Scripps Research chemists have solved a longstanding problem in the field of pharmaceutical chemistry with a relatively simple and controllable method for producing benzocyclobutenes (BCBs), a class of reactive compounds that are highly prized as building blocks for drug molecules. , but they have been relatively difficult to access.
The new method, described in an article in Science on May 12, uses designer ligand molecules with palladium atom catalysts to break pairs of adjacent methylene-type CH bonds in relatively cheap and abundant carboxylic acids. Breaking these ties allows BCB to be manufactured with unprecedented ease through a process called formal. [2+2] cycloaddition.
The researchers demonstrated the new method with relatively easy synthesis of several BCBs found in traditional medicines and in experimental and approved drug molecules.
“Our new method requires only a saturated aliphatic chain and aryl halides as coupling partners for a formal cycloaddition that produces a four-membered ring,” says the study’s lead author, Jin-Quan Yu, PhD, the University Chair of Chemistry. Bristol Myers Squibb and Frank and Bertha Hupp Professor in the Department of Chemistry at Scripps Research. “By contrast, the traditional method of making BCB requires more steps and produces a mixture of products that are difficult to separate.”
BCBs have a unique backbone consisting of a relatively rigid, tense, and reactive ring of four carbon atoms fused to a benzene ring. They are present in some natural medicinal compounds and in the heart failure drug ivabradine. In general, their propensity for biological activity makes them potentially very useful building blocks for drugs. They are also key ingredients in photosensitive polymers, polymer dielectrics, and other advanced materials.
However, the synthesis of BCB has been challenging. Limitations of the various methods that have been published include the inability to control the order in which the individual reactions occur, so that the reaction products include not only the desired product but also the undesired ones. Yu’s new method allows for this control for the first time, a property called regioselectivity.
Last year, Yu’s lab developed a method for the palladium-catalyzed β- and γ-methylene CH functionalization of free aliphatic acids, to make structurally diverse γ- and δ-lactones, also highly valued as potential pharmaceutical components. Taking inspiration from that method and using it as a starting point, they followed a similar approach to overcome the challenge of regioselective synthesis of BCB.
For the new method, they used bidentate amide-pyridone ligands with palladium catalysts to activate the CH bonds of two adjacent methylene units into a carboxylic acid.
“In the presence of a dihaloheteroarene, two CH bonds and two aryl-halogen bonds come together almost miraculously to form a bicyclic BCB scaffold,” says Yu. “Regioselectivity is achieved through differentiation between aryl iodide and bromide sites.”
The chemists demonstrated that the method can be used with a wide range of cyclic and acyclic aliphatic acids to generate various BCBs and hetero-BCBs, a dream come true for many pharmaceutical chemists.
“The ability to make direct use of abundant and structurally varied acyclic and cyclic acids as substrates, without prefunctionalization, substantially expands chemists’ access to various BCB scaffolds, including heterocyclic BCBs that can be very useful in drug molecules,” Yu says. .
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