Straightforward, racemization-free synthesis of peptides with fairly to very bulky di- and trisubstituted glycines

Pinto, Filipa C.S.C.; Pereira-Lima, Sílvia M. M. A.; Maia, Hernâni L. S.

doi:10.1016/j.tet.2009.09.022

Cited by 8 publications

(2 citation statements)

References 31 publications

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“…A similar behavior was also observed for N -acylated peptoids, which trigger the loss of peptoid monomer from the sequence, a phenomenon also explained through an oxazolinium-based mechanism [ 16 ]. Furthermore, the aforementioned acid-cleavable behavior of α,α-dialkylglycines has also been used to carry out the synthesis of tri- and pentapeptides with a central residue of one α,α-dialkylglycine [ 17 ]. Those authors demonstrated that the overall yields of the peptides was significantly related to molecular bulkiness around the reaction center (R2) rather than to the size of the peptide chain involved.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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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Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…This difficulty can only be overcome by taking advantage of synthetic methodologies not usually used in peptide chemistry, such as the methodology based on the Ugi reaction, which we have been developing over the last decade. [17][18][19][20] Several studies on the biological activity of N-methyl, C α,α -dimethylglycine, (Me-Aib) have been reported. Me-Aib has been widely used as a specific model substrate for system A amino acid transport, 21 which is expressed strongly in transformed and malignant cells.…”

mentioning

confidence: 99%

Synthesis of N-alkyl-Cα,α-dimethylglycine derivatives

Monteiro¹,

Pereira-Lima²,

Pereira³

et al. 2014

Arkivoc

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A Half‐Century of the Ugi Reaction: Classic Variant

Ullrich

Kazmaier

2023

Organic Reactions

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The classic Ugi reaction is a four‐component coupling process that involves a carboxylic acid, a carbonyl compound, an amine, and an isocyanide. All reaction components are in a dynamic equilibrium with several intermediates, until an irreversible intramolecular 1,4‐ O → N acyl transfer leads to the formation of an N ‐acylamino acid amide. If chiral components are used in this reaction, a mixture of diastereomers is generally formed with moderate‐to‐low stereoselectivity. The broad scope of substrates that can be used in the Ugi reaction allows for the straightforward synthesis of libraries of structurally related amino acid and peptide derivatives. Therefore, this methodology is often applied to the synthesis of drugs, drug‐like molecules, and natural products. This chapter describes different variations of classic Ugi reactions, including the use of functionalized and cleavable reaction components to illustrate the broad scope of the reaction. In addition, applications in target‐directed synthesis and comparisons to other related multicomponent reactions are presented. Tabular surveys are organized according to the isocyanides used. The literature is discussed from the first disclosure of an Ugi reaction in 1961 through to the end of 2012.

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Straightforward, racemization-free synthesis of peptides with fairly to very bulky di- and trisubstituted glycines

Cited by 8 publications

References 31 publications

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

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

Synthesis of N-alkyl-Cα,α-dimethylglycine derivatives

A Half‐Century of the Ugi Reaction: Classic Variant

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