Biomimetic synthesis of lantibiotics

Cardno, Marianne (1997) Biomimetic synthesis of lantibiotics. University of Southampton, Doctoral Thesis.

Record type: Thesis (Doctoral)

Abstract

Lantibiotics are polycyclic peptide antibiotics, active against a range of gram positive bacteria. They are synthesised from peptides derived ribosomally which are post-translationally modified to give the mature antibiotic. The lantibiotics possess many unusual amino acids including dehydroalanine and dehydroamino butyrate as well as lanthionine and methyl lanthionine which form thio-ether peptide based rings. It is proposed that Michael addition of a cysteine thiol to a dehydroamino acid results in formation of the lanthionine and methyl lanthionine residues. This reaction must be stereoselective since only _meso-lanthionine is found in the lantibiotics.

This thesis describes the synthesis and incorporation of dehydroalanine into peptides using a combination of solid and solution phase peptide synthesis. Biomimetic cyclisation studies on two model dehydroalanine containing lantibiotic precursor peptides are described.

Dehydroalanine was incorporated into Boc-Leu-Dha-OH (10) via serine dehydration. Intermolecular Michael addition of Fmoc-Cys-Oallyl to (10) resulted in a non-stereospecific reaction with a ~2:1 mixture of diastereoisomers of the thio-ether product (24). Biomimetic cyclisation of H-Leu-Dha-Ala-Asn-Cys-Lys-Ile-OH (48), however, resulted in 100% stereoselectivity forming only one diastereoisomer of the cyclic product (50). Modelling studies of the ring conformation during thiol attack and the planar (enolate) intermediate predicted formation of _meso-lanthionine as found in nature, however, nmr studies were unsuccessful in establishing the stereochemistry conclusively. Biomimetic cyclisation studies of H-Leu-Dha-Ala-Cys-Asn-Cys-Lys-Ile-OH (49) resulted in formation of two of a possible four products.

The final results chapter of this thesis describes a simple system which expands on the present use of SPPS and allows multiple release of peptide from the resin into solution. Three linkers are used to attach peptides to a solid support, each allowing release of peptide under different conditions. Consequently, peptide can be cleaved into solution for analysis and synthesis continued with the remaining peptide-resin.

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