Hanrahan, Jane (1995) The synthesis of substituted phosphonic acids. PhD thesis, University of Warwick.

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Abstract

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 .

Item Type:	Thesis or Dissertation (PhD)
Subjects:	Q Science > QD Chemistry
Library of Congress Subject Headings (LCSH):	Phosphonic acids, Amino acids, Antiviral agents
Official Date:	August 1995
Dates:	Date Event August 1995 Submitted
Institution:	University of Warwick
Theses Department:	Department of Chemistry
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Hutchinson, D. W. (David Wesley), Taylor, Paul C., Crout, D. H. G.
Extent:	xxi, 241 leaves
Language:	eng

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