Approaches to the biomimetic synthesis of β-lactam antibiotics
Degree GrantorUniversity of Canterbury
Degree NameMaster of Science
The C4 benzoyloxy substituted β-lactams (65)-(68) were formed by the copper-promoted reaction of β-lactarns (42)-(45) with t-butyl perbenzoate. The benzoyloxylation of the azetidin-2-one ring occurs at C4 with no competing reaction at the C3 position. The relative ease of abstraction by t-butoxy radicals of hydrogens bonded to the endocyclic and exocyclic carbons adjacent to the amide nitrogen was determined from the reaction of the β-lactam (47). This reaction gave the endocyclic substituted β-lactam (69), the exocyclic substituted β-lactam (70) and the disubstituted β-lactam (71). Substitution solely at the exocyclic carbon occurred in the reaction of the β-lactam (48), which gave the β-lactam (73). The mode of substitution of the β-lactams (42)-(45), (47) and (48) is discussed. Reaction of the γ-lactam (80) with t-butyl perbenzoate gave the C5 substituted γ-lactam (90) and the exocyclic substituted γ-lactam (87). The mode of formation and ratio of these two products is discussed. Bromination of N-benzoylvaline methyl ester (19) with N-bromosuccinimide, followed by reaction with tri-n-butyltin hydride gave N-benzoyl-3-bromovaline methyl ester (93). The synthesis of this compound is discussed. Reaction of 1-(1-methoxycarbonyl-2-methypropyl)azetidin-2-one (31) with sulphuryl chloride gave the azetidin-2-one (102). An independent synthesis of 1-(3-chloro-1-methoxycabonyl-2-methylpropyl)-3,3-dimethylazetidin-2-one (102) from N-(3-bromo-2,2-dimethylpropanoyl)valine methyl ester (100) is described and the mechanism of these reactions is discussed.