Isoxazolidines and oxazines: preliminary studies for the synthesis of N,O-heterocyclic systems via an organocatalyzed 1,3-Dipolar Cycloaddiction and a tandem reaction mediated by TEMPO salts

This thesis is the result of the study of two reactions leading to the formation of important heterocyclic compounds of potential pharmaceutical interest. The first study concerns the reaction of (1,3)-dipolar cycloaddition between nitrones and activated olefins by hydrogen bond catalysis of thioureas derivatives leading to the formation of a five-membered cyclic adducts, an interesting and strategic synthetic intermediate, for the synthesis of benzoazepine. The second project wants to explore the direct oxidative C(sp3)-H α-alkylation of simple amides with subsequent addition of an olefin and cyclization in order to obtain the corresponding oxazine. Both reactions are still under development.

Development of Organocatalytic stereoselective SN1 type reactions

The proposal in my thesis has been the study of Stereoselective α-alkylation through SN1 type reaction. SN1 type reaction involves a stabilized and reactive carbocation intermediate By taking advantages of stability of particular carbocations, the use of carbocations in selective reactions has been important. In this work has been necessary to know the stability and reactivity of carbocations. And the work of Mayr group has helped to rationalize the behaviour and reactivity between the carbocations and nucleophiles by the use of Mayr’s scale of reactivity. The use of alcohols to performed the stable and reactive carbocations have been the key in my thesis. The direct nucleophilic substitution of alcohols has been a crucial scope in the field of organic synthesis, because offer a wide range of intermediates for the synthesis of natural products and pharmaceutics synthesis. In particular the catalytic nucleophilic direct substitution of alcohols represents a novel methodology for the preparation of a variety of derivatives, and water only as the sub-product in the reaction. The stereochemical control of the transformation C-H bond into stereogenic C-C bond adjacent to carbonyl functionalized has been studied for asymmetric catalysis. And the field of organocatalysis has introduced the use of small organic molecule as catalyst for stereoselective transformations. Merging these two concepts Organocatalysis and Mayr’s scale, my thesis has developed a new approach for the α-alkylation of aldehydes and ketones through SN1 type reaction.

Spin-crossover in metallomesogens of iron(II)

Covalent grafting mesogenic groups to the coordination cores of the parent mononuclear low-spin and spin-crossover compounds afforded metallomesogenic complexes of iron(II). In comparison with the parent complexes the spin-crossover properties of the alkylated derivatives are substantially modified. The type of the modification was found to be dependent on the properties of the parent system and the nature of the used anion, however, the general tendency is the destabilization of the low-spin state at the favor of spin-crossover or high-spin behavior below 400 K. The structural insight revealed the micro-segregated layered organization. The effect of the alkylation of the parent compounds consists first of all in the change of the lattice to a two-dimensional lamellar one retaining significant intermolecular contacts only within the ionic bilayers. The comprehensive analysis of the structural and thermodynamic data in the homologous series pointed at the mechanism of the interplay between the structural modification on melting and the induced anomalous change of the magnetic properties. A family of one-dimensional spin-crossover polymers was synthesized and characterized using a series of spectroscopic methods, X-ray powder diffraction, magnetic susceptibility measurements and differential scanning calorimetry. The copper analogue of was also synthesized and its crystal structure solved. In comparison with the mononuclear systems, the polymeric mesogens of iron(II) are less sensitive to the glass transition, which was attributed to the moderate concomitant variation of the structure. Nevertheless, the observed increase of the magnetic hysteresis with lengthening of the alkyl substituents was ascribed to the interplay of the structural reorganization of the coordination core due to spin-crossover with the structural delay in the spatial reorganization of the mesogenic substituents. The classification of mononuclear and polymeric metallomesogens according to the interactions between the structural- and the spin-transition and analysis of the data on the reported spin-crossover metallomesogens led to the separation of three types, namely: Type i: systems with coupling between the electronic structure of the iron(II) ions and the mesomorphic behavior of the substance; Type ii: systems where both transitions coexist in the same temperature region but are not coupled due to competition with the dehydration or due to negligible structural transformation; Type iii: systems where both transitions occur in different temperature regions and therefore are uncoupled. Fine-tuning, in particular regarding the temperature at which the spin-transition occurs with hysteresis properties responsible for the memory effect, are still a major challenge towards practical implementation of spin-crossover materials. A possible answer to the problem could be materials in which the spin-crossover transition is coupled with another transition easily controllable by external stimuli. In the present thesis we have shown the viability of the approach realized in the mesogenic systems with coupled phase- and spin-transitions.

Investigation of heterogeneous catalysts for the synthesis of fine chemicals

In order to match the more stringent environmental regulations, heterogenization of traditional homogeneous processes is one of the main challenges of the modern chemical industry. Great results have been achieved in the fields of petrochemicals and base chemicals, whereas in fine chemical industry most of the synthetic procedures are based on multistep processes catalyzed by homogeneous catalysts mainly used in stoichiometric amounts. In the fine chemicals manufacture not so much efforts have been devoted to the investigation of suitable solid catalysts for the development of greener processes, then this sector represent a very attractive field of research. In this context, the present work deals with the extensive investigation of the possibility to heterogenize existing processes, in particular two different classes of reactions have been studied: alkylation of aromatic and heteroaromatic compounds and selective oxidation of aromatic alcohols. Traditional solid acid catalysts, such as zeolites, clays and alumina have been tested in the gas phase alkylation of 1,2-methylendioxybenzene, core building block of many drugs, pesticides and fragrances. The observed reactivity were clarified through a deep FTIR investigation complemented by ab initio calculation. The same catalysts were tested in the gas phase isopropylation of thiophene with the aim of clearly attribute the role of the reaction parameters in the reaction proceeding and verify the possibility to enhance the selectivity of one of the two possible isomers. Finally various Au/CeO2 catalysts were tested in the synthesis of benzaldehyde and piperonal, two aldehydes largely employed in the manufacture of fine chemical products, through liquid phase oxidation of the corresponding alcohols in very mild conditions.

Synthesis and investigation of functional polymer materials

Funktionelle Materialien sind in einer Vielzahl von Materialklassen wie Polymeren, Biomaterialien, Gläsern, Metallen, Keramiken und Verbundwerkstoffen anzutreffen. Sie besitzen eine spezifische, intrinsische Funktion, welche auf dem zu Grunde liegenden Design der Verbindung beruht. In dieser Dissertation wurden zwei funktionelle Materialien studiert: ein durch Phosphonatadditive mechanisch verstärktes Epoxidharz und protonenleitende Blockcopolymere, welche Potential für den Einsatz in Brennstoffzellen besitzen. Die Materialien wurden vorranging mittels Festkörper Kernspinresonanzspektroskopie (NMR) untersucht, welche sich besonders für die Untersuchung der lokalen Struktur und Dynamik amorpher Polymere eignet.rnrnPhosphonate sind eine neue Klasse sogenannter molekularer Verstärker, die die mechanischen und thermischen Kennzahlen geeigneter Epoxidharze erhöhen. Es wurde eine Reihe von Phosphonatderivaten synthetisiert um systematische den Effekt der chemischen Struktur und des Aushärteprozesses auf die Eigenschaften eines Modellepoxidharzes zu untersuchen. Die Aufklärung des Verstärkungsmechanismus ergab, dass die Phosphonate währen der thermischen Aushärtung des Epoxidharzes die Aminofunktionalitäten des Härters alkylieren. Dies führt zu der Bildung von homogen verteilten, positiven Ladungen auf der Polymerkette, während negative Phosphonatanionen als Gegenionen wirken. Es konnte gezeigt werden, dass die Struktur des Additivs einen entscheidenden Einfluss auf die Eigenschaften des ausgehärteten Epoxidharzes sowie seine Alterung, d.h. den allmählichen Verlust der Verstärkung, hat.rnrnDes Weiteren wurde eine Serie von sulfonierten Blockcopolymeren synthetisiert. Es handelte sich hierbei um Multiblockcopolyimide, wobei die Polymerketten aus einer alternierenden Sequenz von sulfonierten (hydrophilen) und unsulfonierten (hydrophoben) Blöcken bestanden. Diese Polymere bilden nach einem ‚solvent cast‘ Prozess feste, duktile und transparente Membrane. Sulfonierte Blockcopolymermembrane zeigten im Vergleich mit statistisch sulfonierten Vergleichssubstanzen eine erhöhte Leitfähigkeit, sowie eine erhöhte Wasseraufnahme. Dies wurde auf eine bessere Phasenseparation im Festkörper zurückgeführt. Die Morphologie der Filme war eindeutig anisotrop und stark abhängig von der Blocklänge der Polymere. Durch diverse Festkörper-NMR Methoden konnte gezeigt werden, dass die Protonenmobilität in den Membranen von der betrachteten Längenskala abhängig ist und nicht notwendigerweise mit der makroskopisch beobachteten Leitfähigkeit korreliert.

Geochemistry of tetrapyrrole, tetraterpenoid, and perylene pigments in sediments from the Gulf of California

Results and discussion cover pigment analyses of 36 sediment samples recovered by Deep Sea Drilling Project Leg 64, and six samples from the Leg 64 site-survey cruise in the Guaymas Basin (Scripps Institution of Oceanography, Leg 3). Pigments investigated were tetrapyrroles, tetraterpenoids, and the PAH compound perylene. Traces of mixed nickel and copper ETIO-porphyrins were ubiquitous in all sediment samples, except for the very surface (i.e., <2 m sub-bottom), and their presence is taken as an indication of minor influxes of previously oxidized allochthonous (terrestrial) organic matter. Phorbides and chlorins isolated from Site 479 sediment samples (i.e., the oxygen-minimum locale, northeast of the Guaymas Basin) well represent the reductive diagenesis ("Treibs Scheme"; see Baker and Palmer, 1978; Treibs, 1936) of chlorophyll derivatives. Three forms of pheophytin-a, plus a variety of phorbides, were found to give rise to freebase porphyrins, nickel phylloerythrin, and nickel porphyrins, with increasing depth of burial (increasing temperature). Sediments from Sites 481, 10G, and 18G yielded chlorophyll derivatives characteristic of early oxidative alterations. Included among these pigments are allomerized pheophytin-a, purpurin-18, and chlorin-p6. The high thermal gradient imposed upon the late Quaternary sediments of Site 477 greatly accelerated chlorophyll diagenesis in the adjacent overlying sediments, that is, the production of large quantities of free-base desoxophylloerythroetioporphyrin (DPEP) occurred in a section (477-7-5) presently only 49.8 meters sub-bottom. Present depth and age of these sediments are such that only chlorins and phorbides would be expected. Carotenoid (i.e., tetraterpenoids) concentrations were found to decrease rapidly with increasing sub-bottom depth. Less deeply buried sediments (e.g., 0-30 m) yielded mixtures of carotenes and oxygen-substituted carotenoids. Oxygencontaining (oxy-, oxo-, epoxy-) carotenoids were found to be lost preferentially with increased depth of burial. Early carotenoid diagenesis is suggested as involving interacting reductions and dehydrations whereby dehydro-, didehydro-, and retro-carotenes are generated. Destruction of carotenoids as pigments may involve oxidative cleavage of the isoprenoid chain through epoxy intermediates, akin to changes in the senescent cells of plants. Perylene was found to be a common component of the extractable organic matter from all sediments investigated. The generation of alkyl perylenes was found to parallel increases in the existing thermal regime at all sites. Igneous sills and sill complexes within the sediment profile of Site 481 altered (i.e., scrambled) the otherwise straightforward thermally induced alkylation of perylene. The degree of perylene alkylation is proposed as an indicator of geothermal stress for non-contemporaneous marine sediments.

Interaction of an alkylating camptothecin derivative with a DNA base at topoisomerase I-DNA cleavage sites.

DNA topoisomerase I (top1) is a ubiquitous nuclear enzyme. It is specifically inhibited by camptothecin, a natural product derived from the bark of the tree Camptotheca acuminata. Camptothecin and several of its derivatives are presently in clinical trial and exhibit remarkable anticancer activity. The present study is a further investigation of the molecular interactions between the drug and the enzyme-DNA complex. We utilized an alkylating camptothecin derivative, 7-chloromethyl-10,11-methylenedioxycamptothecin (7-ClMe-MDO-CPT), and compared its activity against calf thymus top1 in a DNA oligonucleotide containing a single top1 cleavage site with the activity of its nonalkylating analog, 7-ethyl-10,11-methylenedioxycamptothecin (7-Et-MDO-CPT). In the presence of top1, 7-ClMe-MDO-CPT produced a DNA fragment that migrated more slowly than the top1-cleaved DNA fragment observed with 7-Et-MDO-CPT. Top1 was unable to religate this fragment in the presence of high NaCl concentration or proteinase K at 50 degrees C. This fragment was resistant to piperidine treatment and was also formed with an oligonucleotide containing a 7-deazaguanine at the 5' terminus of the top1-cleaved DNA (base + 1). It was however cleaved by formic acid treatment followed by piperidine. These observations are consistent with alkylation of the +1 base (adenine or guanine) by 7-ClMe-MDO-CPT in the presence of top1 covalent complexes and provide direct evidence that camptothecins inhibit top1 by binding at the enzyme-DNA interface.

A mechanism for posttranslational modifications of proteins by yeast protein farnesyltransferase.

Protein farnesyltransferase catalyzes the alkylation of cysteine in C-terminal CaaX sequences of a variety of proteins, including Ras, nuclear lamins, large G proteins, and phosphodiesterases, by farnesyl diphosphate (FPP). These modifications enhance the ability of the proteins to associate with membranes and are essential for their respective functions. The enzyme-catalyzed reaction was studied by using a series of substrate analogs for FPP to distinguish between electrophilic and nucleophilic mechanisms for prenyl transfer. FPP analogs containing hydrogen, fluoromethyl, and trifluoromethyl substituents in place of the methyl at carbon 3 were evaluated as alternative substrates for alkylation of the sulfhydryl moiety in the peptide dansyl-GCVIA. The analogs were alternative substrates for the prenylation reaction and were competitive inhibitors against FPP. A comparison of kcat for FPP and the analogs with ksolv, the rate constants for solvolysis of related p-methoxybenzenesulfonate derivatives, indicated that protein prenylation occurred by an electrophilic mechanism.

CC-1065 and the duocarmycins: unraveling the keys to a new class of naturally derived DNA alkylating agents.

Key studies defining the DNA alkylation properties and selectivity of a new class of exceptionally potent, naturally occurring antitumor antibiotics including CC-1065, duocarmycin A, and duocarmycin SA are reviewed. Recent studies conducted with synthetic agents containing deep-seated structural changes and the unnatural enantiomers of the natural products and related analogs have defined the structural basis for the sequence-selective alkylation of duplex DNA and fundamental relationships between chemical structure, functional reactivity, and biological properties. The agents undergo a reversible, stereoelectronically controlled adenine-N3 addition to the least substituted carbon of the activated cyclopropane within selected AT-rich sites. The preferential AT-rich non-covalent binding selectivity of the agents within the narrower, deeper AT-rich minor groove and the steric accessibility to the alkylation site that accompanies deep AT-rich minor groove penetration control the sequence-selective DNA alkylation reaction and stabilize the resulting adduct. For the agents that possess sufficient reactivity to alkylate DNA, a direct relationship between chemical or functional stability and biological potency has been defined.

Organic reactions in ionic liquids: ionic liquid-accelerated facile synthesis of 3-alkyl-2,4-thiazolidinediones

The room temperature ionic liquid [bmim]PF6 is a new green solvent for the N-alkylation of 2,4-thiazolidinones. Significant rate enhancement and improved yields have been observed.

Synthesis of triplex-forming oligonucleotide conjugates of the anticancer drug temodal

Covalent attachment of the anticancer drugs temozolomide (Temodal) and mitozolomide to triplex-forming oligonucleotides (TFOs) is a potential way of targeting these alkylating agents to specific gene sequences to maximise site-selectivity. In this work, polypyrimidine TFO conjugates of both drugs were synthesised and targeted to duplex DNA in an attempt to effect site-specific alkylation of guanine residues. Concurrently, in an attempt to enhance the triple helix stability of TFOs at neutral pH, the thermal stabilities of triplexes formed from TFOs containing isoguanine, 2-O-benzyl- and 2-O-allyl-adenine were evaluated. A novel cleavage and deprotection procedure was developed which allowed for the solid phase synthesis of the base-sensitive TFO-drug conjugates using a recently developed silyl-linked controlled pore glass (SLCPG) support. Covalent attachment of either temozolomide or mitozolomide at the 5'-end of TFO conjugates caused no destabilisation of the triplexes studied. The synthesis of a phosphoramidite derivative of mitozolomide enabled direct incorporation of this reagent into a model sequence during DNA synthesis. After cleavage and deprotection of the TFO-drug conjugate, the 5'-end mitozolomide residue was found to have decomposed presumably as a result of ring-opening of the tetrazinone ring. The base-sensitive antibacterial and antitumour agent, metronidazole, was also successfully incorporated at the 5'-end of the oligonucleotide d(T8) using conventional methods. Two C2-substituted derivatives of 2'-deoxyadenosine containing 2-O-benzyl and 2-O-allyl groups were synthesised. Hydrogenolysis of the 2-O-benzyl analogue provided a useful route, amenable to scale-up, for the synthesis of the rare nucleoside 2'-deoxyisoguanosine (isoG). Both the 2-O-allyl and 2-O-benzyl derivatives were incorporated into TFO sequences using phosphoramidite methodology. Thermal melting experiments showed that the 2-O-allyl and 2-O-benzyl groups caused marked destabilisation of the triple helices studied, in contrast to hexose-DNA duplexes, where aralkyl substituents caused significant stabilisation of duplexes. TFOs containing isoG were synthesised by Pd(O)-catalysed deallylation of 2-0-allyl adenine residues. These sequences containing isoG, in its N3- or 02-H tautomeric form, formed triple helices which were equally as stable as those containing adenine.

Studies on the mechanism of action on antitumour imidazotetrazinones

The imidazotetrazinones are clinically active antitumour agents, temozolomide currently proving successful in the treatment of melanomas and gliomas. The exact nature of the biological processes underlying response are as yet unclear.This thesis attempts to identify the cellular targets important to the cytotoxicity of imidazotetrazinones, to elucidate the pathways by which this damage leads to cell death, and to identify mechanisms by which tumour cells may circumvent this action. The levels of the DNA repair enzymes O6-alkylguanine-DNA-alkyltransferase (O6-AGAT) and 3-methyladenine-DNA-glycosylase (3MAG) have been examined in a range of murine and human cell lines with differential sensitivity to temozolomide. All the cell lines were proficient in 3MAG despite there being 40-fold difference in sensitivity to temozolomide. This suggests that while 3-methyladenine is a major product of temozolomide alkylation of DNA it is unlikely to be a cytotoxic lesion. In contrast, there was a 20-fold variation in O6-AGAT levels and the concentration of this repair enzyme correlated with variations in cytotoxicity. Furthermore, depletion of this enzyme in a resistant, O6-AGAT proficient cell line (Raji), by pre-treatment with the free base O6-methylguanine resulted in 54% sensitisation to the effects of temozolomide. These observations have been extended to 3 glioma cell lines; results that support the view that the cytotoxicity of temozolomide is related to alkylation at the O6-position of guanine and that resistance to this drug is determined by efficient repair of this lesion. It is clear, however, the other factors may influence tumour response since temozolomide showed little differential activity towards 3 established solid murine tumours in vivo, despite different tumour O6-AGAT levels. Unlike mitozolomide, temozolomide is incapable of cross-linking DNA and a mechanism by which O6-methylguanine may exert lethality is unclear. The cytotoxicity of the methyl group may be due to its disruption of DNA-protein interactions, or alternatively cell death may not be a direct result of the alkyl group itself, but manifested by DNA single-strand breaks. Enhanced alkaline elution rates were found for the DNA of Raji cells treated with temozolomide following alkyltransferase depletion, suggesting a relationship between O6-methylguanine and the induction single-strand breaks. Such breaks can activate poly(ADP-ribose) synthetase (ADPRT) an enzyme capable of rapid and lethal depletion of cellular NAD levels. However, at concentrations of temozolomlde relevant in vivo little change in adenine nucleotides was detected in cell lines, although this enzyme would appear important in modulating DNA repair since inhibition of ADPRT potentiated temozolomide cytotoxicity in Raji cells but not O6-AGAT deficient GM892A cells. Cell lines have been reported that are O6-AGAT deficient yet resistant to methylating agents. Thus, resistance to temozolomide may arise not only by removal of the methyl group from the O6-position of guanine, but also from another mechanism involving caffeine-sensitive post-replication repair or mismatch repair activity. A modification of the standard Maxam Gilbert sequencing technique was used to determine the sequence specificity of guanine-N7 alkylation. Temozolomide preferentially alkylated runs of guanines with the intensity of reaction increasing with the number of adjacent guanines in the DNA sequence. Comparable results were obtained with a polymerase-stop assay, although neither technique elucidates the sequence specificity of O6-guanine alkylation. The importance of such specificity to cytotoxicity is uncertain, although guanine-rich sequences are common to the promoter regions of oncogenes. Expression of a plasmid reporter gene under the control of the Ha-ras proto~oncogene promoter was inhibited by alkylation with temozolomide when transfected into cancer cell lines, However, this inhibition did not appear to be related to O6~guanine alkylation and therefore would seem unimportant to the chemotherapeutic activity of temozolomide.

Antitumour imidazotetrazines: probes for the major groove of DNA

The antitumour imidazotetrazinones are believed to act as prodrugs for the triazene series of alkylating agents, showing a marked pteference for the alkylation of the middle guanine residue in a run of three or more contiguous guanines. However, the. exact nature of the interactions of imidazotetrazinones within the micro~environment of DNA are; as yet unknown. In order to examine such interactions a three pronged approach involving molecular modelling, synthetic chemistry and biological analysis has been undertaken during the course of this project. . Molecular modelling studies have shown that for the 8-carboxamido substituted imidazotetrazinones antitumour activity is dependent upon the. presence of a free NH group which can be involved in the formation of both intramolecular and intermolecular hydrogen bonds, and the presence of a non-bulky substituent with a small negative potential . volume. Modelling studies involving the docking of .mitozolomide into the major groove of DNA in the region of a triguanine sequence has shown that a number of hydrogen bonding interactions are feasible. A series of 8-substituted carboxamide derivatives of mitozolomide have been synthesised via the 8-acid chloride and 8-carboxylic acid derivatives including a number of peptide analogues. The peptide derivatives were based upon the key structural features of the helix-turn-helix motif of DNA-binding proteins with a view to developing agents that are capable of binding to DNA with greater selectivity. An examination of the importance of intramolecular hydrogen bonding in influencing the antitumour activity:of :the imidazotetrazinones has led to the synthesis of the novel pyrimido[4',5' :4,3]pyrazolo[5,1-d]-1,2,3,5-tetrazine ring system. In general, in vitro cytotoxicity assays showed that the new derivatives were less active against the TLX5 lymphoma cell line. than the parent compound mitozolomide despite an increased potential for hydrogen bonding interactions. Due to the high reactivity of the: tetrazinone ring system it is difficult to study the interactions between the imidazotetrazinones and DNA. Consequently a number of structural analogues that are stable under physiological conditions have been. prepared based upon the 1,2,3 triazin-4(3H)-one ring system fused with both benzene and pyrazole rings. Although the 3-methylbenzotriazinones failed to antagonise the cytotoxic activity of temozolomide encouraging results with a 3-methylpyrazolotriazinone may suggest the existence of an imidazotetrazinone receptor site within DNA. The potential of guanine rich sequences to promote the alkylating selectivity of imidazotetrazinones by acting as a catalyst for ring cleavage and thereby generation of the alkylating agent was examined. Experiments involving the monitoring: of the rate of breakdown of mitozolomide incubated in the presence of synthetic oIigonucleotides did not reveal any catalytic effect resulting from the DNA. However, it was noted that the breakdown of mitozolomide was dependent upon the type of buffer used in the incubations and this may indeed mask any catalysis by the oligonucleotides.

Novel 5-HT7 ligands as antidepressants:automated synthesis of N-substituted-N-[1-methyl-3-(4-methylpiperidin-1-yl)propyl]-arylsulfon amides

The 5-HT7 receptor is linked with various CNS disorders. Using an automated solution phase synthesis a combinatorial library of 384 N-substituted N-[1-methyl-3-(4-methylpiperidin-1-yl)propyl]-arylsulfonamides was prepared with 24 chemically diverse amines 1-24 and 16 sulfonyl chlorides A-P. The chemical library of alkylated sulfonamides was evaluated in a receptor binding assay with [3]H-5-CT as ligand. The key synthetic step was the alkylation of a sulfonamide with iodide E, which was prepared from butanediol in 4 synthetic steps. The target compounds 1A, 1B .....24A ... 24P were purified by solvent extraction on a Teacan liquid handling system. Sulfonamide J20, B23, D23, G23, G23, J23 , I24 and O24 displayed a binding affinity IC50 between 100 nM and 10 nM. The crystalline J20 (IC50=39 nM) and O24 (IC50=83 nM) were evaluated further in the despair swimming test and the tail suspension assay. A significant antidepressant activity was found in mice of a greater magnitude than imipramine and fluoxetine at low doses. © 2006 Bentham Science Publishers Ltd.

New methods for the asymmetric synthesis of α-alkylated ketones and 1,3-amino alcohols

A large number of optically active drugs and natural products contain α-functionalised ketones or simple derivatives thereof. Furthermore, chiral α-alkylated ketones are useful synthons and have found widespread use in total synthesis. The asymmetric alkylation of ketones represents one of the most powerful and longstanding procedures in organic chemistry. Surprisingly, however, only one effective methodology is available, and this involves the use of chiral auxiliaries. This is discussed in Chapter 1, which also provides a background of other key topics discussed throughout the thesis. Expanding on the existing methodology of chiral auxiliaries, Chapter 2 details the synthesis of a novel chiral auxiliary containing a pyrrolidine ring and its use in the asymmetric preparation of α-alkylated ketones with good enantioselectivity. The synthesis of racemic α-alkylated ketones as reference standards for GC chromatography is also reported in this chapter. Chapter 3 details a new approach to chiral α-alkylated ketones using an intermolecular chirality transfer methodology. This approach employs the use of simple non-chiral dimethylhydrazones and their asymmetric alkylation using the chiral diamine ligands, (+)- and (-)-sparteine. The methodology described represents the first example of an asymmetric alkylation of non-chiral azaenolates. Enantiomeric ratios up to 83 : 17 are observed. Chapter 4 introduces the first aldol-Tishchenko reaction of an imine derivative for the preparation of 1,3-aminoalcohol precursors. 1,3-Aminoalcohols can be synthesised via indirect routes involving various permutations of stepwise construction with asymmetric induction. Our approach offers an alternative highly diastereomeric route to the synthesis of this important moiety utilising N-tert-butanesulfinyl imines in an aldol-Tishchenko-type reaction. Chapter 5 details the experimental procedures for all of the above work. Chapter 6 discusses the results of a separate research project undertaken during this PhD. 2-alkyl-quinolin-4-ones and their N-substituted derivatives have several important biological functions such as the role of Pseudomonas quinolone signal (PQS) in quorum sensing. Herein, we report the synthesis of its biological precursor, 2-heptyl-4-hydroxy-quinoline (HHQ) and possible isosteres of PQS; the C-3 Cl, Br and I analogues. N-Methylation of the iodide was also feasible and the usefulness of this compound showcased in Pd-catalysed cross-coupling reactions, thus allowing access to a diverse set of biologically important molecules.