Structure-Acid Lability Relationship of N-Alkylated α,α-Dialkylglycine Obtained via a Ugi Multicomponent Reaction.

Iván Ramos-Tomillero,Marisa K Sánchez,Fernando Albericio,Hortensia Rodríguez

doi:10.3390/molecules26010197

Abstract

Using the classical Ugi four-component reaction to fuse an amine, ketone, carboxylic acid, and isocyanide, here we prepared a short library of N-alkylated α,α-dialkylglycine derivatives. Due to the polyfunctionality of the dipeptidic scaffold, this highly steric hindered system shows an interesting acidolytic cleavage of the C-terminal amide. In this regard, we studied the structure-acid lability relationship of the C-terminal amide bond (cyclohexylamide) of N-alkylated α,α-dialkylglycine amides 1a–n in acidic media and, afterward, it was established that the most important structural features related to its cleavage. Then, it was demonstrated that electron-donating effects in the aromatic amines, flexible acyl chains (Gly) at the N-terminal and the introduction of cyclic compounds into dipeptide scaffolds, increased the rate of acidolysis. All these effects are related to the ease with which the oxazolonium ion intermediate forms and they promote the proximity of the central carbonyl group to the C-terminal amide, resulting in C-terminal amide cleavage. Consequently, these findings could be applied for the design of new protecting groups, handles for solid-phase synthesis, and linkers for conjugation, due to its easily modulable and the fact that it allows to fine tune its acid-lability.

Highlights

The classical Ugi four-component reaction (U-4CR) [1,2] is an isocyanide-based multicomponent reaction (IMCR) in which an amine, a carbonyl compound, a carboxylic acid, and an isocyanide render N-alkylated α,α-dialkylglycine derivatives
The lack of solThe derivatives synthesized by means of the ubility of N-alkylated the protectedα,α-dialkylglycine dipeptides hindered the studywere of acidolysis in aqueous solvents
The U-4CR has proved a powerful tool for the preparation of N-alkylated α,αdialkylglycine amides, which show high steric tension due to the large number of bulky substituents present

Summary

Introduction

The classical Ugi four-component reaction (U-4CR) [1,2] is an isocyanide-based multicomponent reaction (IMCR) in which an amine, a carbonyl compound (ketone), a carboxylic acid, and an isocyanide render N-alkylated α,α-dialkylglycine derivatives. The U-4CR has been widely used in heterocyclic chemistry, [3,4] in modern synthetic chemistry [5,6] and for ligation and bioconjugation [7] It has found ample applications for macrocyclization and stapling peptides, [8] the production of pneumococcal multivalent glycoconjugates as vaccine candidates [9], the stabilization of cyclic β-hairpins [10], and even in the total synthesis of exigurin, which is a natural marine product [11]. N-alkylated α,α-dialkylglycine derivatives are characterized by considerable steric hindrance around the two amides, thereby jeopardizing their synthesis in solution and in solid-phase In this context, the U-4CR can be used to prepare these compounds, which, in an acidic medium, are converted into labile systems. Ugi products have a broad range of synthetic applications, only a few studies have addressed the acidolytic

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Conclusion