Mohd Mustapa, Mohd Firouz; (2002) Synthesis of lanthionine-containing peptides on solid phase via an orthogonal protecting group strategy. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Lanthionine (Lan), a monosulfide analogue of cystine, is a naturally occurring amino acid found in a group of polycyclic peptide antibiotics called lantibiotics. Nisin is so far the only lantibiotic that has been produced synthetically. Biological studies of these peptides are of interest, due to their activity against Gram-positive bacteria, especially in the search for new groups of antibiotics. With the difficulty in obtaining lantibiotics in respectable quantities for biological studies it was therefore the aim of this Ph.D. project to establish the fundamentals of the total synthesis of lantibiotics solely on solid phase, by investigating the possibility of a rapid and high yielding method for synthesizing smaller Lan-contaming peptides. Following literature procedures of the formation of Lan residues, the synthesis of Lan derivative 1 was attempted. Using a triply orthogonal protecting group strategy the syntheses of several Lan-containing cyclic peptides were attempted; only the 21- membered nisin ring C analogue 2 yielded enough material for extensive NMR studies (TOCSY, HSQC, HMQC, HMBC) to be carried out. The two major products were found to be diastereoisomers 6 and contained nor-Lan, a regioisomer of the desired product 1. nor-Lan 3 was formed from an enantiomeric mixture of -iodo- - alanine derivatives 4, originally identified in literature as a locked conformer of the desired -iodo- -alanine derivative 5. Despite the lack of success in terms of the target peptides and amino acids, it has been shown that the use of a differentially-protected double-headed amino acid monomer could be used in the synthesis of cyclic peptides on solid phase utilizing an orthogonal protecting group strategy.

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