A simpler way to make complex piperidines

A new, two-step strategy for making substituted piperidines offers chemists a more efficient way to make these biologically relevant molecules. The method, which leverages enzymatic oxidation and radical cross-coupling, helps medicinal chemists quickly access structures that feature piperidine. It also sidesteps many reactions that require precious metal catalysts or expensive chiral ligands, thus making the route appealing to process chemists.

Nitrogen-containing aromatic rings like pyridine have long been popular motifs to include in drug candidates. But drugmakers looking to escape the aromatic flatlands by making molecules that reach into three dimensions have been eyeing piperidine—the unsaturated version of pyridine—as an alternative motif. The problem is that while there is well-established chemistry for adding various groups onto pyridines, there hasn’t been a convenient strategy for adding substituents to piperidines—until now.

“We thought that the combination of enzymatic functionalization and radical coupling could be leveraged to do something groundbreaking,” says Yu Kawamata of Scripps Research, who led the project along with Scripps colleague Phil S. Baran and Hans Renata at Rice University.

“Looking at various piperidines that are present in drug molecules, you see all kinds of substitution patterns,” Renata says. The diversity of arrangements didn’t point to an obvious general strategy. But the approach becomes clear if one considers using radical cross-coupling to make a carbon-carbon bond from a hydroxy group and works backward from there, he says.

The chemists started with commercially available enantiopure 2- and 3-carboxylated piperidines. Using directed evolution, they developed a series of enzymes that selectively oxidize a variety of C–H bonds on the piperidine, which provides access to a series of carboxylated piperidines with hydroxy handles. They then used radical cross-coupling reactions to forge C–C bonds on the piperidines at the sites of those hydroxy handles. Those compounds are intermediates en route to complex substituted piperidines, including the neurokinin 1 antagonist (+)-L-733,060 (shown) and the natural product swainsonine (Science 2024, DOI: 10.1126/science.adr9368).

Frank Lovering, a consultant with Thames Pharma Partners who has advocated for making more drug candidates with saturated motifs, says that using enzymes to direct functionalization of the piperidine at specific points around the ring gives chemists access to multiple molecules of interest. “However, these enzymes will need to be commercially available for this approach to be viable in the medicinal chemistry setting,” he says in an email, and currently they are not.

L.-C. Campeau, head of small-molecule process chemistry at Merck & Co., says the reaction combination demonstrates a way to eliminate inefficient steps on the way to key building blocks. “This is the type of strategy that can significantly streamline routes and enable a more green and sustainable future for chemical synthesis,” he says in an email.