Biomimetic synthesis of subtilin

Burrage, Sarah Anne (1998) Biomimetic synthesis of subtilin. University of Southampton, Doctoral Thesis.

Record type: Thesis (Doctoral)

Abstract

Subtilin belongs to a class of naturally occurring polycyclic peptide antibiotics known as the lantibiotics and contains a high proportion of unnatural amino acids. These amino acids include dehydroalanine, dehydroaminobutyrate, and the thioether bridged lanthionine and methyl-lanthionine. Biosynthetically, subtilin is produced from a ribosomally derived pre-pro-peptide by a series of post-translational modifications. Dehydration of serine and threonine residues results in the formation of dehydroalanine and dehydroaminobutyrate residues respectively, while lanthionine is thought to originate from a regiospecific Michael addition of a cysteine thiol onto the α,β unsaturated amino acid. This reaction is also stereospecific yielding only (2S,6R)- meso-lanthionine.

This thesis describes the synthesis of dehydroalanine containing peptides by oxidation and elimination of an S-methyl cysteine residue. The study was then extended to the inclusion of multiple dehydroalanine residues into a pentapeptide. The synthesis of peptides containing both a dehydroalanine and a cysteine residue was carried out using a mixture of solid phase and solution chemistry. Biomimetic cyclisation studies using the precursor to the B ring of subtilin (2) were found to occur stereospecifically both in solution and in the solid phase. The cyclisation of the A ring precursor (6) was found to occur regiospecifically, producing the natural ring size. Some degree of stereospecificity was also observed since the ring products were obtained in a 3:1 ratio. Molecular modelling and NMR studies were utilised to determine the stereochemistry of the cyclic compounds however, these studies were unsuccessful in establishing the absolute configuration conclusively. Assignment of the stereochemistry of the cyclic peptides by comparison with a sample of (2R,6S)-lanthionine obtained from nisin was also unsuccessful.

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