New synthetic methods for the synthesis of Beta - lactam antibiotics

Knight, John (1986) New synthetic methods for the synthesis of Beta - lactam antibiotics. University of Southampton, Doctoral Thesis.

Abstract

Two novel approaches to key intermediates for carbapenem synthesis were investigated. The first employed an intramolecular nitrile oxide cycloaddition (INOC) reaction to generate a tricyclic β-lactam bearing useful latent functionality. Attempts to unmask the required functionality failed. An alternative INOC approach was investigated resulting in a new acylative cycloaddition reaction. A series of nitroalkenes were prepared bearing an appended dipolarophile and furnished cycloadducts when treated with t-butyliso-cyanide. The validity of the mechanism is briefly discussed. Cycloaddition precursors for carbapenem synthesis were also prepared. The second approach employed the radical cyclisation reaction to generate the bicyclic β-lactam nucleus. Selective syntheses of a carbapenam and a carbacepham are described from the same intermediate by application of the appropriate experimental conditions. The directive effect of an angular methyl substituent resulting in regioselective carbapenam sythesis is also described. The carbapenams were obtained diastereoselectively with a 1-methyl substituent by the 5-exo trig cyclisation mode. A new mechanistic pathway for vinyl bromide/tri-n-butyltin hydride reactions is proposed. In addition a palladium (II) catalysed cyclisation was found to yield a carbacephem. (D72194/87)

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