Approaches to the synthesis of phosphorus analogues of the beta-lactam antibiotics.

  • Stuart J. Mickel

Student thesis: Doctoral ThesisPhD


In pursuit of routes to phosphorus containing analogues of the beta-lactam antibiotics, a range of organophosphorus and azetidin-2-one chemistry has emerged. New reactions, synthetic methods and intermediates of potential use in analogue synthesis have been defined. The organophosphorus systems, phosphonoformaldehyde (I) and 2-oxophosphonomalonate (II), were synthesised and their reactions with substituted azetidin-2-ones investigated. Azetidin-2-ones (III), (IV) and (V) were prepared by a new route in good overall yield (35-40%) from 4-acetoxyazetidin-2-one. A literature method for bis-deprotection of phosphonate methyl esters was extended and monophosphonic acids (VI) and (VII) were prepared. Intermolecular coupling of (VII) with 4-acetoxy-azetidin-2-one afforded the novel beta-lactam (VIII) in low yield. Application of the deprotection methodology to azetidin-2-ones (III) and (V) afforded silyl oxyphosphonates (IX) and (X), aqueous hydrolysis of which gave the unstable phosphonic acids (XI) and (XII) which could not be isolated. Model studies on a monophosphonic acid led to phosphonochloridate (XIII) and mixed O,S-alkylphosphonoacetates (XIV). The interesting synthetic intermediate, 4-chloroazetidin-2-one (XV), was prepared by chlorinolysis of azetidin-2-ones (XVI). The potential of (XV) in beta-lactam synthesis was shown by its conversion to (XVII) and (XVIII) on treatment with silver acetate or silver isothiocyanate. Mono deprotection at phosphorus in azetidin-2-ones (XIX) and (XX) led to the novel phosphonic acids (XXI) and (XXII) which were found to be unstable. Rhodium acetate catalysed intermolecular insertion of the carbene derived from 2-diazomethylacetoacetate into the NH bond of 4-dimethylphosphonoazetidin-2-one afforded the new beta-keto ester (XXIII) in good yield (35-50%). Conversion of (XXIII) to the enamines (XXV) and (XXVI) proceeded in high overall yield (80%) via the enol mesylate (XXIV).
Date of Award1982
Original languageEnglish
Awarding Institution
  • University of Bath

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