Concise summary of pleurotin

From the point of view of chemists, pleurotin is an intriguing molecule.

It There is strong evidence of untapped therapeutic properties as a tumor inhibitor and antibiotic. It has a fascinating complex composition (6 rings! eight stereocenters!). And it has been difficult to synthesize over the decades. The last time chemists did this was in 1988 and they needed 26 steps to do so.

For Princeton Chemistry’s Sorensen Lab, these qualities were part of the attraction for a long-term investment of time and effort. energy which materialized.

The laboratory reports a concise synthesis of pleurotin by the Diels-Alder reaction and a radical epimerization which transforms a cis-hydrindane into a trans- hydrindane desired. Their late-stage intermediate intersects with the synthesis of 1988 near the end of the process, reducing the full number of steps required for synthesis by thirteen.

The lab’s process could produce an extended family of pleurotin-like cancer screening candidates that ultimately could be useful to pharmaceutical companies seeking to exploit the promise of pleurotin as a as a new generation drug.

“Pleurotine is a very smart molecule, it is very reactive. But it hasn’t proven itself as a medicine yet, partly because it’s not very soluble in water,” said a third-year graduate student. Jean Hoskin, lead author of the article. “Ideally, you want to modify its structure: modify here, modify here, put a hydroxy here or a phosphate there, make some very careful modifications.

“And since you cannot to really do this from the pleurotin itself, our approach will be to incorporate the changes from a basic synthesis, which is only possible due to the shortness of the route. Then you end up with what are called analogues that are very similar to this natural product but have these strategic changes.”

A Concise Synthesis of Pleurotin Enabled by a Nontraditional CH Epimerization was published last month in the Journal of the Modern American Chemical society (JACS) by Hoskin and PI Erik SorensenProfessor Arthur Allan Patchett in Organic Chemistry in the Department of Chemistry.

“When a chemist analyzes a framework like this, there are no obvious strategies to adopt to create it from of simple compounds,” Sorensen said. His laboratory began working on pleurotine in 1988 only to encounter a series of disappointments. So far.

“If you take oyster mushroom and say, I want to do selective chemistry on its periphery so that we can build new molecules with improved properties, then maybe there will be better anti-cancer agents,” he added. “So John and I were drawn to the challenge of developing a chemical approach to building this framework in as few steps as possible.

“Eight steps is a pretty small number of steps for a molecule of this complexity,” Sorensen said. “This research is a testament to John’s skill as the designer and executor of organic synthesis.”

Untapped promise since 1947

Pleurotin derives from the fungus Pleurotus griseus. The researchers first described the molecule in a write-up published in 1947 as inhibiting the growth of Staphylococcus aureus, the source of staph infections. That was 41 years before the landmark synthesis of pleurotin by David Hart, now professor emeritus at Ohio Point out University.

But due to the inability to synthesize it easily, the pleurotin has no not been studied to its full potential. That’s when the Sorensen Lab stepped in.

To shorten the steps to synthesis, the researchers used a proven tactic in organic synthesis called hydrogen atom transfer 1.5, in which a reactive radical centered on the oxygen “extends” and strips a hydrogen from a carbon which is part of the composition of the pleurotine to form a new radical. The researchers then used this radical to receive hydrogen from an exogenous thiol that would allow the stereocenter to switch to an alternate or trans configuration.

“We tried many different strategies and ultimately what worked was this reversal step to go from this cis-hydrindane to trans-hydrindane. That’s the key idea,” Hoskin said. “Using the functionality inherent in the molecule – this oxygen – we could, as if using a pair of microscopic tweezers, pull out this hydrogen and turn this carbon around to obtain the necessary trans-hydrindane.”

The process generates a racemic end product, creating left and right variations in equal proportions. Only one of them is claimed to be bioactive. Now that the formal synthesis has been completed in a more concise manner, Hoskin said, the next challenge will be to produce a single mirror-image variation of the molecule and its analogs.

This research shows the power of a brief summary,” Hoskin said. “It only takes a week to do the whole course.”

Sorensen added: “I think this work put us in a favorable position towards our goal more significant to expand the class of pleurotin-based anticancer agents.”

This research is supported by funding from the Countrywide Science Basis (CHE-2102663).

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