Mothia, B; (2012) Hybrid Lantibiotics: Combining Synthesis and Biosynthesis. Doctoral thesis , UCL (University College London).

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Abstract

The synthesis of two sets of different orthogonally protected lanthionine ready for incorporation into solid phase peptide synthesis to form cyclised peptides is described in this thesis, along with the cyclisation of individual rings D and E and the overlapping rings D and E. Previously developed orthogonally protected lanthionine containing Aloc, allyl, Fmoc and tBu protecting groups was synthesised using published synthetic route developed by Tabor’s group. A novel orthogonally protected lanthionine containing Teoc, TMSE, Fmoc and Tce group derivative has also been synthesised, after carrying several synthetic pathways. Both lanthionine residues contain protecting groups which are orthogonal to each other, which are also orthogonal to the transient Fmoc and permanent Boc/tBu protecting groups which are used in Fmoc based solid phase peptide synthesis. Incorporation of the previously developed lanthionine with Aloc/allyl protecting groups was carried out to form an analogue of ring E of nisin for the first time. Deprotection of the Aloc/allyl protecting groups were carried out with Ph(PPh3)4 using N’,N-dimethyl-barbituric acid (NDMBA). The second orthogonally protected lanthionine was also incorporated into solid phase peptide synthesis to synthesise an analogue of ring D of nisin. This was also to see whether this can be used to synthesise lanthionine-containing thio-ether bridged cyclic peptide by solid phase peptide synthesis. Teoc and TMSE deprotection was carried out in the presence of TBAF without effecting the other side chain and Fmoc protecting groups. Full characterisation of individual rings D and E were obtained. Quadruply orthogonal protecting group strategy was used to synthesise bicyclic peptide with two overlapping lanthionine bridges rings D and E. An effective methodology has been developed for the synthesis of the overlapping rings D and E of nisin by solid phase peptide synthesis.

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