Hydrazinopeptide Motifs Synthesized via the Ugi Reaction: An Insight into the Secondary Structure

Abstract

A number of N a -alkyl,N b -acylhydrazines have been synthesized via the Ugi reaction of N-acylhydrazones with an isocyanide and trifluoroacetic acid. The trifluoroacetic acid acted as a 'silent partner' and becomes removed upon basic workup of the reaction. These compounds have been efficiently modified further via reductive alkylation to produce N a ,N a -dialkyl,N b -acylhydrazines. The two groups of novel hydrazinopeptide motifs have been shown by simple 1 H NMR spectroscopic experiments to display two different secondary structure patterns. These observations were confirmed by X-ray crystallographic analysis. Combining the hydrazone and carboxylic acid moieties in one reaction precursor offers the opportunity for an 'intramolecular' hydrazino-Ugi reaction, which was also demonstrated.

Synthesis of acylhydrazino-peptomers, a new class of peptidomimetics, by consecutive Ugi and hydrazino-Ugi reactions

“…The choice of TFE as the solvent for the hydrazino-Ugi reaction was important because the same reaction carried out in methanol, often the solvent of choice for Ugi reactions, provided the formation of a complex mixture. This fact has already been reported [34]. …”

“…In this sense, the Ugi four-component reaction (U-4CR) has proven to be a robust and versatile method for the synthesis of peptoids and peptide-peptoid hybrids (peptomers) [49–53]. This reaction has also been combined with other protocols for the synthesis of bioactive peptides [54–55] and hydrazinopeptide motifs [33–34]. In continuing our research on the synthesis of peptoids [53,56–57], herein we describe the synthesis of a new class of peptidomimetics, which we have called acylhydrazino-peptomers (Fig.…”

A Catalytic Asymmetric Ugi‐type Reaction With Acyclic Azomethine Imines

“…To provide a completely new solution to this long‐standing problem, we came up with an idea to use acyclic azomethine imines I , which was recently revealed by us as a novel prochiral electrophile generated with a catalytic amount of axially chiral dicarboxylic acid 7. 8 By applying this reaction system in the Ugi reaction, we envisaged that the intermediary nitrilium ion II would be trapped internally by the oxygen of the hydrazide to give heterocyclic compound III , and the carboxylic acid could be regenerated to enter the next catalytic cycle 9…”

A Catalytic Asymmetric Ugi‐type Reaction With Acyclic Azomethine Imines

“…The only solution reported to date is the use of isocyanoacetamides in the presence of chiral phosphoric acid, [3,4] a strategy that is more successful in the related Passerini reaction. [9] As a source of the isocyanide, we opted to use 2-benzoyloxyphenyl isocyanide 3 a developed by Pirrung and co-workers, [10] because of its odorless nature, and more importantly, its equivalency to a pharmaceutically valuable benzoxazole unit (see below). [7,8] By applying this reaction system in the Ugi reaction, we envisaged that the intermediary nitrilium ion II would be trapped internally by the oxygen of the hydrazide to give heterocyclic compound III, and the carboxylic acid could be regenerated to enter the next catalytic cycle.…”

“…[7,8] By applying this reaction system in the Ugi reaction, we envisaged that the intermediary nitrilium ion II would be trapped internally by the oxygen of the hydrazide to give heterocyclic compound III, and the carboxylic acid could be regenerated to enter the next catalytic cycle. [9] As a source of the isocyanide, we opted to use 2-benzoyloxyphenyl isocyanide 3 a developed by Pirrung and co-workers, [10] because of its odorless nature, and more importantly, its equivalency to a pharmaceutically valuable benzoxazole unit (see below). [11] Preliminary experiments using benzaldehyde and N'-benzylbenzohydrazide (2 a) in the presence of the representative chiral dicarboxylic acids (R)-1 a and (R)-1 b were rather disappointing in terms of both the reactivity and selectivity (Table 1, entries 1 and 2).…”