||Syntheses and Applications of Chiral a-Hydroxyphosphonates
|University / Research institution
||Institut für Organische Chemie, Universität Wien
||ENZYME, ALPHA-HYDROXPHOSPHONATE, ALPHA-AMINOPHOSPHONSÄUREN, PHOSPHAT-PHOSPHONAT-UMLAGERUNG, ENZYMINHIBITOREN, CARBANIONEN
Chiral 1-hydroxyphosphonates were prepared by enzymatic hydrolysis and the phosphate-phosphonate
rearrangement and transformed into 1-aminophosphonic acids. Some of them were
tested as inhibitors of the phenyalanine ammonia lyase.
Phosphonic acids and their derivatives are important classes of compounds in
organophosphorus chemistry. These compounds contain a carbon-phosphorus bond.
Some of them, especially the 1-aminophosphonic acids, have interesting biological
properties. They block enzymes und thus disrupt the metabolism of living cells.
A small group of natural products are also phosphonic acids, of which the majority
are antibiotics. The best known compound is fosfomycin, which is used clinically.
1-Hydroxyphosphonates are of central importance for the project. Many other
phosphonates and phosphonic acids can be prepared thereof. Racemic hydroxyphosphonates
can be prepared easily, but not chiral, nonracemic ones. We have used two methods
to prepare them, the enzymatic resolution and the phosphate-phosphonate rearrangement.
Enzymes are used in organic chemistry more and more to resolve racemates, because
only antipodes are of biological relevance. We started with racemic hydroxyphosphonates,
esterified them with acetic or chloroacetic anhydride and tested whether they
are hydrolysed by hydrolases such as lipases and proteases in a biphasic system,
consisting of phosphate buffer and an organic solvent. The released acid was
neutralised with standard sodium hydroxide.
The second method we used for the preparation of 1-hydroxyphosphonates was the
phosphate-phosphonate rearrangement, primarily for the preparation of racemic
1-hydroxyphosphonate. Later on one enantiomer should be synthesised preferentially.
The main aspect of this rearrangement is the treatment of a phosphoric acid
ester with a strong base, which abstracts a proton. The species formed is very
reactive and isomerises to the hydroxyphosphonates. Interestingly, this reaction
can also be performed with phosporamidates which are derived from amines. Thus
aminophosphonic acids are accessible directly.
Some of the chiral, nonracemic 1-hydroxyphosphonates were transformed into phosphonic
acid analogues of proteinogenic and nonproteinogenic amino acids. The Mitsunobu
reaction was used for the introduction of the nitrogen. The protecting groups
were removed and the aminophosphonic acids were purified and crystallised. The
optical purity of the final products was determined by high pressure liquid
chromatography on chiral stationary phases (in cooperation with Prof. W. Lindner
from the Department of Analytical Chemistry of the University of Vienna).
Additionally, phosphonic acids analogue of compounds structurally related to
phenylalanine were prepared, which are potential inhibitors of the phenylalanine
ammonia lyase. Blockers of this key plant enzyme are interesting as potential
herbicides. The compounds were tested for their biological activity by two foreign
cooperation partners (in Switzerland and Germany).
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