engleski

Multicomponent synthesis of hydrazino depsipeptides

Multicomponent reactions (MCRs) offer numerous advantages over traditional sequential reactions for the synthesis of diverse structurally demanding compounds. Isocynide-based MCRs, particularly Passerini and Ugi reactions, are of special importance, because they provide peptide-like compounds able to mimic structure and/or function of natural peptides and proteins. Natural and non-natural amino acids are widely exploited in MCRs as mono- and bifunctional building blocks to increase the number of stereocentres and scaffold diversity. We are interested in exploring the utility of -hydrazino acids in synthesis of hydrazino peptidomimetics. To the best of our knowledge, chiral -hydrazino acids have not been used as carboxylic components in the Passerini reaction. We have developed methodology for the synthesis of peptidomimetics by multicomponent reaction of an -hydrazino acid, an aldehyde or ketone and an isocyanide component. -Hydrazino acids bearing different protecting groups at N were used to allow further specific modification of Passerini products. The Passerini reaction of -hydrazino acids, carbonyl compounds and isocyanides yielded hydrazino depsipeptides, a new class of backbone extended peptidomimetics comprising amide bond isoster. A wide range of carbonyl and isocyano components were used, along the alpha-hydrazino acids carrying three different N-alpha protecting groups. N-alpha-benzyl, Nβ-Boc protected hydrazino acids gave hydrazino depsipeptides in considerably better yields then their N-alpha-Boc and N-alpha-Cbz-protecting analogues. The kinetics and thermodynamic equilibrium of the rate-determining step of the reaction with different alpha-hydrazino acids were studied by DFT approach.

multicomponent reactions; hydrazino acids; hydrazino depsipeptides

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