Solid phase synthesis of lysobactin analogues and reaction monitoring by SPIMS

Lysobactin is an eleven residue cyclic depsi-peptide antibiotic with a two to four fold greater potency than vancomycin against Gram-positive bacteria. This thesis describes a solid phase synthetic strategy to Lysobactin and its analogues. The strategy involves non-traditional solid phase reactions which require an efficient monitoring technique. Current methods of solid phase reaction analysis are discussed with reference to both the monitoring of Lysobactin synthesis and the synthesis of solid phase libraries. A new methodology is described utilising matrix assisted laser desorption/ionisation time of flight mass spectrometry(MALDI-TOF MS) to allow the rapid optimisation of non-traditional solid phase reactions in a time and material efficient manner. This technique, which has been termed Solid Phase in situ Mass Spectrometry (SPIMS), is demonstrated with the use of a range of linkage agents to monitor various solid phase chemistries for application in the synthesis of compound libraries. The technology is utilised in the monitoring of the synthesis of Depsipeptide I, an analogue of Lysobactin. Finally, the synthesis and appropriate protection of the unnatural β-hydroxy amino acids of Lysobactin are described.