Hook-and-slide strategy extends amides

Extending or trimming the length of a drug molecule’s carbon backbone by just a couple of atoms can significantly alter its activity, even if nothing else in the structure changes. So reactions that can change the number of carbons in complex molecules are extremely useful to medicinal chemists who want to make several homologs, or versions of a molecule with different numbers of carbons, without having to resort to a bunch of synthetic backtracking.

Now, researchers at the University of Chicago have devised what they call a “hook-and-slide” homologation strategy for adding multiple carbons to carbon chains adjacent to amides, all at once. “Ideally, we can homologate as long as we want,” says Guangbin Dong, who led the work (Science 2023, DOI: 10.1126/science.adk1001).

The researchers “hook” an additional carbon chain to the molecule they’re modifying using a base-mediated alkylation reaction at the carbon adjacent to the amide’s carbonyl, creating a branch point. They then use a directing group to guide a rhodium catalyst into the bond between the carbonyl and the branch point. Once inserted, the metal “slides” to the end of the added chain, taking the amide with it and resulting in a molecule with an extended linear carbon backbone. Finally, the directing group is removed by hydrolysis.

While the method involves several steps, there are few other ways to directly extend amides, says Dong.

In proof-of-concept experiments, the researchers successfully added extensions of up to 16 carbons to model compounds. No matter how long the chain, the catalyst always shuttled the amide straight to the end of it without stopping or creating side products. Additional experiments uncovered that the kinetics of the reaction discourage it from stopping early, says Dong.

The researchers illustrated the utility of their new method by adding chain extensions to several complex bioactive molecules, including an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) modulator (shown). The hook-and-slide strategy also works on carboxylic acids, though the molecules have to be temporarily made into amides to make the directing group work. Altering the final hydrolysis restores the carboxylic acid.

Vittorio Pace of the University of Torino, who published a book about homologation earlier this year, calls the new method “brilliant” and “extremely well-conceived.” He says that it expands not only the scope but also the definition of homologation chemistry beyond single-carbon insertion reactions.

Molecular editing expert Richmond Sarpong of the University of California, Berkeley, says the strategy is “bound to capture the imagination of many scientists that are interested in new ways to modify amides.”

Currently, the technique only works if there is an aromatic group on the substrate. “It doesn’t bother us too much for now,” Dong says. There are plenty of drug motifs that fit the requirement, but eventually it would be good to find a way around it, he adds. The team is also working on getting the directing group installation to work under milder conditions.