SUSTAINABLE MECANOCHEMICAL MULTICOMPONENT ONE-POT SYNTHESIS OF BIS AMIDES, 2,5-DICETOPIPERAZINES TRI-SUBSTITUTED AND 0,6-UNSATURATED-V-IACTAMS.

Abstract

This method represents an unprecedented contribution to the chemistry of peptidomimetic molecules, compared to patented and / or published methodologies for the one-pot synthesis of bis-amides (pseudopeptides) as well as heterocyclic or conformationally restricted peptides such as 2,5-DKPS and γ-lactams. One of its main contributions is the use of a green energy source, namely mechanical energy (there is no precedent for one-pot mechanochemical synthesis of heterocyclic peptidomimetics). It offers several advantages: the transformation of raw materials to yield the target peptidomimetics occurs in a single reaction step, minimizing byproducts, reagents, solvents, energy, and working time, resulting in an environmentally friendly synthesis, since the reaction sequence occurs at room temperature (25 °C), and an economical one.The target molecules exhibit a high degree of functionalization, which means they could serve as synthetic platforms for accessing other derivatives or analogs of greater structural complexity. Finally, we demonstrate the effectiveness and versatility of the mechanochemical CMR of Ugi-4-CR in the SSOD of heterocyclic peptidomimetics. Using the same methodology, it is possible to access two structurally very different types of molecules, generating the highest level of structural diversity (2,5-DKPs and gamma-lactams are completely different), under the most environmentally friendly conditions of all the patented or published contributions using the Ugi-4C CMR. This is of significant impact and one of the main challenges for synthetic chemists. The relevance of registered peptidomimetic molecules in the design of new bioactive molecules constitutes an area of ​​research in constant development.The methodologies developed represent a dual contribution to both the area of ​​sustainable multicomponent synthesis and peptidomimetic chemistry. In addition to our work, there are no other publications on sustainable syntheses like those listed. Peptidomimetic molecules are of particular interest in the design of new bioactive molecules or drugs, and are a focus of attention for the pharmaceutical industry; therefore, the sustainable syntheses presented could be of interest to them from both an ecological and economic perspective. Furthermore, the well-documented versatility and broad scope of Ugi's RMC-1 and its impact on the synthesis of linear and / or cyclic peptidomimetic molecules are noteworthy.