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Synthesis of Diketopiperazine Based Bioactive Compounds via Palladium Catalyzed Cascade Alkynylation Reactions

Final Report Summary - CASDKP (Synthesis of Diketopiperazine Based Bioactive Compounds via Palladium Catalyzed Cascade Alkynylation Reactions)

The design and efficient synthesis of molecules of increasing complexity is essential to sustain progress in diverse fields of fundamental and applied sciences, such as organic chemistry, chemical biology, materials science or medicine. Whole industry domains, such as polymers, agrochemicals, materials or pharmaceuticals have realized impressive achievements in the last centuries thanks to small organic molecules and have changed forever our daily life. To keep pace with the increasing needs of a constantly growing humanity, it is an important task for fundamental research in Academia to develop new reactions and reagents to accelerate the discovery of innovative molecules with improved bioactivities or physical properties. In the application-driven world of industry, there is unfortunately no time anymore for fundamental development in synthetic chemistry. The enabling impact of developing new synthetic methods cannot be overstated: whereas focusing on one specific illness may result in discovering a new drug, developing a new reaction may accelerate research to find hundreds of drugs.
In this context, the goal of this project was to make use of the exceptional reactivity of a special class of reagents, called hypervalent iodine, to discover new synthetic methods. More specifically, we wanted to use the commercially available reagent TIPS-EBX recently investigated in our group for the introduction of alkynes into small bioactive organic molecules. Alkynes are very simple organic molecules constituted of two carbon atoms linked by a triple bond, which have found extended applications in the field of synthetic chemistry, materials science and chemical biology. It is indeed possible to use the alkyne group as a linchpin to “click” together molecules. This reaction has been used to build up libraries of bioactive compounds to discover new drugs, to install fluorescent molecules onto proteins, to combine the properties of different organic materials or to construct antibody-drugs conjugates to treat severe sicknesses.
The first specific objective was to install the alkyne group onto diketopiperazine, an important class of bioactive compounds, and to test the activity of the obtained compounds in collaboration with biologists. However, this first objective failed, and we turned to the even more exciting functionalization of thiols. The sulfur containing thiols can be found in many important molecules, like drugs, peptides or proteins and their high reactivity has led to intensive use in the functionalization of surfaces and materials. Being able to put the versatile alkyne group on thiols could have consequently a major impact in applied fields. Nevertheless, before this project, the methods reported to achieve this transformation were complex and required to be done in absence of air and moisture. They consequently often failed on complex substrates even in the hand of experts. Not surprisingly, applied researchers did even not consider it as a possible option to functionalize bioactive compounds or materials. During the timespan of this project, we were able to use TIPS-EBX to introduce alkynes onto thiols in a simple and straightforward way. The procedure just required the researcher to add the commercially available reagent to a thiol-containing molecule of his choice in a flask open to air and moisture, and the transformation was usually finished in less than one minute!
This key discovery has suddenly propelled the alkynylation of thiols from an exotic reaction to a highly useful process accessible for non-specialists. Many applications can be expected, especially in chemical biology and materials science. Collaboration with scientists in life sciences are now starting to investigate the direct functionalization of biomolecules, and a fluorophore could already be introduced onto a peptide by using a “Click” reaction on the introduced alkyne. The success of this project serves as a further testimony of the importance of fundamental research in synthetic chemistry to create new tools for more applied scientists in neighboring fields or industries.