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Версия для печати | Главная > Центр > Научные советы > Научный совет по катализу > ... > 2024 год > № 109

№ 109

 

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  • Доклад академика В.Н. Пармона на Общем собрании СО РАН
  • XXV Международная конференция по химическим реакторам ХимРеактор-25
  • За рубежом
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Доклад академика В.Н. Пармона на Общем собрании СО РАН

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XXV Международная конференция по химическим реакторам ХимРеактор-25

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Photochemistry unleashes a one-two radical punch for efficient ring synthesis

Iridium and nickel catalysts cooperate to install nonaromatic rings in drug molecules

Alight-driven reaction sequence that bolts nonaromatic rings onto het-eroarenes, such as pyridines, offers a rapid route to medicinal molecules that would be troublesome to make using existing methods (Nature 2024, DOI: 10.1038/s41586-024-07181-x).

Adding saturated sp3 carbons into drug candidates can improve properties such as solubility and target-binding affinity. But fusing nonaromatic rings to heteroarenes can be laborious, leaving this type of structure underrepresented in medicinal chemistry compound libraries.



A team led by David W. C. MacMillan at Princeton University has now developed a one-pot reaction system that creates these fused ring sys-tems using simple and readily-available radical precursors such as diols and bromoalcohols. Collaborators at Janssen Research and Development are already using it in their medicinal chemistry work.

The process initially uses blue light and an iridium photocatalyst to generate a carbon radical from the precursor. A nickel catalyst then helps that radical to couple to the heteroarene. MacMillan’s group reported this strategy in 2021, but the new system now adds a second coupling to the mix.

After the precursor has been tethered to the arene, the iridium removes its other functional group to generate another carbon radical. This locks on to an adjacent point on the heteroarene to close up a nonaromatic ring.

The team showcased more than 50 examples with a range of heteroarenes—including pyridines, quinolines, and pyrimidines—and created analogues of drugs such as the cystic fibrosis treatment Lumacaftor (shown). The reaction does not interfere with other functional groups in the molecules, so medicinal chemists can use it to modify complex molecules in the final stages of a synthesis. “We were surprised how well-behaved the whole thing was,” MacMillan says.

He adds that the reaction could be applied to a much wider range of coupling partners than diols or bromoalcohols. “You can make radicals from almost anything now,” MacMillan says. “So this strategy should work with almost any two functional group precursors that you want to use.”

 

Thermoset plastic made from wood waste catalyzes its own degradation

Scientists design tough cross-linked material that can be chemically recycled under mild conditions



A future when tough polymer resins and composites such as those found in wind turbine blades could be made entirely from plant-based, recyclable components just got a little closer. Researchers led by Katalin Barta at the University of Graz have designed a new thermoset polymer, derived from wood, that can be broken down in methanol with no added catalyst (Science 2024, DOI: 10.1126/science.adj9989).

Thermoset polymers have cross-linked networks that make them exceptionally tough and useful materials. But they are also practically impossible to break down or recycle. And epoxyamine resins, one of the most common thermoset plastics, are typically made using bisphenol A (BPA), which is an endocrine disruptor.

Plenty of researchers have tried making degradable thermoset plastics by incorporating functional groups whose bonds can be severed by a catalyst or other external trigger. Barta and coworkers designed their new biobased epoxyamine polymer similarly, with easily cleaved ester groups in the polymer backbone. But the polymer turned out not to need an external catalyst to break it down. “The fact that it catalyzes its own degradation was definitely serendipity,” Barta says. “We didn’t hope for such a wonderful effect.” Research in Barta’s group focuses on developing useful chemical building blocks from plant-based feedstocks such as lignin, a waste product from papermaking. To make the recyclable resin, the researchers combined lignin-derived 4,4′-methylenebiscyclohexanamine (MBCA) with an epoxy component made from 2,5-furandicarboxylic acid and glycidol, both of which also come from plant-based sources.

The polymer has physical properties matching those of petrochemical-based materials, including its glass transition temperature. It’s also resistant to most solvents, including acidic and basic aqueous solutions, acetone, and dichloromethane. But Barta and Xianyuan Wu, who worked on the project as a graduate student, were surprised to discover that the material started breaking down and dissolving when soaked in methanol.

The researchers determined that hydrogen-bonding interactions between the ester, amine, and methanol activate the carbonyl and initiate a trans-esterification process that breaks up the polymer network. It takes about 48 h at 70 °C for the polymer to degrade to the point at which the methyl ester of 2,5-furandicarboxylic acid can be recovered in 90% yield. The researchers could also recover the MBCA and glycidol pieces can be separated out, so every component of the polymer is recyclable to some degree.

Eugene Y.-X. Chen, a polymer chemist at Colorado State University who was not involved in the work, calls it “a superb example of demonstrating that biobased polymers, even in a robust cross-linked network form, can also exhibit recyclability advantages.” He says it was “truly remark-able” to see an epoxy-amine resin that can be depolymerized under relatively mild conditions with no external catalyst.

The team is still working to optimize the recycling process and expand the scope of recyclable epoxy-amine polymers, but “there is definitely a potential there,” Barta says. She hopes to start looking into industrial partnerships and applications for the material soon.

 

Boldly going where no C–H activation has gone before

Chiral catalyst reaches remote bonds on cyclic compounds



The researchers used their method to shave the synthesis of a
histone deacetylase (HDAC) inhibitor from 10 steps to 2.

C–H activation is the art of snipping specific bonds between carbon and hydrogen atoms on an organic molecule to graft a new functional group in place of the relatively unreactive H atom. Over the years, chemists have devised increasingly effective and selective ways to do C-H activation. But some bonds remain tantalizingly out of reach.

Jin-Quan Yu and his team at Scripps Research in California have been working for over 20 years to push the boundaries of which C–H bonds are possible to alter. In a new Science paper, they describe how they ste-reoselectively snipped a C–H bond and added aryl groups to the position three or four atoms away from the carbonyl carbon of cyclic carboxylic acids (2024, DOI: 10.1126/science.ado1246).

Chemists have gotten pretty good at stereoselectively adding atoms one or two spaces away from carbonyl groups, which coordinate to metal catalysts to direct them to the correct place to carry out the reaction. Proximity to a carbonyl group also makes a C–H bond easier to break. The ability to also add a stereocenter three carbons away, in the γ position, is “very enabling” for synthesis, Yu says. He and his team pub-lished a nonstereoselective γ-arylation reaction last year; introducing chirality was the natural next step (Nature 2023, DOI: 10.1038/s41586-023-06000-z).

The pursuit of reactions that can access remote C–H bonds with perfect control over the product’s 3D structure has a somewhat fraught history. In 2019, Frances Arnold’s group at the California Institute of Technology published a Science paper detailing engineered enzymes that produced chiral four-, five-, and six-membered lactam rings through C–H amidation. In 2020, a team from Hokkaido University reported, also in Science, a method using an iridium catalyst to install boron groups at the γ position of amide and ester compounds. Both papers were retracted because the results couldn’t be replicated.

The reaction Yu and his team developed relies on a palladium catalyst with a chiral oxazoline-pyridone ligand that reaches across the ring from the carboxylic acid to the γ position. It can attach a range of aryl halides to acids with five-, six-, and seven-membered rings, creating two new stereocenters in the process. The team also devised a slightly modified catalyst that can access C–H bonds four carbons away from the acid.

“I think it is really spectacular,” Huw Davies, an organic chemist at Emory University, says in an email. The Yu group has a long track record of making big advances in C–H activation methods, he adds, and this work clearly builds on those past insights. He’s interested to see what other functionality will become possible to install stereoselectively to the γ position.

Yu says he has filed a patent for the reaction and has established a start-up, Architect Therapeutics, that is based on using C–H activation catalysts to build novel scaffolds for drug discovery. Identifying how to expand the list of atoms and functional groups that can be attached to the γ position is also on his to-do list, he says. Ideally, he says, an effective C–H activation method means “you could replace the C–H bond with anything you want.”

Chemical & Engineering News


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