Towards the Synthesis of Novel Siderophores

Abstract

As the use of antibiotics becomes increasingly common, the rise of antibiotic resistant bacteria has also occurred due to the prevalence of antibiotics in cattle feed and overuse by humans. This problem can be solved through the novel use of siderophores that scavenge free iron ions from the environment and transport them across a cell wall. Iron is crucial for supporting almost all processes for life. Siderophores are secreted by bacteria to acquire iron for use in DNA synthesis and metabolism. This process can be exploited to transport certain antibiotics across the cell wall via a ‘Trojan Horse’ compound and can open up a new path for antimicrobial therapeutics. In this thesis, the efforts to synthesis a novel siderophore which is the sulfonamide analogue of the naturally occurring enterobactin begins with the catechol ligand. The use of commercially available 2,3-dimethoxybenzoic acid to synthesis 2,3 dimethoxybenzenesulfonyl chloride, the ligand to N,N’,N’’-((3S,7S,11S)-2,6,10-trioxo-1,5,9-trioxacyclododecane-3,7,11-triyl)tris-(2,3-dimethoxybenzenesulfonamide) is reported in 47% yield. This is an improvement onto the previous procedure of 2,3 dimethoxybenzenesulfonyl chloride . The three-step procedure for the synthesis of 2,3 Dimethoxybenzenesulfonyl chloride is detailed within. The successful synthesis of tert-butyl(2,3-dimethoxyphenyl)carbamate from the compound 2,3-dimethoxybenzoic acid then the deprotection to 2,3-dimethoxyanaline hydrochloride in one-step is detailed within. The synthesis of N,N-Dicyclohexylbenzenesulfonimide from dicyclohexylamine using benzenesulfonyl chloride and synthesis of N-cyclohexylbenzenesulfonimide from cyclohexylamine is reported with yield of 21% and 16.5% respectively. As the amount of the sulfonamide analogue of enterobactin is limited, the borylation of N-cyclohexylbenzenesulfonamide and N,N-Dicyclohexylbenzenesulfonimide via iridium catalyst is attempted instead to simulate similar chemical environments. The successful synthesis of methyl trityl-L-serinate from L-serine methyl ester is reported with a yield of 33%.

Date of Award	1 Aug 2021
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Peter Quayle (Supervisor) & Roger Whitehead (Supervisor)