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Organic Chemistry
Organic Synthesis
Professor Lew Mander
http://rsc.anu.edu.au/research/mander.php
Our research interests encompass two
major overlapping themes. The first of these is focused on methods
and strategies for the synthesis of complex natural products that
have interesting biological properties, while the second is concerned
with the molecular basis of plant growth regulation, using organic
synthesis as an enabling technology. Within this context, members of
the group have successfully completed syntheses of numerous complex
natural products and developed a number of useful synthetic
procedures. The second major activity in the
group is concerned with natural plant bioregulators with special
reference to the gibberellins (GAs). GAs effect numerous aspects of
plant growth and development, for example, germination,
induction of stem growth and flowering, and there are several
commercially valuable applications. Studies pursued in collaboration
with groups in the CSIRO and the University of Calgary have led to
the discovery of semi-synthetic derivatives that interfere with the
plant's natural production of phytohormones, thereby inhibiting
growth.
Structural and Synthetic Studies on New Gibberellins
There
are now approximately one hundred and thirty confirmed naturally
occurring gibberellins, with tentative assignments of structure for a
further ten or so. Most of the recently isolated compounds have been
obtained in trace amounts and so the usual tools for structure
elucidation cannot be deployed. Fortunately, it is possible to make
educated guesses regarding the new structures from mass spectra and
then to confirm the assignments by synthesis from one of the more
readily available fungal GAs. Over the past year, methodology has
been developed for the preparation of several 11,13-dihydroxy-GAs.
These GAs display a characteristic signature in mass spectra of a
base peak at m/z 296 plus a strong peak at m/z 239 and
has allowed the identification of two new GAs, one from loquat fruit
(11b-hydroxy-GA20 1) and
the other from strawberries (11ß-hydroxy-GA3
2).
A
pivotal step in these syntheses is the hydroboration of the
9(11),16-diene function in 13-acetoxy-GAs, e.g. 3.
(with E.J. Beck, J.R. Crow, O.E. Hutt, T.P. Le, and B.
Twitchin)
See
also :
http://www.plant-hormones.info/gibberellins.htm
Total Synthesis of Natural Products
Synthetic
studies are being directed towards the assembly of several highly
caged natural products. They include members of an unusual group of
alkaloids isolated from the Northern Australian rain forest species,
Galbulimima belgraveana. One compound, himbacine, is a potent
muscarinic antagonist and is a lead compound in the search for drugs
to treat Alzheimer's disease. Our own efforts have been focused on
the more complex members of the family, for example, himandridine 4
and himaline (GB 13) 5. The synthesis of 5 has been achieved and the
full hexacyclic skeleton of 4 assembled.
Preliminary
studies on the construction of the heptacyclic family of diterpenoid
alkaloids typified by hetisine 6 have been undertaken. A
number of promising leads have been developed, but have failed
because of the intervention of unusual and unprecedented
rearrangements. An enantio-convergent synthesis of the anti-fungal
agent sordaricin 7 has been completed, while a promising
beginning has been towards the total synthesis of the anti-malarial
diterpenoid, diisocyanoadociane 8. (with K.A. Fairweather,
M.M.W. McLachlan, P.D. O'Connor, R.J. Thomson)
Isolation of New Natural Products from the Marine Sponge
Aaptos aaptos
Two
new marine alkaloids have been isolated by reverse phase HPLC from
methanolic extracts of the marine sponge Aaptos aaptos
collected from the Bunaken Sea Garden, North Sulawesi, Indonesia. 1H
and 13C NMR together with mass spectroscopic studies
established the major compound as
8,9-dihydroxy-1H-benzo[de][1,6]naphthyridine 9
(isolated as the trifluoroacetate salt) and the derived sulfonate
10. The parent compound was synthesised earlier by Steglich
et al. and has been proposed as a biosynthetic precursor of
three marine alkaloids previously isolated from Aaptos. These
compounds, which were also isolated from our Aaptos extract,
show antagonistic effects on a-adrenergic
receptors as well as anti-tumour activity. (with A.J. Herlt, and
W.A.R. Romberg, R.J. Rumampuk [State U. Manado, Indonesia], W.
Steglich, Ludwig-Maximilians-U., Munich, Germany])
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