synthesizing drug candidates.

“This work demonstrates the power of combining selective enzymatic conversion of hydrocarbons with modern cross-coupling to unlock new molecular spaces for drug discovery,” Renata said.

“By combining biocatalytic oxidation and radical cross-coupling, we are able to obtain molecules that were previously thought to be inaccessible or prohibitively expensive,” said Yu Kawamata, co-author and institute researcher in the Scripps Research Department of Chemistry. .

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

In addition to Renata and Kawamata, Phil Baran, professor in the Department of Chemistry at Scripps Research, is also a co-corresponding author. Jiayan He, a postdoctoral fellow at Scripps Research, and Kenta Yokoi, a postdoctoral researcher at Rice University, are the first authors of the paper. Breanna Wixted, a student in Renata’s lab at Rice studying under a National Science Foundation Undergraduate Research Experience grant, and Benxiang Zhang, a postdoctoral researcher at Scripps Research, also contributed.

Financial support for this work was provided by fellowship support from the National Institutes of Health (GM-118176 and GM-128895), the Welch Foundation (C2159), the Naito Foundation, and NSF REU grant 2150216.