N-Amino-imidazolin-2-one Peptide Mimic Synthesis and Conformational Analysis

Abstract

Base-promoted 5-exo-dig cyclizations of aza-propargylglycinamides provided N-amino-imidazolin-2-one peptide mimics, which exhibited turn geometry in X-ray crystallographic and NMR spectroscopic analyses. Sonogashira coupling prior to cyclization afforded N-amino-imidazolin-2-ones with diverse 4-position aromatic substituents with potential to serve as Phe and Trp mimics.

Synthesis and alkylation of aza‐glycinyl dipeptide building blocks

“…For example, benzhydrylidene aza‐glycinyl‐proline tert ‐butyl ester has served as a precursor in the synthesis of azapeptides 3 (Figure ), which block myometrial contractions by modulating the activity of the prostaglandin F2 α receptor through a mechanism featuring biased signalling and which exhibit potential as prototypes to develop inhibitors of preterm labour . In the alkylation of benzhydrylidene aza‐glycinyl phenylalanine tert ‐butyl ester 6a with propargyl bromide (Scheme ), racemisation has been avoided by employing tetraethylammonium hydroxide as a milder base, instead of potassium tert ‐butoxide or tert ‐butylaminotri(pyrrolidino)phosphorane . The resulting aza‐propargylglycinyl dipeptide 7a and related analogues have served as versatile building blocks for broadening further the diversity of azapeptides, because the propargyl moiety has reacted effectively in Sonogashira cross‐coupling chemistry with various aryl and heteroaryl halides , in copper‐catalyzed azide‐alkyne cycloadditions and in 5‐ exo‐dig cyclizations (Scheme ) .…”

“…The resulting aza‐propargylglycinyl dipeptide 7a and related analogues have served as versatile building blocks for broadening further the diversity of azapeptides, because the propargyl moiety has reacted effectively in Sonogashira cross‐coupling chemistry with various aryl and heteroaryl halides , in copper‐catalyzed azide‐alkyne cycloadditions and in 5‐ exo‐dig cyclizations (Scheme ) . The latter reaction has provided a series of N ‐amino imidazolin‐2‐one dipeptide building blocks, which were shown by X‐ray crystallography and NMR spectroscopy to mimic turn geometry in model peptide 4 .…”

Aza‐propargylglycine installation by aza‐amino acylation: Synthesis and Ala‐scan of an azacyclopeptide CD36 modulator

“…Notably, azaPra residues have been reacted in copper‐catalyzed azide alkyne cycloadditions (Cu‐AAC) and Mannich‐like reactions to, respectively, prepare aza‐1,2,3‐triazole‐3‐alanine 2 and aza‐lysine residues 3 . Sonogashira cross‐couplings have been used to add various aryl and heteroaryl halides to the terminal alkyne of azaPra residues . Moreover, intramolecular 5‐exo‐ dig cyclizations of azaPra residues have provided N ‐amino‐imidazolin‐2‐one peptides 5 , which have been shown to mimic β ‐ and γ ‐turn conformations…”

Optimization of on-resin palladium-catalyzed Sonogashira cross-coupling reaction for peptides and its use in a structure–activity relationship study of a class B GPCR ligand

“…It has been applied to the synthesis of various molecules including natural products, pharmaceuticals, and organic materials [6]. In the field of peptide chemistry, this reaction was mostly performed in solution [1,2,7,10,14,16,18,21,22,25,26]. In fact, to the best of our knowledge, only a few studies describing the use of the Sonogashira cross-coupling reaction on solid phase, such as intramolecular peptide cyclization [24], peptide conjugation [23], or diversity-oriented synthesis of proline-containing peptides [21] were reported.…”