Novel methods for the synthesis of naturally occuring oxygen and nitrogen heterocycles

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dc.contributor.author Pelly, Sameshnee
dc.date.accessioned 2010-04-14T06:59:09Z
dc.date.available 2010-04-14T06:59:09Z
dc.date.issued 2010-04-14T06:59:09Z
dc.identifier.uri http://hdl.handle.net/10539/7977
dc.description.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. en_US
dc.language.iso en en_US
dc.title Novel methods for the synthesis of naturally occuring oxygen and nitrogen heterocycles en_US
dc.type Thesis en_US


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