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Structure-Acid Lability Relationship of N-alkylated α,α-dialkylglycine Obtained via a Ugi Multicomponent Reaction

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...

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Autores principales: Ramos-Tomillero, Iván, Sánchez, Marisa K., Rodríguez, Hortensia, Albericio, Fernando
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794957/
https://www.ncbi.nlm.nih.gov/pubmed/33401754
http://dx.doi.org/10.3390/molecules26010197
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author Ramos-Tomillero, Iván
Sánchez, Marisa K.
Rodríguez, Hortensia
Albericio, Fernando
author_facet Ramos-Tomillero, Iván
Sánchez, Marisa K.
Rodríguez, Hortensia
Albericio, Fernando
author_sort Ramos-Tomillero, Iván
collection PubMed
description 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.
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spelling pubmed-77949572021-01-10 Structure-Acid Lability Relationship of N-alkylated α,α-dialkylglycine Obtained via a Ugi Multicomponent Reaction Ramos-Tomillero, Iván Sánchez, Marisa K. Rodríguez, Hortensia Albericio, Fernando Molecules Article 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. MDPI 2021-01-02 /pmc/articles/PMC7794957/ /pubmed/33401754 http://dx.doi.org/10.3390/molecules26010197 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ramos-Tomillero, Iván
Sánchez, Marisa K.
Rodríguez, Hortensia
Albericio, Fernando
Structure-Acid Lability Relationship of N-alkylated α,α-dialkylglycine Obtained via a Ugi Multicomponent Reaction
title Structure-Acid Lability Relationship of N-alkylated α,α-dialkylglycine Obtained via a Ugi Multicomponent Reaction
title_full Structure-Acid Lability Relationship of N-alkylated α,α-dialkylglycine Obtained via a Ugi Multicomponent Reaction
title_fullStr Structure-Acid Lability Relationship of N-alkylated α,α-dialkylglycine Obtained via a Ugi Multicomponent Reaction
title_full_unstemmed Structure-Acid Lability Relationship of N-alkylated α,α-dialkylglycine Obtained via a Ugi Multicomponent Reaction
title_short Structure-Acid Lability Relationship of N-alkylated α,α-dialkylglycine Obtained via a Ugi Multicomponent Reaction
title_sort structure-acid lability relationship of n-alkylated α,α-dialkylglycine obtained via a ugi multicomponent reaction
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794957/
https://www.ncbi.nlm.nih.gov/pubmed/33401754
http://dx.doi.org/10.3390/molecules26010197
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