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Synthesis

Video: Chemists synthesize perseanol—a natural insecticide—for first time

Complex natural product’s 16-step synthesis includes a palladium-catalyzed cascade reaction

by Bethany Halford , Matt Davenport
September 26, 2019 | APPEARED IN VOLUME 97, ISSUE 38

 

Credit: Jebulon/Wikimedia Commons/C&EN

Although chemists have known about the molecule perseanol since the 1990s, no one has completed a total synthesis of the complex, polycyclic insecticide, until now. California Institute of Technology chemistry professor Sarah E. Reisman and graduate students Arthur Han and Yujia Tao constructed perseanol in just 16 steps, starting from a commercially available vinylogous ester and pulegone—a compound found in plants like catnip. The chemists’ strategy features a one-pot palladium-catalyzed cascade and carbon monoxide insertion reaction that stitches together most of perseanol’s polycyclic core (Nature 2019, DOI: 10.1038/s41586-019-1580-x). Learn more at cenm.ag/perseanol.

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The following is the script for the video. We have edited the interviews within for length and clarity.

Matt Davenport: In the 1990s, a team of scientists was in Tenerife, in the Canary Islands, hoping to find some interesting molecules in the island’s plants. They snagged some samples from a local tree, the Persea indica, and chopped those samples up, and then prepared an extract that they described as a syrupy gum. And in that goo, they indeed found several molecules that had never been seen before, including this one, perseanol.

Scientists think that perseanol could be a natural pesticide because it resembles ryanodine, which was an active ingredient in an insecticide that people used in the mid-20th century. And they used a lot of it before finding cheaper alternatives. But there are some chemically and perhaps biologically interesting differences between perseanol and ryanodine.

You can see their skeletons are similar but not quite identical. And check out the pyrrole-2-carboxylate ester on ryanodine, which is absent in perseanol. Some studies suggest that without this ester, perseanol and related molecules can target insects without also affecting mammals.

So it’s an interesting molecule. And at Caltech, Sarah Reisman and her students Arthur Han and Yujia Tao became the first chemists to make it from scratch. You know, instead of hiking out to the Canaries and extracting tree goo. And this is where I stop being useful because I just don’t get total synthesis. But don’t worry. I know someone who does. Hey, Bethany.

Bethany Halford: Hey, Matt.

Matt: Can you break down this synthesis for us?

Bethany: Sure. So perseanol presented a formidable challenge, but Reisman’s lab had some familiarity with this type of molecule. They completed an 18-step total synthesis of ryanodine in 2017.

Sarah Reisman: So to us that seemed like a good opportunity for synthesis. We might be able to take some of the lessons we learned from ryanodine and sort of use them to guide our strategy. It was very clear that we were going to have to come up with some new approaches as well because of the differences in the structural framework, and so that also gives a good opportunity to explore some new chemistry.

Bethany: The Caltech team came up with a strategy to make perseanol from anhydroperseanol, by creating an epoxide on one part of the molecule and then generating an anion that would attack and open up that epoxide, stitching up the last ring in perseanol in the process. Chemists in Pierre Deslongchamps’s lab at the University of Sherbrooke used a similar strategy in 1979 in the first total synthesis of a related compound, ryanodol.

To get to anhydroperseanol, the team stitched together two simpler fragments, which were themselves built from simpler starting molecules. For one fragment, the team started with pulegone, which is found in a variety of plants, including catnip. Six steps later, they had their first fragment.

To make the other fragment, they also needed six steps, this time starting with a commercially available vinylogous ester. Next, they coupled those fragments together. And that molecule became fodder for a palladium-catalyzed cascade, followed by a carbon monoxide insertion reaction, to get to anhydroperseanol. All told, to go from the fragments to anhydroperseanol then to perseanol, took 10 steps.

Remember Deslongchamps, the chemist who made ryanodol in the 1970s? I talked with him about this synthesis and he said making perseanol “in only 16 chemical operations is an absolutely outstanding achievement.” He also called it “an overall genius strategy.”

Matt: He sounds impressed. I do have one more question, though. If both fragments took six steps to make, then it’s 10 more to the final product, how is that a 16-step synthesis?

Bethany: So yeah, chemists count only the longest linear sequence of steps. So they give themselves a little discount on one of the fragments.

Matt: So synthetic chemists must not be paid by the step.

Bethany: Yeah, it’s more like golf.

Matt: Mulligans and all.

Thanks for watching everyone. We’d love to cover more synthesis with our videos. So please let us know about cool new papers in the field. You can leave us feedback in the comments or find us on social media.

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Comments
Shankar (October 2, 2019 12:11 PM)
Nice video summary! Good job.
Matt Davenport (October 2, 2019 4:57 PM)
Thanks so much, Shankar!
Jack W Horvath (October 2, 2019 3:27 PM)
Wow! And nature makes this all the time somewhere or other.
Shane Broussard (October 7, 2019 9:38 AM)
What was the final yield?

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