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Synthesis Of Natural Products Based On CyclohexadienesHariprakasha, H K 12 1900 (has links)
The thesis entitled "Synthesis of Natural Products Based on Cyclohexadienes" consists of two chapters.
Chapter 1 is divided into two parts. Part I gives a brief introduction to the structure, synthesis, biosynthesis and biological activities of some naturally occurring phthalides (eg. mycophenolic acid 1, zinniol2, phthalides 3 & 4). A general strategy for the preparation of highly substituted phthalides is also described. Cycloaddition of 1,s-dimethoxycoclohexa-1, 4-diene with dimethylacetylenedicarboxylate(DMAD) followed by an Alder-Rickert reaction gave the diester 5 which upon hydrolysis with KOH and refluxing with acetic anhydride gave the phthalic anhydride 6. Regioselective reductions of the anhydride 6 gave the phthalides 7 and 8. Using a similar strategy the phthalides 11 & 12 were prepared from 2,6dimethoxytoluene through the intermediates 9 & 10. The aromatic ethers 13 & 14 upon Birch reduction followed by Diels-Alder reaction with maleic anhydride gave the bicyclic anhydrides 15 & 16 respectively. Attempts to dehydrogenate 15 using variety of conditions failed. But refluxing 15 in nitrobenzene gave a poor yield of 17 which is an important intermediate in the synthesis of mycophenolic acid. Part II describes the first total synthesis of zinniol 2, phthalide-1 3 & phthalide-2 4. Thus the diene 18, obtained from 2-methylcyclohexane-1,3dione, upon Diels-Alder and Alder-Rickert with DMAD gave the diester 19. Prenylation of 19 afforded the diester 20 which was convened into 21 upon hydrolysis and DCC treatment. DIBAL reduction of 20 gave Zinniol 2 which on oxidation provided the phthalides 3 & 4 (7:3 ratio respectively). The anhydride 21, on selective reduction, gave the same phthalides in 2:8 ratio which could be readily separated and characterized.
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Investigations of the Biological Roles of Substituted CyclohexadienesBench, Bennie John 2009 December 1900 (has links)
In recent years there have been two cycloterpenals, molecules consisting of a
cyclohexadienal core, isolated from nature. Cyclocitral, the condensation product of
citral, has been isolated from the North Sea bryozoans Flustra foliacea. In the human
eyes, cycloretinal has been isolated and is a toxic by product of the vision cycle. This
retinal dimer is believed to contribute to age related macular degeneration, the leading
cause of blindness in the elderly. In 1992, it was discovered that if [beta]-ionylideneacetaldehyde was incubated with beta-lactoglobulin ([beta]-LG), the principal
whey protein in dairy milk, that it would mediate the formation of cyclo-[beta]-ional. No
follow up studies were performed on this protein mediated reaction or what biological
activities these cycloterpenals may possess.
This dissertation investigates the biological roles of substituted
cyclohexadienes including cycloterpenals and cyclohexadiene enaminonitriles. To
mimic the protein mediated reaction, we developed a synthetic procedure to produce a
wide array of cycloterpenal by utilizing L-proline. Over 100 cycloterpenals were
synthesized and screened for their biological activities against an array of cell based
screens. The phenotypic effects of these cycloterpenals were screened against a PC12 assay where dramatic effects were observed on neurite outgrowth. During the
synthesis of starting materials for the production of our cycloterpenal library, it was
discovered that if excess base was added to the Horner-Wadsworth-Emmons reaction
between a methyl-ketone and diethyl-(cyanomethyl)-phosphonate, conversion of the
[alpha]-[beta]-unsaturated nitrile into an enaminonitrile was observed. This new synthetic
procedure was optimized to generate a library of enaminonitriles as well as their
quinazoline derivatives.
The work within also includes the investigation of the [beta]-LG mediated reaction
formation of cycloterpenals with natural and unnatural [beta]-methyl aldehydes. We were
able to demonstrate that [beta]-LG could mediate the conversion of [alpha],[beta]-unsaturated
aldehydes into their corresponding cycloterpenal. In vitro analysis was also
performed with store bought milks and the [beta]-LG present was able to mediate the
formation of cyclocitral. An in vivo experiment was also performed by utilizing New Zealand White rabbits to demonstrate the formation of cycloretinal within the blood
stream by feeding a source of [beta]-LG with retinal.
Interestingly, in human blood, [beta]-LG is present at concentrations of 0.7-1.2
g/dL. The protein has been identified within drusen pigments and lipofuscin granules
that accumulate in the retina of macular degeneration patients. As humans do not produce beta-lactoglobulin, the source of this protein is from milk and milk products.
With these experiments, we clearly demonstrate that under the appropriate conditions,
cycloretinal can be produced with [beta]-LG. We have clearly established a direct link
between [beta]-LG chemistry and age-related macular degeneration.
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Synthèse et désymétrisation d'arylcyclohexa-2,5-diènes : application à la synthèse totale de l'épi-ElwesineRousseau, Géraldine 13 November 2008 (has links)
La désymétrisation d’arylcyclohexa-2,5-diènes est une méthode très efficace pour obtenir en une seule étape des squelettes complexes à partir de synthons simples. Lors de cette thèse, une nouvelle approche à la synthèse d’arylcyclohexadiènes porteur d’un centre quaternaire a été développée. L’une des structures synthétisées par cette voie a ensuite été désymétrisée par une réaction d’hydroamination diastéréosélective, nous permettant de réaliser la première synthèse énantiosélective de l’épi-Elwesine. Notre démarche s’est ensuite orientée vers la synthèse et la désymétrisation de nouveaux types de diènes spirocycliques de type oxindoles. La présence dans ces diènes de deux faces très différenciées nous a permis de réaliser des processus complètement diastéréosélectifs. De plus une nouvelle séquence réarrangement-alkylation a été mise au point, nous permettant d’accéder efficacement à des squelettes de type phénanthridinones de façon régio- et diastéréosélective. / The desymmetrization of arylcyclohexa-2,5-dienes is a powerful method to synthesize complex structures from simple synthons in a single step. We first developed a new protocol to obtain arylcyclohexa-2,5-dienes bearing a quaternary center. One of these structures was desymmetrized via a diastereoselective hydroamination and further elaborated into epi-Elwesine, an Amaryllidaceae alkaloid. We next turned our attention towards the synthesis and desymmetrization of spirocyclic cyclohexadienes. Diastereoselective processes were carried out due to the presence of two well- differentiated faces. A new rearrangement-alkylation process was developed and provides efficient access to phenanthridinones regio- and diastereoselectively.
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