No description available.

No / Biarylpyrimidines bearing ω-aminoalkyl substituents have been designed as ligands for high-order DNA structures: spectrophotometric, thermal and competition equilibrium dialysis assays showed that changing the functional group for substituent attachment from thioether to amide switches the structural binding preference from triplex to tetraplex DNA; the novel ligands are non-toxic and moderate inhibitors of human telomerase.

This thesis describes the first total synthesis of ancistrotanzanine A, a member of the naphthylisoquinoline class of natural products. In Chapter 1 the synthetic challenges presented by the naphthylisoquinoline alkaloids are discussed and strategies that have been adopted in previous syntheses of naphthylisoquinoline alkaloids overviewed. Chapter 2 describes the preparation of the key 5,3'-biaryl linkage via the Pinhey-Barton reaction. Studies into forming the linkage atropselectively were investigated using chiral hydrobenzoin acetal auxiliaries. This was found to have limited success with an atropisomeric ratio of 65:35 obtained. Changing the base from the achiral pyridine to the chiral brucine was also investigated and found to give no enhancement in the diastereoselectivity. From the results presented in Chapter 2, it was concluded that hydrobenzoin acetal auxiliaries were not appropriate for the diastereoselective synthesis of the key biaryl linkage of ancistrotanzanine A. As the chiral acetal strategy outlined in Chapter 2 failed to yield an atropselective process, efforts were re-focused on a new approach to the naphthylisoquinolines. In Chapter 3, an overview of all the methods available for the synthesis of chiral 3,4-dihydroisoquinolines is provided. From this, it was decided to apply the alkylation of o-tolylnitriles with chiral sulfinimines, as originally developed by Davis, to the synthesis of naphthylisoquinolines. Synthesis of the o-tolylnitrile lead reagent was readily achieved, but it was found that the amount of lead tetraacetate had to be carefully controlled to avoid side-reactions in the Pinhey-Barton reaction. After careful optimisation, the key 5,3'-biaryl linkage was prepared in high yield. Application of the Davis methodology to the MOM protected biaryl failed, with no reaction resulting. After much experimentation, it was established that the reaction was very sensitive to steric hindrance. A successful reaction was finally achieved by changing the base to lithium diethylamide. However, it was found the diastereoselection of the alkylation was quite low when p-tolyl sulfinimine was used. The use of the t-butane sulfinimine meant that the diastereoselection was significantly improved, with a ratio of 85:15 being obtained. After 3 more steps, the total synthesis was completed and ancistrotanzanine A was obtained, as a 1:1 mixture of atropisomers. Efforts to separate the atropisomers formed failed and even the use of chiral HPLC failed to resolve the material. To complete the Chapter, two analogues of ancistrotanzanine A were prepared – the tetrahydroisoquinoline and the methoxy ether. Chapter 4 summarises the above results and discusses the future potential of this research. / Thesis (Ph.D.) -- University of Adelaide, School of Chemistry and Physics, 2010

Anthraquinone-xanthone heterodimeric natural products are a diverse family of polyketides highlighted by a unique bicyclo [3.2.2] ring system which links both anthraquinone and xanthone moieties. Both the connectivity of the unique bicyclic ring system and the oxidation state of the two heterocycles vary among the members of this family of natural products. These molecules have been generally isolated as fungal metabolites but also have shown anticoccidial (xanthoquinodin A:0.02 μg/mL), antibiotic (acremonidins A and C; 32 μM and acremoxanthone, MIC; 12.5 μg/mL), and cytotoxicity against various human cancer cell lines. Both anthraquinone and xanthone heterocycles are derived from the anthraquinone chrysophanol, a common biosynthetic intermediate for polyketide synthesis. To date, there have been no reported synthetic efforts or total syntheses of the anthraquinone-xanthone heterodimeric natural products. Related synthetic examples include complex anthraquinone-xanthone biaryls, anthraquinone dimers, and monomeric xanthone and benzophenone-derived natural products. We describe an initial proposed synthesis wherein we aimed to prepare the unique bicyclo [3.2.2] ring system in a late stage operation of functionalized anthraquinone and xanthone units through a photo-mediated cycloaddition. We achieved synthesis of both an anthraquinone-derived oxanthrone ester fragment and the synthesis of several xanthone related natural products, namely graphisin A, sydowinin B, acremonidin E, and pinselin. Key steps involve aryl anion addition to substituted benzaldehyde derivatives, subsequent methyl ester installation, and dehydrative cyclization. Although we have not yet achieved the desired cycloaddition, we contributed to this area by developing efficient, reliable syntheses of various benzophenone and xanthone natural products. We will also describe an alternative strategy to access the bicyclo [3.2.2] core of these natural products via various proposed rearrangements of an anthraquinone-xanthone biaryl intermediate. Cross-coupling of substituted xanthone and naphthalene fragments established the desired biaryl linkage which was further elaborated to afford anthraquinone-xanthone biaryl structures. Attempts to rearrange these biaryls are ongoing to produce the unique core structure of the parent natural products. Initially discovered as a byproduct of the aforementioned cross-coupling reaction, we have achieved homo-coupling of substituted naphthalene fragments. The resulting naphthalene dimers could be further advanced to a series of novel 2,2'-linked anthraquinone dimers including the natural product chrysotalunin.

This thesis describes two new phase-transfer catalysed processes, in which asymmetry is mediated via ion-pairing with a chiral cation. In the first chapter, an enantioselective method for N functionalization of pyrroles is described and a phase-transfer catalysed approach to axial chirality via a cation-directed SNAr reaction is discussed in Chapters 3, 4 and 5.

京都大学 / 新制・課程博士 / 博士(理学) / 甲第23038号 / 理博第4715号 / 新制||理||1676(附属図書館) / 京都大学大学院理学研究科化学専攻 / (主査)教授 依光 英樹, 教授 若宮 淳志, 教授 時任 宣博 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

No description available.

(3aR)-14a-Acetoxy-3aß,4,14,14aa-tetrahydro-6,7,8-trimethoxybenzo[3,4]furo[3',4':6,7]cycloocta[1,2-f][1,3]benzodioxol-3(1H)-one (steganacin), 56, has been a popular synthetic target due to its perceived cytotoxic activity. Our proposed strategy for the construction of the key 8-membered ring embedded within steganacin was via an oxidative phenolic coupling of an appropriate (3R,4R)-4-(benzo[d][1,3]dioxol-5-ylmethyl)-3-benzyldihydrofuran-2(3H)-one analogue which were shown to be readily available from commercially available piperonal in six linear steps involving chain extension, reduction, trichloroacetylation and cyclisation via a copper-catalysed Atom Transfer Radical Cyclisation (ATRC) reaction. In this way, copper-catalysed ATRC reaction of (E)-6-(benzo[d][7’,9’]dioxol-1’-yl)allyl-1,1,1-trichloroacetate afforded (R)-4-{(R)-benzo[d][1,3]dioxol-5-ylchloromethyl}-3,3-dichlorodihydrofuran-2(3H)-one in good isolated yield as a mixture of diastereosiomers. Regiospecific functionalisation of these trihalides at the benzylic position (via an SN1, solvolysis, pathway), followed by dehalogenatioin and subsequent enolate alkylation afforded the key butyrolactone intermediates whose oxidative cyclisation was the key bond construct in our approach to steganacin. Contrary to our expectations it was observed that these substrates suffer intramolecular Friedel-Crafts alkylation reactions, favouring a 3a,4,9,9a-tetrahydronaphtho[2,3-c]furan-1(3H)-one (6 member ring) formation, rather than phenolic oxidative coupling reactions that would favour the steganacin-like (3aR,11aR,Z)-3a,4,11,11a-tetrahydrobenzo[4,5]cycloocta[1,2-c]furan-1(3H)-one (8 member ring) formation, when the oxidant has any Lewis acid capacity. Taking these observations into account we believe that by judicious choice of synthetic route the ATRC chemistry developed during the current research could be applied to a highly convergent (9 step) route to the synthesis of deoxypodophylotoxin.This work also describes, in detail, the efforts of this worker to establish and optimise a robust route that potentially can lead to the formation of steganacin via the alternative route of an initial microwave-assisted Pd-mediated biaryl coupling of either bromopiperonal or an halogenated derivative of the described γ-butyrolactones with an appropriate boronic acid derived from commercially available 3,4,5-trimethoxybenzalcohol to afford the biaryl scaffold present in steganacin. The completion of this synthesis was unfortunately left unaccomplished due to time constraints.

Ce travail de thèse présente de nouvelles réactions catalysées au cobalt de couplages croisés entre un arylzincique et divers électrophiles. Après une introduction générale sur la catalyse au cobalt et les arylzinciques, le premier chapitre est consacré à la formation de biaryles cétones. La réaction entre un arylzincique et le chloroformiate d’éthyle en présence du bromure de cobalt et du ligand bipyridine conduit à la formation de biaryles cétones symétriques avec de très bons rendements dans des conditions simples. Il a été démontré que ce chloroformiate d’éthyle se décompose en monoxyde de carbone au cours de la réaction. Les premiers essais pour étendre cette méthode à la synthèse de biaryles asymétriques sont également décrits à partir d’arylzinciques et de diverses molécules carbonylées. Le deuxième chapitre est quant à lui porté sur le couplage de Negishi entre un arylzincique et un bromure d’aryle ou unchlorure d’hétéroaryle. L’avantage de cette méthode est que le cobalt présent pour former l’arylzincique sert également à former le biaryle, il n’y a donc pas ajout d’un autre catalyseur dans la seconde étape de la réaction. Les premiers résultats obtenus pour la formation de biaryles sont encourageants mais ont besoin d’être approfondis. Une méthode similaire a été utilisée pour la synthèse de nouvelles molécules à fluorescence retardée pour obtenir des diodes électro luminescentes organiques de troisième génération. Le troisième chapitre décrit la réaction catalysée au cobalt entre un arylzincique et des sources électrophiles de soufre, les sels de Bunte. Cependant, ces sulfures d’aryles s’oxydent facilement dans le milieu réactionnel et donnent des sulfoxydes et des sulfones, ce qui limite l’utilisation de cette méthode. Enfin, le dernier chapitre est consacré à des travaux préliminaires sur la trifluorométhylation d’aryl zinciques à partir de sources électrophiles ou nucléophiles trifluorométhylées. / This thesis presents new cobaltcatalyzed cross-coupling reactions between arylzinc derivatives and various electrophilic reagents. After a general introduction on cobalt-catalysis and arylzinc compounds, the first chapter is dealing with the formation of diaryl ketones. Reaction between arylzinc bromides and ethyl chloroformate in presence of cobalt bromide and bipyridine ligand leads to the formation of symmetrical diaryl ketones with very good yields under simple conditions. It has been shown that ethyl chloroformate decomposes into carbon monoxide during the reaction. First attempts to extend this method to the synthesis of unsymetrical diaryl ketones are also described from arylzinc bromides and various carbonyl containing substrates. As for the second chapter, it is focused on the Negishi coupling between arylzinc bromides and an aryl bromide or an heteroaryl chloride. The advantage of this method is that the cobalt used to form the arylzinc bromide also serves to form the biaryl, hence there is no addition of another catalyst in the second step of the reaction. Results about the formation of biaryls are promising, but this reaction needs to be thorough. A similar methodology was used for the synthesis of new delayed fluorescence molecules to obtain highly efficient organic light emitting diodes. The third chapter describes the cobalt-catalyzed reaction between an arylzinc bromide and an electrophilic source of sulfur, a Bunte salt. However, these aryl sulfides can be easily oxidized in the reaction mixture and give sulfoxides and sulfones, which limit the use of this method. Finally, the last chapter is about preliminary works on the trifluoromethylation of arylzinc bromides from electrophilic or nucleophilic trifluoromethyl sources.

A novel target-promoted DNA alkylation system was designed, which consists of a DNA intercalating/alkylating quinone methide (QM) precursor, a removable amine linker, and a sequence-specific delivery. The QM in this system was regenerated by eliminating the amino linker promoted by the hydrophobic interaction between the target DNA and the intercalating QM precursor. Three alkylation model systems (methoxyl polycyclic system, intramolecular hydrogen bonding system and biaryl system) were proposed and synthesized. The potential DNA QM alkylation was investigated by deoxyadenosine (dA) and deoxyguanosine (dG) alkylation with the biaryl system. Only one deoxynucleoside adduct was observed when dA or dG reacted with quinoline or naphthalene QM precursor, in which both dA adducts degraded with time, while dG adducts remained unchanged after 72h at room temperature. The quinoline dG adduct was fully characterized as quinoline dG N1 adduct by NMR techniques. Naphthalene dG was found as a 1:1 mixture of diastereomers.