A cHAT about chemistry

Rice University chemists detail a greener way to make pharmaceutical intermediates

Lori Lesko
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A cHAT about chemistry

HOUSTON—Aimed at providing a greener environment, Rice University scientists have developed a method to reduce alkenes—molecules used to simplify synthesis—to more useful intermediates for drugs and other compounds via a dual-catalyst technique known as cooperative hydrogen atom transfer, or cHAT.

The process enables the hydrogenation of alkenes, hydrocarbons that contain a carbon-carbon double bond, to be performed in a simpler, less costly, and more environmentally friendly way.

The work by Rice chemist Julian West and postdoctoral researcher Padmanabha Kattamuri is detailed in the Journal of the American Chemical Society.

In each step of the process, a catalyst contributes a single electron and a proton. The cHAT method is for both reactions to happen in one synergistic process, with the second catalyst taking over as soon as the first is done.

“The fundamental reaction of hydrogenation is super useful for making molecules,” says West, who joined Rice last year with funding from the Cancer Prevention and Research Institute of Texas (CPRIT). “There are a few elements that are really good at this, and can do a lot of different transformations, but they’re very expensive and not the most sustainable.”

“The practical application of cHAT is to make drug molecules more quickly, efficiently and with less waste,” West tells DDN. “It uses a cheap, non-toxic metal (iron) and works in ethanol, which is a cheap and green solvent. This can be a big savings over methods that use rare, precious metals like palladium, iridium, rhodium, and platinum. The method is so new that it hasn’t had the chance to be adopted by any companies yet. However, iron is 3.4 million times more abundant than palladium in the earth’s crust and much cheaper, making it much more cost-effective and sustainable to use in chemical reactions.”

“What really inspired us in this work is looking at previous methods for hydrogenation using earth abundant elements, where both a reductant and an oxidant are needed in large quantities,” he tells DDN. “This always struck us as strange and wasteful, since hydrogenation is a reductive process, so there shouldn’t be a need for an oxidant. It turns out the oxidant is needed since the catalysts can only use one electron of the two-electron reductant, so the oxidant needs to soak up the remaining electron before the reaction can go again.”

West adds that when “you’re making drugs on the ton scale, you want to avoid generating tons of toxic solvent waste. That’s something to avoid at all costs. So this could be a big win for pharmaceutical companies.”

Many drug syntheses involve hydrogenation steps, West notes. An example of a drug that relies on hydrogenation to be produced is L-DOPA, a powerful molecule for treating Parkinson’s disease.

“We are currently in the midst of using cHAT to synthesize hydrogen isotoplogues, or molecules that contain the heavier isotopes of hydrogen (deuterium and tritium),” he states. “Putting these isotopes into bioactive molecules can improve their pharmacokinetics and are also important for drug development assays such as binding affinity. These studies are still in progress, but we believe the products will be quite useful.”

The main goal of cHAT “is to enable building new chemical reactions that let us make important molecules,” he remarks. “cHAT is just one step of many that could be used to design a new chemical reaction. However, we strongly believe that it is the missing piece for many reactions that are currently not possible, giving us the opportunity to deliver some powerful new methods.”

According to West, the next step “is to realize our main goal—to continue designing new reactions using the power of cHAT. Our lab is just starting (we have been at Rice for 1.5 years), but we are working hard to capitalize on this early discovery and use it to make important advances for the pharmaceutical industry.”

One goal is to make hydrogen atoms more available to react with other molecules of choice to form new compounds, he says. The cHAT process employs no added oxidants, works with a variety of substrates, and is highly scalable. The dual-catalyst approach also serves to produce hydrogenation diastereomers, or a different form of the same product molecule that can’t be made with noble metals.

“Through teamwork, we introduced a strategy to get us to new variations of our products as well,” West comments. “By combining dirt-cheap iron with an organic sulfur compound, we were able to cobble together a nice win-win. The iron catalyst tees up the process by giving it one hydrogen atom, and gets out of the way. Then the sulfur can come in and give it the second one. Our process uses this simple, bench-stable reagent, phenylsilane, as a hydrogen source. We just add it to ethanol with both catalysts and the alkene. And ethanol is a green solvent as well.”

West’s lab at Rice is working to configure its catalysts to produce a variety of products, “giving us a lot of chemical complexity and diversity from a single starting material. We want to know if we can exert this high level of control over the process.”

Lori Lesko

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