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Synthesis of macrocycle compounds with enediyne motif

Multicomponent reactions (MCRs) are powerful tool for introducing chemical diversity and the rapid generation of small-molecule libraries.1 The main advantage of MCRs is an easy access to libraries of complex and structurally diverse compounds in a single reaction step starting from relatively simple components. Isocyanide- based multicomponent reactions (IMCRs, i.e. Passerini, Ugi reaction) are among the most important MCRs. The Ugi reaction provides a rapid route to peptide-like compounds through coupling of an aldehyde, an amine, a carboxylic acid and an isocyanide. The Ugi reaction can be coupled with a post-condensation reactions, like cyclisation, to increase the number of compounds available for screening.2 Our aim was synthesis of macrocycle compounds with enediyne motif utilizing the Ugi reaction/Sonogashira reaction approach coupled with intramolecular cyclisation (Scheme 1). The enediyne structural motif was found in natural products with strong anticancer activity.3 Additionally, enediyne compounds can be used in asymmetric hydrogenation reactions4 and in metal complexation.5 The Ugi reaction of aldehyde 1, different C- protected amino acids, commercially available isocyanides and carboxylic acids gave Ugi products 2. Next, the Sonogashira reaction was carried out with unsaturated alcohol yielding acyclic structures 3. Finally, macrocycle compounds 4 were synthesized by intramolecular esterification (Scheme 1).

macrocyclic compounds ; multicomponent reactions ; Ugi reaction

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