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Title: The synthesis of substituted phosphonic acids
Author: Hanrahan, Jane
ISNI:       0000 0001 3530 5865
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 1995
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Cyclic phosphonic acid analogues of the endogenous amino acids L-aspartic acid and L -glutamic acid have played a major role in the characterisation of excitatory amino acid receptors in the central nervous system. The aim of the first section of this work is to describe the development of a synthetic route that gives access to a novel series of compounds, 3-substituted-cyclobutanephosphonic acids. The synthesis of a valuable intermediate diethyl3-oxocyclobutanephosphonate is described. Elaboration of the ketone functionality of this compound provides allows the synthesis of a number of previously inaccessible 3-substituted-cyclobutanephosphonates, including E- and Z-3-amino-3-carboxy-cyclobutanephosphonic acid, 3-aminocyclobutanephosphonic acid and the four stereoisomers of 3-(amino-carboxymethyl)- cyclobutanephosphonic acid. Enzymatic hydrolysis of the phenyl acetyl derivative of diethyl 3-(amino-cyanomethyl)- cyclobutanephosphonate by penicillinacylase allowed the preparation of 3-(amino-carboxy-methyl)-cyc1obutane-phosphonic acid with high enantiomeric purity. The antiviral activity of phosphonoacetic acid (P AA) has long been recognised. However, a number of problems are associated with the administration of this compound as an antiviral, these include high toxicity to the hosts cells, poor uptake in to cells and absorbtion by teeth and bones. One approach to solving some of these problems may be to make the compounds more lipophilic by increasing the number of carbon atoms in the molecule. The synthesis of a number of cyclic analogues of P AA and the related bisphosphonic acids is described. These compounds are prepared by phase transfer catalysed alkylation of trialkyl phosphonoacetate and tetra alkyl methylenebisphosphonate. The antiviral activity of these compounds against Herpes simplex virus 1 (HSVl) was investigated. A series of chiral at sulfur, a-phosphoryl sulfoxides and ~-hydroxy sulfoxides were prepared. These compounds were investigated for their ability to enantioselectively catalyse the reaction between diethylzinc and benzaldehyde. Although this reaction was catalysed by all of these compounds, this action was not accompanied by enantioselectivity. Comparison of our results with those obtained for ~-hydroxy sulfoximides enabled this lack of enantioselectivity to be explained by the analysis of the proposed transition state complexes.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QD Chemistry