Peptidomimetics

Terminal alkynes display an intriguing versatility as building blocks in organic and medicinal chemistry, as their reactivity is unique. Their chemistry involves several highly selective reactions, e.g., [3 + 2] cycloadditions with azides and isoelectronic functional groups (among them the copper or ruthenium-catalyzed azide-alkyne cycloaddition, CuAAC and RuAAC), the thiol-yne reaction, Diels-Alder reactions and the Sonogashira cross-coupling. While amino acids with a terminal alkyne in the side chain are well-known, the synthesis of their correlates where the carboxy group is replaced by a terminal alkyne is still tedious. Nevertheless, these propargylamines have been frequently used as precursors for the synthesis of diverse bioactive compounds. Their conversion into triazoles is best investigated, since triazoles as amide bond surrogates are found in several inhibitors of proteases such as cathepsin S, cysteine proteases, cruzain 20, caspases and peptidyl aminopeptidases. These protease inhibitors show potential for the treatment of Chagas disease, Huntington´s disease, malaria, autoimmune diseases and the imaging of tumor associated macrophages. Whereas the carboxylic acid function of amino acids can be easily converted into amides or esters, propargylamines have been converted into acids, alcohols or olefins in order to obtain natural products like angustureine and cuspareine. Intramolecular Pauson-Khand reaction, Diels-Alder reaction, gold-catalyzed azetidin-3-one formation, as well as various transition metal-mediated additions and cross-coupling reactions represent further important reactions of propargylamines, providing the potential to form innovative peptidomimetics.