This thesis describes the application of flow chemistry to discovery and development of medicinal compound synthesis and new chemical methodologies respectively. It is divided into three distinct sections. The first section addresses a brief introduction to flow chemistry, highlighting the advantages and challenges that have been faced in the past and present and also the outlook to the future. The second section reports the integration of machine-assisted methods with batch processes to produce two medicinal compounds, a precursor to the sacubitril and OZ439 respectively. In the respect to the precursor to sacubritil, a flow-batch integrated synthesis is developed to provide the desired product in 54% yield over 7 steps from commercially available 4-iodophenyl. In particular, a tube-in-tube gas flow reactor was employed in three gas-liquid reactions without the need for installing a costly highpressure autoclave. These gas-lquid reactions were an ethylene Heck coupling reaction, an anti-Markovnikov Wacker oxidation and a rhodium-catalysed stereoselective hydrogenation respectively. In addition, a diastereoselective Reformatsky-type carbethoxyallylation using zinc metal was also highlighted in this synthesis to install an important stereocentre. A new antimalarial agent, OZ439 containing a trioxolane unit as the main structural feature, has the unique property of providing a single-dose cure for malaria in humans and has recently completed phase IIb trials. A machine-enabled process for the preparation of OZ439 was developed in 33% overall yield over 5 steps without the need of column chromatography purification. This preparation features a selective continuous hydrogrenation, Griesbaum ozonlysis and a Zn-catalysed amide reduction in the present of triethoxylsilane. The third section contains the development of two new methodologies of diazo compounds with organoboron compounds. The first methodology involves an in situ generation of transient allylic boronic species by reacting TMSCHN2 and E-vinyl boronic acids in flow, followed by subsequent trapping with a range of aldehydes (15 examples, 55-97% yield) and on a large scale (10 mmol) to provide homoallylic alcohols with high diastereoselectivity (>20:1 dr confirmed by 1H NMR). This multicomponent metal-free reaction could also be applied under batch conditions (20 further examples, 60-82% yield). The second methodology involves the preparation of an organodimetallic compound, α-trimethylsilyl benzylboronic acid pinacol esters, by reacting TMSCHN2 and phenylboronic anhydrides (21 examples, 60-91% yield), and the development of their applications as bifunctional building blocks to complex structures.

We present here the hypothesis of a possible relationship between metal atom clusters and the formation of organic molecules in the interstellar medium and on small bodies as a possible pathway to the origin of such molecules. Two distinct stages are díscussed: a) the possible formation and presence of atom clusters in space and on the primitive Earth, and b) the synthesis of interstellar and terrestrial prebiotic organic molecules, a process in which metalclusters could be the active catalysts. The confirmatíon of these suggestions might be very important in arder to explain the presence of extra-terrestrial organic molecules in the interstellar medium, small bodies and planetary systems, and therefore would have great relevance in cosmochemistry and in the current theories about the origins of life.

Ketene dimethyl thioacetal monosulfoxide was prepared in 68% overall yield in two steps starting from methylmagnesium chloride. The yield of dithioacetic acid was improved significantly by employing tetrahydrofuran as solvent and using elevated temperatures. A one-pot synthesis of ketene thioacetals from alkyl halides was developed and several ketene thioacetals were prepared by this method. Direct oxidation of ketene thioacetals using m-chloroperoxybenzoic acid provided a general route to ketene thioacetal monosulfoxides. In cases where E and Z isomeric ketene thioacetal monosulfoxides were possible, the E/Z isomeric ratio increased as the substituents on the ketene double bond was increased in size.

Doctor of Philosophy / Department of Chemistry / Duy H. Hua / The first part of this thesis deals with the syntheses of ovalicin and its analogues. Ovalicin inhibits the endothelial cell proliferation. Apart from being anti-angiogenic it also exhibits antibiotic, antitumor, and immunosuppressive properties. Unlike other syntheses, we started with an acyclic compound, ethyl propiolate (1.66). Our flexible route towards the synthesis used intramolecular Heck cyclization reaction to construct an appropriately functionalized 3-methylene-6-(tert-butyldimethylsilyloxy)cyclohexene (1.63) from 1.66 in four steps. A number of synthetic analogues were synthesized via this strategy. Upon selective epoxidation and dihydroxylation of 1.63, a mixture of diols (3S*,4R*,5S*,6S*)-6-(tert-butyldimethylsilyloxy)-1-oxaspiro[2.5]octane-4,5-diol (1.107) and (3S*,4S*,5R*,6R*)-6-(tert-butyldimethylsilyloxy)-1-oxaspiro[2.5]octane-4,5-diol (1.108) were obtained. Subsequent functional group transformations of diols 1.107 and 1.108 gave ketones (3S*,4S*,5R*,6R*)-6-(tert-butyldimethylsilyloxy)-5-methoxy-1-oxaspiro[2.5]octan-4-one (1.112) and (3S*,5S*,6S*)-6-(tert-butyldimethylsilyloxy)-5-methoxy-1-oxaspiro[2.5]octan -4-one (1.117). Addition of vinyl lithium to the ketones followed by functional group transformation gave ovalicin analogues. Several intermediates were subjected to biological activity test for inhibition of growth of T. brucei. Our synthetic efforts towards the synthesis of ovalicin are discussed. The second part of my thesis deals with the synthesis of different tricyclic pyrone (TP) analogues which inhibit the aggregation of Aβ peptides. Alzhemier’s disease (AD) is caused by accumulation of fibrillar amyloid deposits in the AD brain. We synthesized a series of tricyclic pyrone derivatives and evaluated their counteraction on amyloid toxicity. TP analogue, (5aS,7S)-7-[(1R) and (1S)-2-(N3-adenyl)-1-methylethyl]-3-methyl-1H,7H-5a,6,8,9-tetrahyro-1-oxopyranol[4,3 -b] [1] benzopyran (CP2) is nontoxic, small and permeable molecule prevents the death of human neuroblastoma MC65 cells that conditionally expressed SβC gene. We further found that CP2 ameliorates the toxicity and inhibits the formation of Aβ oligomeric complexes. Binding studies using surface plasma resonance and atomic force microscopy studies suggest that CP2 permeates into the cells and interacts with Aβ peptides and inhibits the Aβ oligomerization. To understand the mechanism of Aβ aggregation and toxicity, CP2 and its derivatives are synthesized to evaluate their action. The key intermediate in the synthesis of CP2 is (5aS*,7S*)-7-[(1R*) and (1S*)-2-bromo-1-methylethyl]-3-methyl-1H,7H-5a,6,8,9-tetrahyro-1-oxopyranol[4,3-b][1] benzopyran (2.9), which in turn can be prepared from our previously reported method. Our aim is to synthesize a series of compounds and investigate the biological activities of different TP analogues.

No / The crystal structure of the I-phase of quinacridone was determined from non-indexed X-ray powder data by means of crystal structure prediction and subsequent Rietveld refinement. This I-phase is another polymorph than the -phase reported by Lincke [G. Lincke and H.-U. Finzel, Cryst. Res. Technol. 1996, 31, 441¿452.]. The crystal structures of the and polymorphs were determined from single crystal data. The knowledge of the crystal structures can be used for crystal engineering, i.e., for targeted syntheses of pigments having desired properties, especially for the syntheses of new red pigments.

<p> A number of new ternary borate compounds have been synthesized, and their crystal structures have been characterized via X-ray and neutron diffraction techniques. A series of new compounds with the composition PbMBO4 (M = Cr, Mn, Fe, Ga) has been prepared from solid-state reactions and from single crystal growths using PbO as a flux. They crystallize in the orthorhombic Pnma space group and represent a new structure-type for the family of anhydrous borates. The PbAlBO4 compound undergoes a phase transformation at high temperatures, which has been investigated by in-situ powder neutron diffraction experiments. The structure of β-PbAlBO4 has been solved from powder X-ray diffraction data and subsequently confirmed by a Rietveld refinement of powder neutron diffraction data. The investigation of the SrO - Ga2O3 - B2O3 system has led to the synthesis of a new structure-type, SrGaBO4, from solid-state reactions. Its crystal structure has been determined from powder X-ray diffraction data. It crystallizes in the orthorhombic Pbam space group, and is structurally related to the previously known alumino-borate compounds, SrAlBO4 and CaAlBO4. The "Ba2Ti2B2O9" compound has been re-formulated as Ba3Ti3B2O13, and its crystal structure has been determined by single crystal X-ray diffraction. This compound crystallizes in the non-centrosymmetric P6 2m space group. It is isostructural with K3Ta3B2O12 and the high temperature phase of K3Nb3B2O12.</p> / Thesis / Master of Science (MSc)

<p> Polymers and block copolymers have been grafted from hard and soft polymer micro-spheres by atom transfer radical polymerization (ATRP) and ring opening polymerization (ROP). The hard and soft micro-spheres were prepared by precipitation polymerization of divinylbenzene-80 (DVB80), and of DVB80/hydroxyethylmethacrylate (HEMA), respectively, in neat acetonitrile.</p> <p> Residual vinyl groups in the hard, poly(DVB80) micro-spheres were hydrochlorinated to form benzyl chloride groups that subsequently served as ATRP initiators for poly(styrene) and poly(styrene-block-4-methylstyrene) grafts. Hydrophilic poly(HEMA) and poly(2-( dimethylamino)ethyl methacrylate) poly(DMAEMA) were also grafted from hard micro-spheres containing bromopropionates, using ATRP in the presence of CuBr/Me4Cyclam.</p> <p> Hydroxy groups in soft, poly(DVB80-co-HEMA) micro-spheres were used directly as initiators for ring opening polymerization of ε-caprolactone catalyzed by aluminum compounds. In the addition, they were reacted with α-bromopropionyl bromide to form ATRP initiators.</p> <p> Several combinations of ATRP-ATRP and ROP-ATRP with different monomers were carried out using these initiator micro-spheres. In particular, the soft micro-spheres grafted with poly(methacrylic acid), poly(methylmethacrylate), poly(methylmethacrylate-block-dimethylaminoethylmethacrylate), poly(methylmethacrylate-block-trimethylammoniumethylmethacrylate), poly(methylmethacrylate-block-HEMA), poly(methylmethacrylate-block-glycidylmethacrylate), poly(ε-caprolactone-block- methylmethacrylate), poly(ε-caprolactone-block-dimethylaminoethylmethacrylate).</p> <p> The internal morphology of these homo and block copolymer grafted microspheres was studied using electron microscopy and x-ray microspectroscopy.</p> / Thesis / Doctor of Philosophy (PhD)

Different catalytic approaches have been applied to new -lactams preparations. olefin metathesis has been successfully performed with 3--methylidene--lactams. It was verified that 3--methylidene--lactams olefin metathesis is applicable to preparation of biologically active -lactam of Ezetimibe-type.

The soil bacterium Rhodococcus is a member of the phylum Actinobacteria and is related to Streptomyces, which is known for its production of many secondary metabolites. Recent genomic investigation of Rhodococcus has uncovered many silent gene clusters that appear to code for nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKS) of unknown function. Previous work, showed that Rhodococcus species strain KCHXC3 produces an inhibitory compound in agar culture extracts that displays prominent activity against several Gram positive and Gram negative species including the pathogens Rhodococcus equi, Shigella dysenteriae and Pseudomonas aeruginosa. Using the engineered Rhodococcus transposon vector, pTNR, the goal of this investigation is to screen random mutants of KCHXC3 for strains that no longer produce the inhibitory molecule. A library of 1825 random insertion mutants was produced via electroporation then screened for production of the inhibitory molecule by a disk diffusion assay against Shigella dysenteriae. From this screening, 7 mutants which no longer produce the compound of interest were identified.

The emergence of verdazyl radicals as starting materials for organic synthesis is providing a unique opportunity to create a variety of distinctive heterocyclic scaffolds. These stable radicals have previously been used as spin probes, polymerization inhibitors, mediators of living radical polymerizations, and as substrates for molecular-based magnets. However, verdazyl radicals have never been employed to fulfill an organic synthetic role until recently. In an effort to pioneer the chemistry behind verdazyl radicals as novel organic substrates, our lab has been inspired to expand and explore the scope of reactions involving their synthetic utility. This thesis assesses the synthetic versatility of verdazyl radicals by constructing a library of structurally complex and diverse verdazyl-derived heterocycles in an approach called diversity-oriented synthesis. The synthetic versatility was further expanded to the preparation of a biphenyl-stacked biphenylophane, which exhibited interesting structural and conformational features as highlighted herein.