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Catalysis

Peptide catalyzes macrocycle formation

Yields for rings with 14 or more carbons exceed 80%

by Celia Henry Arnaud
December 23, 2019

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The bifunctional foldamer contains a secondary amine (red) and a primary amine (black) that catalyze macrocyclization. Shown here is the ring-closing step in the synthesis of robustol.
20191223lnp2-foldmer.jpg
The bifunctional foldamer contains a secondary amine (red) and a primary amine (black) that catalyze macrocyclization. Shown here is the ring-closing step in the synthesis of robustol.

Macrocycles are difficult to synthesize because there’s an entropic penalty associated with the ring closure. Chemists have multiple approaches to overcome that penalty and make the rings, each with advantages and disadvantages. For example, ring-closing metathesis has good yields but requires metal catalysts that can be tough to remove from product mixes. Researchers have now come up with a metal-free approach in which they use a synthetic peptide called a foldamer to catalyze macrocycle formation with yields as high as 97% (Science 2019, DOI: 10.1126/science.aax7344).

The catalytic foldamer is a short peptide that contains both α and β amino acids. A repeating pattern of one α amino acid followed by two β amino acids, including β residues with 5-membered rings, stabilizes the foldamer’s helical structure.

“The thing we love about these foldamers is that you know exactly what the shape of the molecule is,” says Samuel H. Gellman of the University of Wisconsin–Madison, who led the team that made the catalyst. “You know where things are going to be in space just based on how you locate them in the sequence, which is trivial to control.”

Gellman’s team made a seven-residue foldamer that catalyzes macrocycle formation via an aldol condensation. The foldamer has two amine groups—a cyclic secondary amine and a primary amine—that form reactive intermediates with aldehydes in the substrate. The foldamer backbone acts as a scaffold that holds the two amine groups in the right orientation so that the resulting intermediates react to close the ring.

The secondary amine probably forms an enamine and the primary amine probably forms an imine that is then protonated to form an iminium, Gellman says. “These two units are much more reactive in aldol-type reactions than the aldehydes themselves,” he says.

The researchers used the catalyst to make macrocycles of various sizes. For rings with 14 or more carbons, the yields were better than 84%. With a smaller 12-membered ring, cyclization introduces too much strain and the yield was much lower, about 55%.

The team also used the catalyst in a synthesis of the 18-membered macrocyclic core of nostocyclyne A and in a total synthesis of the natural product robustol, which contains a 22-membered ring.

Gellman and coworkers didn’t need a metal catalyst for the ring-closing step of the robustol synthesis, but they did need one for a subsequent decarbonylation. “In this particular example, we haven’t necessarily avoided the problem altogether,” Gellman admits.

“This is fascinating and important work,” says Scott J. Miller of Yale University, who also works on peptide catalysts. “New designs and hypotheses for catalysis of complex reactions with foldamer-housed catalytic diads, triads, and even beyond, can be anticipated with great optimism.”

In the future, Gellman hopes to make foldamer-based enzymes. “We have to face the challenge of moving from orienting things along one side of a single helix to creating something like a pocket, where we could bring functional groups from different regions of space toward a central substrate,” he says. “We’d like to build up to things that can rival enzymes.”

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Comments
Larry (January 6, 2020 12:42 PM)
DOI link broken.

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