Linear and Cyclic Hybrids of Alternating Thiophene–Amino Acid Units: Synthesis and Effects of Chirality on Conformation and Molecular Packing

Abstract

The dipeptide isostere 5-aminothiophene carboxylic acid has been combined with L-phenylalanine moieties to provide linear and cyclic hybrid oligopeptides. A suitable protecting group strategy and appropriate coupling methods have been developed to guarantee a high degree of enantiopurity of the resulting amides. Cyclic tetraamides have been efficiently obtained by macrocyclization of the linear derivatives. In the case of racemized cyclization precursors, two diastereomeric macrocycles (S,S/R,R and meso) have been isolated. Their crystal structures show clear effects of the stereogenic centers on the ring conformations and molecular packing.

Heteroaryl Rings in Peptide Macrocycles

“…Of great interest is the fact that all of these molecules have different conformations that are induced by the chiral centers. 119 This is more evidence that thiophene-containing macrocyclic peptides are conformationally labile, which is generally uncommon for other heterocycles. All of these features make thiophene a sort of unique block for the design of novel macrocyclic architectures.…”

“…The synthesis of macrocycle 274 , which incorporates both proteinogenic amino acids and thiophene subunits, was also reported (Scheme ). Two synthetic strategies were reported: Starting from building block 266 , appropriately protected dipeptides 275 and 276 were prepared and were subjected to peptide coupling under different conditions to yield bis-thiophene substrates 277 and 278 . Upon deprotection at C- and N-termini, these compounds were transformed to 279 , which was subjected to intermolecular macrolactamization via two different protocols.…”

“…A racemic (S,S)/(R,R) mixture of 274 as well as meso - 274 were examined via X-ray crystallography. Of great interest is the fact that all of these molecules have different conformations that are induced by the chiral centers . This is more evidence that thiophene-containing macrocyclic peptides are conformationally labile, which is generally uncommon for other heterocycles.…”

Heteroatom‐Interchanged Isomers of Lissoclinamide 5: Copper(II) Complexation, Halide Binding, and Biological Activity

“…Applying the HI concept to naturally occurring cyclic peptide templates was envisaged to afford analogues that direct the sulfur atom of each heterocyclic unit towards the cyclic cavity . This heteroatom relocation is therefore anticipated to have a major influence on metal chelation due to the very different features of sulfur and nitrogen in metal binding; the interchange may also be expected to impact biological activity.…”

Developing Cyclic Peptide Heteroatom Interchange: Synthesis and DFT Modelling of a HI‐Ascidiacyclamide Isomer

“…by interchanging the sulfur and nitrogen atoms of the thiazoles), and in an earlier study we reported the first example, HI‐lissoclinamide 5 (Figure ) . With the sulfur atoms relocated to the center of the cyclic cavity, the molecular conformation and metal‐binding properties of the peptide were significantly altered , . Using a combination of experimental and theoretical techniques we report herein the influence of heteroatom interchange on the molecular conformation and metal‐binding ability of ascidiacyclamide ( 2 ).…”