Mimicking Enzymes, University of Wisconsin-Madison Chemists Produce Large, Useful Carbon Rings

At the end of 2000, the W. M. Keck Foundation made a $1.5 million [philanthropic investment] in the University of Wisconsin-Madison’s Center for Chemical Genomics.  While the initial work proposed by PI Laura Kiessling and Co-PI Sam Gellman, both faculty members in the Chemistry Department, was completed in 2005, the Foundation’s support continues to pay scientific dividends today.  For example, the Dec. 20, 2019 issue of Science includes the report “Foldamer-templated catalysis of macrocycle formation” by Professor Gellman and three members of his research group.

Nature prefers the disorder of a long, flexible molecule to the order of a constrained ring, which makes it notoriously difficult for chemists to coax large rings to form in the lab.  “If the linear molecules get long enough, it’s as if the ends don’t know anymore that they’re connected, and they’re just as likely to bond with other molecules as they are to come together,” said Professor Gellman.  Yet biological enzymes can easily bring these ends together and form rings of all sizes, thanks to their complex, three-dimensional shapes that act as a specialized lock – the linear molecule fits into place like a key in just the right way for an organized reaction to take place.  

To both study how enzymes work and mimic their abilities, Gellman’s team turned to much smaller, three-dimensional protein-like molecules called foldamers that their lab has helped develop.  Because the foldamer has a three-dimensional shape that can grab on to the ends of the flexible precursor molecule and orient them correctly, it greatly increases the odds that the ends find one another.  At the same time, the foldamer catalyzes the right reaction that links the ends into a closed ring.  The upshot is straightforward and predictable synthesis of a challenging, and useful, molecular shape.

As they wrote in Science, “Macrocycles, compounds containing a ring of 12 or more atoms, find use in human medicine, fragrances, and biological ion sensing.  The efficient preparation of macrocycles is a fundamental challenge in synthetic organic chemistry because the high entropic cost of large-ring closure allows undesired intermolecular reactions to compete.  Here we present a bioinspired strategy for macrocycle formation through carbon–carbon bond formation.  The process relies on a catalytic oligomer containing a- and b-amino acid residues to template the ring-closing process.  The a/b-peptide foldamer adopts a helical conformation that displays a catalytic primary amine–secondary amine diad in a specific three-dimensional arrangement.  This catalyst promotes aldol reactions that form rings containing 14 to 22 atoms.  Utility is demonstrated in the synthesis of the natural product robustol.”

This discovery may represent preliminary progress toward deciphering how enzymes, honed by evolution, so efficiently produce natural compounds.  More immediately, the new method could help researchers synthesize drugs that have large ring backbones, such as those for hepatitis.

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