The one-pot reaction creates a versatile building block for bioactive molecules

The one-pot reaction creates a versatile building block for bioactive molecules

Illustration of the new synthetic route for functionalized Z-alkenes. Idea: Dr. Sofiya Runikhina, University of Groningen. Credit: Stutpak Illustration and Animation, Deventer, The Netherlands

Chemists at the University of Groningen have found a simple way to produce previously inaccessible chiral Z-alkenes, molecules that provide a significant synthetic shortcut for the production of bioactive molecules.


Instead of eight to ten synthetic steps to produce these molecules, the new reaction can be done in three steps, with no purification required. The key lies in a phosphine molecule that is normally used to make metal-containing catalysts, but which turns out to be the ideal starting point for this chemical reaction. The results were published in Advances in science on January 13.

Organic compounds are very versatile. Their carbon atoms can be linked by single, double or triple bonds. In addition, many biologically important molecules contain chiral centers, parts of the molecule that can be in two mirror-image positions, comparable to a left and a right hand. Molecules that have a double bond, a chiral center, and a reactive group for synthetic modifications all next to each other are also important, but chemists find these very difficult to make.

Unstable

Alkenes are compounds that contain two carbon atoms that are linked by a double bond. When we picture these two carbons horizontally, we can distinguish Z-alkenes, where both carbons are connected to another carbon on the same side (both pointing up), and E-alkenes, where the connected carbons are on opposite sides (one up and one down). Z-alkenes are unstable because the carbons that are connected on the same side are forced to be close together.

“The molecule doesn’t like this, and if it has a chance, it will convert to the more stable E-alkene. That’s why it’s hard to make less stable Z-configured alkenes,” explains Syuzanna Harutyunyan, professor of homogeneous catalysis at the University of Groningen. “Z-alkenes are very useful, but also difficult to make.”

The team needed to make the less stable Z-alkenes, where the double bond is connected to a chiral carbon center, still connect to a highly reactive carbon center, which is very complicated.

The one-pot reaction creates a versatile building block for bioactive molecules

This image shows the configuration of Z- and E-alkenes (top panel) and the one-pot synthesis of functionalized Z-alkenes. Credit: Harutyunyan Lab, University of Groningen

Reactive salt

Using known synthetic methods, it would take about eight to ten separate steps to create such a structure. Harutyunyan and her team tried to simplify this, starting with a molecule called phosphine. Co-author Roxana Postolache says: “This molecule is normally used to produce metal-containing catalysts. In previous work, we developed a way to make a chiral phosphine, which formed the basis of our new synthetic route to Z-alkenes.”

Harutyunyan states, “We took our phosphine and turned it into a salt. This would allow a double bond to be created with the Z configuration”.

But this salt is very reactive, and all attempts to introduce a double bond resulted in a lot of products that the scientists didn’t want. “So we had to find a way to tune the reactivity,” explains Postolache.

Blackboard

This step required a blackboard and chalk approach, which Harutyunyan and her team used to discuss options. A potential solution was found in adding a special group to the phosphine to make a different type of salt. Harutyunyan says, “We thought this should pull electrons away from the phosphor and allow us to tune the reactivity.”

First author Luo Ge took the idea from the blackboard to the lab. “We tried to make this idea work and we succeeded on our first try. It was a pleasant surprise to see that our idea actually worked.” They subsequently optimized the reaction and then used their method to modify real bioactive compounds.

opportunities

A big advantage of the new synthetic route is that it takes fewer steps and is essentially a one-pot reaction. Only room temperature is needed for the first step, mild heating (50–70 °C) to make salt, and –78 °C for the final step to make the double bond with a Z configuration.

Joint first author Esther Sinnema says: “Using our phosphine as a synthetic tool rather than a catalyst opened up all sorts of possibilities. We could make a large number of new chiral Z-alkenes and use the method to modify bioactive compounds. In the paper, we present 35 different molecules that were made with our method.”

“We expect our study to pave the way for using commercially available simple alkenes to produce much more complex functionalized alkenes via phosphine and salt intermediates,” says Harutyunyan.

More information:
Luo Ge et al, Enantio- and Z-selective synthesis of functionalized alkenes bearing a tertiary allylic stereogenic center, Advances in science (2023). DOI: 10.1126/sciadv.adf8742. www.science.org/doi/10.1126/sciadv.adf8742

Provided by the University of Groningen

Citation: One-pot reaction creates versatile building block for bioactive molecules (2023, January 13) Retrieved January 14, 2023, from https://phys.org/news/2023-01-one-pot-reaction-versatile- block-bioactive.html

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