Taking Inspiration From Nature To Make Molecules Like Nature Does

In the Science paper, Nelson describes a new chemical synthesis technique that is highly selective in making either left-handed or right-handed molecules, depending on what is desired. The technique makes use of a class of molecules called carbocations, which are simply ions in which a carbon atom carries a positive charge.

Carbocations have a long history in chemistry because they are powerfully reactive. Carbocation reactions have been used for the productions of polymers, steroids, and pharmaceutical products, but until now, researchers have not been able to control the reactions in a way that results in the production of only left-handed or right-handed molecules.

However, carbocation reactions are also found throughout the natural world, and they are used to make the proteins, sugars, and many other molecules necessary for every living organism.

“Carbocations are a fundamental building block of all the molecules of life,” Nelson says. “Nature uses them to make molecules of one hand or the other all the time. We haven’t been able to do that.”

But now we can. Using a class of catalysts developed by German chemist Benjamin List (who won the Nobel Prize in chemistry in 2021), Nelson has harnessed carbocation reactions in such a way that they produce only the left-handed or right-handed form of a desired molecule.

These carbocation reactions work by inserting a molecular chunk containing a single carbon atom and hydrogen atom into a precise location in a larger molecule.

On their own, these reactions will produce both forms of the desired molecule. The synthetic catalysts used by Nelson borrow a trick from their natural counterparts, enzymes, to force one form or the other to be made. Both enzymes and the catalysts inspired by them do this by having a cavity in which the reaction takes place. The shape of the cavity dictates which form will be created.

To picture how this works, imagine if you wanted to make a bunch of rubber hands, but you wanted all the hands to be left-handed. One way you could do that would be to get a left-handed glove and then pour liquid rubber into it. After the rubber set, you could pop the rubber hand out of the glove and it would be left handed. A right-handed glove would yield right-handed rubber hands

Nelson says he would like to see the reaction be made more practically applicable in order to move it out of the experimental laboratory setting and into the pharmaceutical chemistry world where he hopes it will eventually be used to synthesize medications more efficiently.

The paper describing the work, titled “Catalytic asymmetric C–H insertion reactions of vinyl carbocations,” appears in the December 9 issue of Science. Co-authors are Caltech graduate chemistry students Sepand K. Nistanaki and Chloe G. Williams; Benjamin Wigman, Jonathan J. Wong, Stasik Popov, and K. N. Houk of UCLA; and Brittany C. Haas, Jacob Werth, formerly of the University of Utah, now with Pfizer, and Matthew S. Sigman of the University of Utah.

Funding for the research was provided by the National Institutes of Health and the National Science Foundation.

Source – Caltech