Chemists from the University of Groningen have found an easy option to produce previously inaccessible chiral Z-alkenes, molecules that provide a major synthetic short-cut for the production of bioactive molecules. As an alternative of eight to 10 synthetic steps to provide these molecules, the brand new response will be done in three steps, without the necessity for any purification. The important thing lies in a phosphine molecule that is generally used to make metal-containing catalysts but that seems to be the perfect start line for this chemical response. The outcomes were published in Science Advances on 13 January.

Organic compounds are very versatile. Their carbon atoms will be connected by single, double, or triple bonds. Moreover, many biologically vital molecules contain chiral centers, parts of the molecule that will be in two mirror image positions, comparable to a left and a right hand. Molecules which have a double bond, a chiral centre, and a reactive group for synthetic modifications all next to one another are also vital, but chemists find that these are very difficult to make.

Unstable

Alkenes are compounds that contain two carbon atoms which can be connected by a double bond. When picturing these two carbon atoms horizontally (see Figure 1), we are able to distinguish Z-alkenes, whereby each carbon atoms are connected to a different carbon on the identical side (each pointing up), and E-alkenes, whereby the connected carbons are on opposite sides, (one up and one down). Z-alkenes are unstable because carbons which can be connected on the identical side are forced to be close to one another.

‘The molecule doesn’t like this and if it gets a probability it’ll transform into the more stable E-alkene. That’s the reason it is tough to make less stable Z-configured alkenes,’ explains Syuzanna Harutyunyan, Professor of Homogeneous Catalysis on the University of Groningen. ‘Z-alkenes are very useful, but in addition difficult to make.’ The team needed to make the less stable Z-alkenes, where the double bond is connected to a chiral carbon centre, further hook up with a highly reactive carbon centre, which could be very tricky.

Reactive salt

Using known synthetic methods, it might take about eight to 10 separate steps to create such a structure. Harutyunyan and her team tried to simplify this by starting out with a molecule called phosphine.

This molecule is generally used to provide metal-containing catalysts. In previous work, we developed a option to make a chiral phosphine, which formed the premise for our latest synthetic path to Z-alkenes.”

Roxana Postolache, Co-Writer

Harutyunyan: ‘We took our phosphine and turned it right into a salt. This might allow the creation of a double bond with Z-configuration.’ But this salt could be very reactive and all of the attempts to introduce a double bond resulted in plenty of products that the scientists didn’t want. ‘So, we had to search out a option to tune the reactivity,’ explains Postolache.

Blackboard

This step required a blackboard and chalk approach, which Harutyunyan and her team used to debate options. A possible solution was present in adding a special group to the phosphine to make a unique sort of salt. Harutyunyan: ‘We figured that this could pull electrons away from the phosphorus and would allow us to tune the reactivity.’ First writer Luo Ge took the thought from the blackboard to the laboratory: ‘We tried to make this concept work and we got it right with our first attempt. It was a nice surprise to see that our idea really worked.’ They subsequently optimized the response after which used their method to switch real bioactive compounds.

Possibilities

A giant advantage of the brand new synthetic route is that it takes fewer steps and is actually a one-pot response. It just requires room temperature for step one, mild heating (50-70 °C) to make the salt, and –78 °C for the ultimate step of creating the double bond with a Z-configuration (see Figure 2). Joint first writer Esther Sinnema: ‘Through the use of our phosphine as an artificial tool, somewhat than a catalyst, we opened up every kind of possibilities. We could make numerous latest chiral Z-alkenes and use the strategy to switch bioactive compounds. Within the paper, we present 35 different molecules that were made with our method.’ Harutyunyan: ‘We expect that our study will pave the way in which for using commercially available, easy alkenes to make far more complex functionalized alkenes via phosphine and salt intermediates.’

Source:

Journal reference:

Ge, L., et al. (2023) Z-Selective synthesis of chiral alkenes by formal Wittig olefination of terminal alkenes. Science Advances. doi.org/10.1126/sciadv.adf8742.