Synthesis of some furanone derivatives : putative quorum sensing or chitinase inhibitors

Jolivet, Benoît. Synthesis of some furanone derivatives : putative quorum sensing or chitinase inhibitors. 2005, Doctoral Thesis, University of Basel, Faculty of Science.


Official URL: http://edoc.unibas.ch/diss/DissB_7339

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Bacteria are able to communicate through chemical signals. They can for instance
estimate their population by the use of signalling compounds: this phenomenon is called
quorum sensing. Some of these signalling compounds are derivatives of homoserine lactones.
When their concentration reaches a certain level, bacterial genes are triggered, which leads to
virulence, bacterial film formation, and so on. Natural halogenated furanones 22 and 23
extracted from the marine alga Delisea pulchra proved to inhibit the quorum sensing. Other
natural furanones 24a-27a extracted from Streptomyces antibioticus TÜ 99 were also quorum
sensing inhibitors. As the structures of these natural compounds were similar to the
homoserine lactones, additional furanones were synthesized in order to investigate their
properties towards the quorum sensing.
Following the synthetic route published by Grossmann [11], the compounds 56a, 56b,
and 58 were prepared. The key step of the synthesis, which is a condensation of the
menthylated furanone 38b and an aldehyde with LDA under kinetic conditions, was
optimized. The biological activity of these three compounds, as well as of all intermediates,
was investigated. The tests were carried out with a mutant strain of Chromobacterium
violaceum, called CV026.
Some of the synthetic furanones proved indeed to be weak quorum sensing inhibitors,
however none of them was more active than the natural compound 22 [22]. In addition, some
of these compounds were toxic for Chromobacterium violaceum.
The Grossmann method, followed by a reduction of the side chain, was also used for
the preparation of the flavour furanone 64, which had previously shown a weak inhibition of the pristinamycin production by Streptomyces pristinaespiralis. Further tests were carried out
with mammalian cells, but the compound 64 proved to be toxic [21].
Other biological tests showed that some menthylated furanones were weak chitinase
inhibitors. Starting from the assumption that menthylated furanones could have structure
analogy with the most potent chitinase inhibitor allosamidin (75), the synthesis of
glycosylated furanones was attempted. The main purpose was to replace the menthyl group by
a monosaccharide or a disaccharide in a very short and very cheap process.
The starting furanone 37 was treated with trichloroacetonitrile to give the
trichloroacetimidate 93, which was submitted to glycosylation following a “reversed type
Schmidt glycosylation” procedure using TMSOTf as Lewis acid. The obtained acetylated
compounds 92, 96, and 97 were treated with guanidine. The deacetylated monosaccharides
101 and 102 were obtained in low yields whereas 97 was not completely deacetylated.
The glycosylation afforded for each compounds 92, 96, and 97 a mixture of four
diastereomers. Only the diastereomers of 96 could be partially separated by chromatography
on silica gel. The structures of the a-anomers could not be completely elucidated, whereas the
structures of the b-anomers could be obtained from an X-ray structure determination of 96d.
The starting furanone 37 was also treated with (+)-isomenthol and (+)-menthol to give
the compounds 104 and 105 respectively. These compounds, as well as the glycosylated
furanones 92, 96a, 96b, 96c, 96d, 102, 104, and 105, were tested but none of these synthetic
furanones were active as chitinase inhibitors.
Advisors:Séquin, Urs Marcel
Committee Members:Rohmer, M.
Faculties and Departments:05 Faculty of Science > Departement Chemie > Former Organization Units Chemistry > Physikalische Chemie (Maier)
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:7339
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:125
Identification Number:
Last Modified:23 Feb 2018 11:41
Deposited On:13 Feb 2009 15:21

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