Molecular compound with molecules colored white, gray, red and green.
UC Davis researchers report the successful synthesis of specific chiral molecules using rearrangements of simple achiral hydrocarbons in the presence of complex organic catalysts. (Courtesy of Dean Tantillo)

Harnessing Aliphatic Hydrocarbons: Researchers Step Closer to Mimicking Nature’s Mastery of Chemistry

In nature, organic molecules are either left- or right-handed, but synthesizing molecules with a specific handedness in a lab is hard to do. Make a drug or enzyme with the wrong “handedness” and it just won’t work. Now chemists at the College of Letters and Science at UC Davis are getting closer to mimicking nature’s chemical efficiency through computational modeling and physical experimentation. 

In a study appearing in the journal Nature, Professor of Chemistry Dean Tantillo, graduate students William DeSnoo and Croix Laconsay, and their colleagues at the Max Planck Institute report the successful synthesis of specific chiral molecules using rearrangements of simple achiral hydrocarbons in the presence of complex organic catalysts. Most biological compounds, including many prescription drugs, are chiral.

Tantillo and colleagues hope the findings will enable scientists to better harness hydrocarbons for a variety of purposes, such as precursors to medicines and materials.

“The novelty of this paper is that this is really the first time, to my knowledge, that someone has been able to get a carbocation shift that makes one of the mirror image products rather than the other with high selectivity,” Tantillo said.  

Little balls of grease

In chemistry, chirality is a property that refers to a pair of molecules that share atomic makeup but are mirrored in structure. Similar to how your right hand and left hand are mirror images, these molecules, like your hands, cannot be superimposed on each other.

“Synthetic chemists often want to make molecules that come in mirror image forms, but they only want one of them,” Tantillo said. “For example, if you want to make a drug molecule, often you need one of the two chiral forms to bind selectively to a protein or enzyme target.”

Achieving this using simple carbocations can be difficult in a lab setting because such molecules, according to Tantillo, are often like “little balls of grease with some positive charge smeared around them.”

The greasy-like nature of these molecules typically makes binding by a chemical catalyst in one orientation over another difficult due to the lack of charged groups for the catalyst to grab on to.

But the researchers found a solution. Using imidodiphosphorimidate, a chiral organic acid, as a catalyst, the team successfully performed carbocation rearrangements of achiral alkenyl cycloalkanes, producing chiral molecules of interest called cycloalkenes. Through computational methods, Tantillo and colleagues deduced how the catalyst selectively produces one chiral form over the other.      

Similarities to nature

According to Tantillo, the resulting reaction bears similarity to how enzymes that make hydrocarbon natural products called terpenes behave in nature. Part of Tantillo’s research concerns mapping terpene reaction pathways using quantum mechanical methods.

“If there are multiple possible pathways to a product, then every time you stop at an intermediate on that pathway, you have the possibility to get byproducts that come from that intermediate,” he said. “So it is important to know when and why a carbocation wants to stop en route to a given terpene if one wants to understand and ultimately reengineer terpene-forming enzymes.”

The new method published in Nature could in principle be harnessed to produce both natural molecules and non-natural molecules. 

“Whether these things will ever be done is hard to say, but petroleum is a source of a lot of hydrocarbons and if you could catalytically turn those into molecules with defined chirality, you’ve increased the value of those molecules,” Tantillo said.  

Additional co-authors are: Vijay Wakchaure, Markus Leutzsch and Benjamin List, Max Planck Institut für Kohlenforschung, Mülheim an der Ruhr, Germany; and Nobuya Tsuji, Hokkaido University, Sapporo, Japan.

The work was supported in part by the Max Planck Society, the Deutsche Forschungsgemeinschaft and the European Research Council, and the U.S. National Science Foundation. 

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