Design and Synthesis of Alpha-helix Minimalist Peptidomimetics
Design en synthese van alfa-helix peptidomimetica
Egle, Brecht; S0188902
We have attempted to contribute to the arsenal of methods to modulate protein-protein interactions, targets that are increasingly important for pharmaceutical applications. Minimalist alfa-helix peptidomimetics, scaffolds that can display amino acid side chains in a topologicaly similar way as an alfa-helix, were synthesized. The basic architecture consisted of a multimeric scaffold that was made using a modular synthesis strategy. This was accomplished via the assembling of (hetero)cyclic monomers using a palladium catalyzed aminocarbonylation amide bond formation. These monomers were designed in such a way that amino acid side chains can be attached to them, including those bearing reactive functional group. Additionally, the option to introduce other functionalities (for post- modification) is also present.Flow chemistry was used to expand our repertoire of synthetic tools and several flow protocols were developed with a much wider applicability than just our target molecules. This includes a Negishi aryl-alkyl coupling method using a supported catalyst and a safer carbonylation method using carbon monoxide precursors. A novel unstable carbon monoxide precursor was also utilized in flow and when using a special tube-in-tube reactor design, interesting results were obtained that call for further research.The end result was the successful preparation of a variety of oligoaryl amide alfa-helix mimetics displaying diverse amino acid side chains.