Novel methods for the synthesis of naturally occuring oxygen and nitrogen heterocycles
Date
2010-04-14T06:59:09Z
Authors
Pelly, Sameshnee
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Abstract
Pyranonaphthoquinones are a class of naturally occurring compounds that exhibit a wide
range of biological properties ranging from antibiotic to anti-cancer activities. These
compounds and their non-natural analogues are therefore of synthetic interest. This PhD
describes the first total synthesis of cardinalin 3, previously isolated from the New Zealand
toadstool Dermocybe cardinalis. We then proceeded to investigate possible novel
stereoselective syntheses of 1,3-dimethylated pyranonaphthoquinones using arene
tricarbonylchromium chemistry as well as the synthesis of other 1,3-disubstituted
pyranonaphthoquinones using cross metathesis as a key step.
The racemic total synthesis of cardinalin 3 was achieved in 15 steps using a bidirectional
approach. Starting from commercially available 1,3-dimethoxybenzene, the biaryl axis was
introduced using an Ullmann coupling reaction to afford 2,2′,6,6′-tetramethoxy-1,1′-
biphenyl. Further elaboration of the biphenyl to form the bis-naphthalene ring system
diethyl [4,4′-diacetoxy-6,6′,8,8′-tetramethoxy-7,7′-binaphthalene]-2,2′-dicarboxylate was
achieved with a Stobbe condensation and Friedel-Crafts acylative cyclisation. A Wacker
oxidation was then employed to construct the pyran ring onto either side of the
appropriately substituted naphthalene dimer to form (±)-5,5'-bis(benzyloxy)-7,7',9,9'-
tetramethoxy-1,1',3,3'-tetramethyl-1H,1'H-8,8'-bibenzo[g]isochromene. The remaining
transformations included hydrogenation to (±)-7,7',9,9'-tetramethoxy-cis-1,3-cis-1',3'-
tetramethyl-3,3',4,4'-tetrahydro-1H,1'H-8,8'-bibenzo[g]isochromene-5,5'-diol, followed by
oxidation to the quinone (±)-7,7',9,9'-tetramethoxy-cis-1,3-cis-1',3'-tetramethyl-
3,3',4,4',6,9-hexahydro-1H, 1'H-8,8'-bibenzo[g]-isochromene-5,5',10,10'-tetrone and a
selective O-demethylation reaction to furnish cardinalin 3, in an overall yield of 2.2%.
In a study on the usefulness of arene chromiumtricarbonyl chemistry to construct 1,3-
dimethylisochromane systems, an arene chromiumtricarbonyl system was made from (R)-
5,8-dimethoxyisochroman-4-ol. Unexpectedly, this complexation occurred without
diastereoselectively forming both the syn and anti diastereomers which fortuitously could
be separated. Despite several attempts we were unsuccessful in performing the required
oxidation of the complexed isochromanol to (5,8-dimethoxyisochroman-4-
one)tricarbonylchromium (0).
In another model study, cross metathesis of ethyl acrylate and silyl protected (2-allyl-3,6-
dimethoxyphenyl)methanol successfully produced the α,β-unsaturated ester (E)-ethyl 4-(2-
((tert-butyldimethylsilyloxy)methyl)-3,6-dimethoxyphenyl)but-2-enoate which
subsequently underwent a spontaneous intramolecular Michael addition to produce ethyl 2-(5,8-dimethoxyisochroman-3-yl)acetate. A similar strategy was employed to produce ethyl
2-(5,8-dimethoxy-1-methylisochroman-3-yl)acetate.
In the last part of this PhD we attempted the stereoselective synthesis of a chiral indoline
ring system wherein we utilise a Trost asymmetric allylic alkylation reaction. The specific
indoline moiety synthesised, 1-methyl-2-(prop-1-en-2-yl)indoline, is found embedded in
many biologically useful compounds including the nodulisporanes which display potent
insecticidal properties. The synthesis began from commercially available N-methyl aniline
which was suitably functionalised and subjected to a Horner-Wadsworth-Emmons reaction
to furnish (E)-ethyl 4-(2-(tert-butoxycarbonyl)phenyl)-2-methylbut-2-enoate to begin the
construction of the dihydro pyrrole ring system. The asymmetric allylic alkylation was
carried out on (E)-methyl-2-methyl-4-(2-(methylamino)phenyl)but-2-enyl carbonate using
a palladium catalyst in the presence of the chiral Trost ligand to afford 1-methyl-2-(prop-1-
en-2-yl)indoline. An enantiomeric excess of 32% was achieved suggesting that this
reaction has potential scope for future investigation.