Heterocycles in peptide chemistry

Hollis, Stephen James (2000). Heterocycles in peptide chemistry. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000d3a4

Abstract

The synthesis of 5-membered heterocyclic rings that bear both amine and carboxylic acid functional groups has been investigated using a 1,3-dipolar cycloaddition reaction strategy. These molecules, on incorporation into a chain of amino acids, have the potential to restrict the conformational freedom of the peptide.

Cycloaddition of a nitrile oxide, derived from a Boc-protected naturally-occurring a-amino acid, with a pyrrolidine en amine led to a Boc-protected 3-aminoalkylisoxazole amino acid ester. The nitrogen and carbon termini of this isoxazole were coupled to other a-amino acids. Analysis of the dipeptide from coupling to (S)-alanine indicated that the integrity of the chiral centre of the isoxazole had been retained during the synthesis. Molecular modelling of a tripeptide unit incorporating the isoxazole showed that the presence of the ring had, as intended, restricted the conformational freedom of the molecule.

Analogous cycloadditions using azomethine imines as the dipole yielded the corresponding tetrahydropyrazoles (pyrazolidines). These dipoles were generated by reaction of an aldehyde with a 1,2-disubstituted hydrazine, followed by elimination of the elements of water from the resulting aminol. Reaction with a dipolarophile bearing an electron withdrawing substituent gave predominantly the 4-substituted pyrazolidine. A study of the scope of the reaction found that, although the required carboxylic acid group could easily be incorporated by use of methyl acrylate as the dipolarophile, it proved impossible to attach an amine group to the ring using this methodology. However, by using one of the nitrogen atoms in the ring as the N-terminus, two pyrazolidines with protected amine and carboxylic acid groups were prepared, and these can be thought of as conformationally restricted B-amino acids.