The electrochemical synthesis of 3-tert-Butyl-4-Methoxybenzaldehyde

This project was concerned with the evaluation of three potential synthetic routes for 3-tert-butyl-4-methoxybenzaldehyde, a useful fine chemical intermediate and ingredient in many sunscreen agents. The three synthetic routes all involved the selective oxidation of the 3-tert-butyl-4-methoxytoluene to the desired benzaldehyde by (a) catalytic air oxidation, (b) direct electrochemical oxidation, and (c) indirect electrochemical oxidation. In order to decide whether catalytic oxidation should precede the alkylation of 4-methoxytoluene, the selective oxidation using the well-known cobalt(II)- bromide catalyst system in acetic acid solutions were investigated with the view to determine whether increased electron density on the aromatic ring improves selectivity to the desired benzaldehyde or not. In addition, the effect of various important reaction variables was also investigated. These studies showed that increased electron density, hence increased substitution, increases the desired benzaldehyde selectivity. In addition, while reaction conditions such as reaction temperature, catalyst concentration, water concentration, etc. may be optimised for maximum 3-tert-butyl-4- methoxybenzaldehyde yields (~80 percent), such yields can only be achieved at relatively low (<40 percent) alkoxytoluene conversions. The direct electrochemical oxidation of 3-tert-butyl-4-methoxytoluene was investigated in methanol solutions containing various supporting electrolytes and using constant current electrolysis with the intention of optimizing the production of 3-tert-butyl-4-methoxybenzyl dimethyl acetal which can later be hydrolyzed using sulfuric acid to the 3-tert-butyl-4-methoxybenzaldehyde. In this study, various parameters such as supporting electrolyte and electrodes were studied. Previous studies showed undoubtedly that methanol as a solvent gave better results amongst the rest of the solvents. Indirect route was also studied as a method of synthesizing 3-tert-butyl-4- methoxybenzaldehyde and compared to the direct electro synthesis

Bismuth nitrate-induced novel nitration of eugenol and estradiol: An exploratory study

Molecules originating in nature have held an important place in chemistry and in society. Many of the important useful compounds of all time were first discovered in nature. Eugenol, a multi-functionalized biologically active constituent, is present in high quantity in natural clove. Eugenol is an important herb due to its medicinal activities; therefore, research on this molecule is necessary. Nitration of Eugenol was performed through various metal nitrates and solid surface combinations. Estrogens are contributors of the development of many secondary sex characteristics in females; they play various important roles in the nervous system. Direct nitration of estradiol has been carried out using metal nitrates on solid surfaces under milder condition. The effect of various metal nitrate/solid surface combinations toward nitration has been extensively studied. Bismuth nitrate pentahydrate/KSF clay is found to be the best reagent to synthesize 2- and 4- nitro estradiol effectively

The production, purification and catalytic utility of lignin peroxidase from "sporotrichum pulverulentum"

Production, purification and catalytic utility of lignin peroxidase (LiP) from Sporotrichum pulverulentum. The study of Lip has been hampered by the difficulty in producing this enzyme in sufficient quantities. Several strains of Phanerochaete chrvsosporium and Sporotrichum Pulverulentum were screened for LiP expression under different culture conditions to find a method of producing adequate supplies of the enzyme for the proceeding work in this thesis. A reliable method of Lip production was achieved using 750m1 agitated cultures of S. pulverulentum containing the detergent tween 80. Lip from S. pulverulentum was purified by HPLC and was found to consist of up to 14 isozymes which varied in molecular weight, pH optimum and specific activity for veratryl alcohol. However, their catalytic spectra were similar. The isozymes from S. pulverulentum had higher molecular weights and lower pI values than those published for LiP from P. chrvsosporium, which suggested that they were not as closely related as had been assumed. Lip from S. pulverulentum was able to oxidise a range of methoxy-substituted benzyl alcohols to their respective aldehydes. The susceptibility of benzyl alcohol oxidation by LiP depended upon the amount and position of methoxyl group substitution. LiP oxidation of these substrates was dependent upon how electron-rich the molecular π-orbitals of the substrates were, but steric effects may also have been important. LiP oxidation of benzyl alcohols under aerobic conditions led to additional products such as quinones, ring-cleavage products and chloro-substituted aromatics. These latter products provided evidence for the existence of LiP-derived aryl radical cations for a range of benzyl alcohol substrates, which is consistent with the peroxidative one-electron oxidation theory of Lip degradation of lignin. In addition LiP was shown to catalyse the peroxidative oneelectron oxidation of phenolics such as p-cresol and catechol to produce dimers and polymers. Lyophilised LiP was shown to be catalytically active in organic solvents such as ether and propyl acetate. An increase in enzyme stability of up to 30 times of that in water and a broadening of its catalytic spectrum was observed. Lip was also found in C. versicolor demonstrating that LiP may be a common constituent of ligninolytic white-rot fungi. In addition, other. extracellular peroxidases were present in this fungus. These peroxidases were novel compared to the extracellular peroxidases from P. chrysosporium since at least one of these could not oxidise veratryl alcohol and neither of these peroxidases were manganese-dependent

Development and Characterization of Non-heme Iron Biocatalysts for Complex Molecule Synthesis

Nature has evolved myriad biocatalytic tools for selective synthesis. The three-dimensional architecture of an enzyme active site enables the direct construction of new bonds with exquisite site-, chemo-, and stereo-selectivity. Seeking to take advantage of these characteristics, researchers have leveraged biocatalysts for the rapid synthesis of natural products and complex molecules, developing sustainable methods to address long-standing challenges in synthetic chemistry. In recent years, this approach has been expanded to combine chemo- and biocatalytic methods in a single vessel, enabling transformations of increasing complexity to occur in a streamlined process. This thesis describes the development of novel, one-pot chemoenzymatic methods for the synthesis of complex molecules and natural products. Specifically, this work leveraged non-heme iron (NHI) alpha-ketoglutarate-dependent enzymes to access reactive ortho-quinone methide (o-QM) and radical intermediates for the construction of chroman and tropolone natural products. These studies provide a platform for the development of NHI enzymes as scalable and selective catalysts for the synthesis of complex molecules. The described research involved the development NHI enzymes CitB and ClaD to perform selective benzylic C–H hydroxylation of ortho-phenolic compounds. This biocatalytic method offered numerous advantages over small molecule oxidants, which often exhibit poor site- and chemo-selectivity for benzylic hydroxylation reactions. In comparison, CitB and ClaD provided strict control over the site of oxidation, avoiding the need for blocking or protecting groups to achieve selective catalysis. The substrate scope of this transformation was evaluated for these biocatalysts and a scalable reaction platform was developed for this transformation, demonstrating the ability of NHI enzymes to serve as sustainable and selective catalysts for benzylic C–H hydroxylation. The products of this selective oxidation were fully characterized and were shown to serve as reactive precursors for the formation of o-QMs in a one-pot process. Compared to traditional synthetic approaches to one-pot o-QM generation, a biocatalytic route offers the advantage of selective oxidation, leading to controlled generation of the reactive o-QM intermediate. These intermediates were elaborated in one-pot, modular chemoenzymatic fashion through 1,4-addition and [4+2] cycloaddition reactions demonstrating the synthetic utility of this approach for synthesizing complex scaffolds. Overall, this biocatalytic reaction platform offered an improved selectivity profile over traditional oxidative approaches to o-QM synthesis, enabling facile one-pot benzylic oxidation and functionalization in a scalable reaction format. A second focus of this work involved the chemoenzymatic synthesis of 7-membered aromatic compounds known as tropolones. Efficient synthetic access to this structurally-diverse class of metabolites represents a significant challenge to the development of novel tropolone pharmaceuticals. To address this hurdle, NHI enzymes XenC and TropC were leveraged for their native ring expansion function to develop an efficient one-pot, two-enzyme reaction for the synthesis of substituted tropolones. Reactions with XenC were leveraged in the efficient chemoenzymatic synthesis of a variety of non-natural tropolones including the deoxygenated form of tropolone natural product epolone B. The reactivity of a putative Diels-Alderase was also explored in this reaction, providing a potentially selective route to the synthesis of bioactive tropolone natural products. Furthermore, this work explored the mechanism of the native ring expansion reaction performed by NHI enzyme TropC and provided evidence of a radical-based reaction through structural characterization of the enzyme, as well as mutagenesis and computational analysis. These observations led to a revised proposal for fungal tropolone biosynthesis and provided critical insight into an understudied NHI-catalyzed transformation.PHDChemical BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/163195/1/tydoyon_1.pd

Thesis

Enantioenriched amino ketones are convenient building blocks for a variety of synthetic transformations as well as important structural features in a wide array of natural products. N-heterocyclic carbene (NHC) catalyzed benzoin reactions are of great strategic value for obtaining such motifs. Initial efforts focus on a chiral auxiliary approach towards the NHC-catalyzed aza-benzoin transformation. It was investigated whether enantio-enriched α-aminoketones could be obtained using t-butanesulfinimines under NHC-catalyzed reaction conditions. Moderate yields and diastereomeric ratios are obtained between furfural-derived aldehydes and aldimines using this method. The unsatisfactory results prompted further investigation into alternative synthetic methods towards enantioenriched amino ketones. The chemo- and enantioselectivity of cross-benzoin transformations has been the major focus of several recent studies. In contrast, the use of chiral aldehydes in diastereoselective cross- benzoin reactions has received scant attention. This may be explained by the poor reactivity of sterically hindered substrates and/or difficulties in controlling the chemoselectivity. N-Protected α-amino aldehydes, owing to a synergistic balance between their electronic and steric properties, were used to address the chemoselectivity issues associated with NHC-catalyzed cross-benzoin reactions. This thesis describes the first examples of NHC-catalyzed chemo- and diastereoselective cross-benzoin reactions between two aliphatic aldehydes. The optimized reaction conditions can deliver a variety of enantio-enriched α-hydroxy-β-amino ketones with excellent chemoselectivity and good to excellent diastereoselectivity. Having developed viable methodologies to access enantio-enriched amino diols, the application of these methods was investigated in the synthesis of two natural products: D-arabino-phytosphingosine and hyacinthacine A1. Progress towards completion of the synthesis as well as future directions are discussed. With an emphasis on expanding the scope of the application of α-amino aldehydes in NHC-catalyzed transformations, this thesis concludes with a general discussion and proposal for future directions

Preparation, Characterization and Catalytic Applications of Pillared Clay Analogues and Clay-Polymer Composite Materials

Cr-pillared montmorillonite clay (Cr-P) was prepared by intercalation of chromium oxyhydroxy cationic clusters into the clay interlayer and subsequent thermal activation. The Cr-P material was characterized by XRD, FTIR, UV–Vis and sorptometric techniques. The expansion in the clay lattice as a result of pillaring was confirmed from the XRD study. The UV–Vis study of the pillared clay revealed the presence of Cr3+species as Cr2O3 nanoclusters inside the clay interlayer.The IR study was employed to show the presence of acidic and non-acidic hydroxyl groups in the pillared clays. The Cr-P material was used as an efficient heterogeneous catalyst for the synthesis of benzoxanthenes and octahydroxanthenes. The benzoxanthenes were synthesized by condensation of two mole of -naphthol with one mole of benzaldehyde. Similarly, the octahydroxanthenes were synthesized by the condensation of two mole of dimedone with one mole aryl aldehydes.Structurally diverse xanthene derivatives were synthesized under solvent free conditions and microwave irradiation using Cr-P as heterogeneous catalyst. The Cr-P clay was used further as support for dispersion of silicotungstic acid (STA). The STA particles were dispersed in the micropores of Cr-P clay by wet impregnation method. The synthesized materials were characterized by XRD, FTIR, UV-Vis, sorptometric, TGA, SEM and TEM techniques. IR and UV-Vis study illustrates the structural integrity of the STA particles in the micropores of the pillared clay. N2 adsorption/ desorption shows that the synthesized materials are microporous in nature. The catalytic activity of the STA/Cr-P materials was evaluated for synthesis of 1,4-dihydropyridines (DHPs) by multicomponent reaction of aldehydes/chalcones, ethylacetoacetate and ammonium acetate.Structurally diverse DHPs are prepared by using aryl aldehydes and chalcones as starting materials.A series of Zr-pillared clay (Zr-P)-polyphosphoric acid (PPA) and Zr-pillared claysulfonated polyvinyl alcohol (SPVA) composites were synthesized by adopting different preparative strategies. Initially, the polymeric species were intercalated to the clay matrix with and without the use of structure expanding agent (CTAB)

Continuous flow photooxidation of p-substituted phenols using singlet oxygen in supercritical CO2 applied to telescoped syntheses

Interest in photochemical processes both in academia and industry is increasing, but uptake is still limited due to low efficiency and/or scalability of current processes. Photochemical synthesis of highly reactive hydroperoxides so-called ‘p-peroxyquinols’ is of particular interest for synthetic organic chemistry and pharmaceutical manufacturing, given their involvement in the synthesis of antimalarial drugs and complex natural products. Batch synthesis of p-peroxyquinols in large scale can be challenging, given its instability in flammable solvents and long reaction times of up to 48 h. Continuous flow photooxidation of p-substituted phenols using singlet oxygen and supercritical CO2 could be a suitable alternative. In this Thesis, this methodology is explored in telescoped syntheses of compounds with potential pharmaceutical interest. Chapter 1 gives an introduction to flow chemistry including an overview of parameters and concepts used in the field. It highlights the advantages, challenges, and applications of flow chemistry both in academia and industry. A brief description of continuous flow photochemistry is also given, including recent advances using singlet oxygen in supercritical CO2. Chapter 2 describes the high-pressure batch and flow reactors used in this work, as well as the Standard Operating Procedures (SOP) for each system. Chapters 3 and 4 explore the continuous flow dearomatisation of p-substituted phenols using singlet oxygen in supercritical CO2 (Chapter 3) and its applications in the telescoped synthesis of 1,2,4-trioxanes, a scaffold present in antimalarial drugs such as Artemisinin (Chapter 4). The dearomatisation of p-substituted phenols was carried out using a photosensitiser and Light Emitting Diodes (LEDs) to generate singlet oxygen. 1,2,4-trioxanes were then synthesised via an acid catalysed acetalization/oxa-Michael addition cascade with aldehydes. The substrate scope was expanded to a variety of p-peroxyquinols and 1,2,4- trioxanes, investigating functional group robustness, degree of substitution, and type of substituent. Chapter 5 reports the telescoped synthesis of 2-substituted-1,4-benzoquinones, an important class of compounds with a variety of medicinal properties. The p-peroxyquinols formed through dearomatisation of p-substituted phenols, following the methodology developed in Chapter 3, were converted into 2-substituted-1,4-benzoquinones via acid- catalysed 1,2-alkyl shift of p-peroxyquinols. Optimisation of reaction conditions was initially carried out in batch, and the best conditions were then transferred to the continuous flow system. Several packed bed reactor designs were investigated in order to optimise the reaction yields. Chapters 6 and 7 present studies for the telescoped synthesis of 1,2,4-dioxazinanes and 1,3-oxazolidines, respectively. For both target compounds, an aminalisation/aza-Michael addition step using either a N-sulfinyl imine or N-sulfonyl imine was involved in the process. In Chapter 6, the synthesis of 1,2,4-dioxazinanes was investigated as this scaffold has been shown to have antimalarial activity, but synthetic methodologies to produce these compounds are scarce in the literature. The reaction conditions for both the asymmetric and racemic synthesis of 1,2,4-dioxazinanes were attempted in batch using a p-peroxyquinol and N-sulfonyl/sulfinyl imines previously synthesised. In Chapter 7, a synthetic route was designed for the asymmetric synthesis of 1,3-oxazolidines in four steps starting from the dearomatisation of p-substituted phenols. The reduction of p-peroxyquinols was examined in batch, and subsequent experiments were carried out to make 1,3-oxazolidines from p- quinols and N-sulfinyl imines. In Chapter 8, a summary of the work developed in this Thesis is outlined, highlighting the main findings and challenges in exploring the continuous flow photooxidation of p- substituted phenols in telescoped syntheses. The discussion is guided by the Thesis aims defined in the introduction chapter. Ideas for potential future work are also presented. Author name: Bruna Abreu Millard and Bruna Millar

Continuous flow photooxidation of p-substituted phenols using singlet oxygen in supercritical CO2 applied to telescoped syntheses

Interest in photochemical processes both in academia and industry is increasing, but uptake is still limited due to low efficiency and/or scalability of current processes. Photochemical synthesis of highly reactive hydroperoxides so-called ‘p-peroxyquinols’ is of particular interest for synthetic organic chemistry and pharmaceutical manufacturing, given their involvement in the synthesis of antimalarial drugs and complex natural products. Batch synthesis of p-peroxyquinols in large scale can be challenging, given its instability in flammable solvents and long reaction times of up to 48 h. Continuous flow photooxidation of p-substituted phenols using singlet oxygen and supercritical CO2 could be a suitable alternative. In this Thesis, this methodology is explored in telescoped syntheses of compounds with potential pharmaceutical interest. Chapter 1 gives an introduction to flow chemistry including an overview of parameters and concepts used in the field. It highlights the advantages, challenges, and applications of flow chemistry both in academia and industry. A brief description of continuous flow photochemistry is also given, including recent advances using singlet oxygen in supercritical CO2. Chapter 2 describes the high-pressure batch and flow reactors used in this work, as well as the Standard Operating Procedures (SOP) for each system. Chapters 3 and 4 explore the continuous flow dearomatisation of p-substituted phenols using singlet oxygen in supercritical CO2 (Chapter 3) and its applications in the telescoped synthesis of 1,2,4-trioxanes, a scaffold present in antimalarial drugs such as Artemisinin (Chapter 4). The dearomatisation of p-substituted phenols was carried out using a photosensitiser and Light Emitting Diodes (LEDs) to generate singlet oxygen. 1,2,4-trioxanes were then synthesised via an acid catalysed acetalization/oxa-Michael addition cascade with aldehydes. The substrate scope was expanded to a variety of p-peroxyquinols and 1,2,4- trioxanes, investigating functional group robustness, degree of substitution, and type of substituent. Chapter 5 reports the telescoped synthesis of 2-substituted-1,4-benzoquinones, an important class of compounds with a variety of medicinal properties. The p-peroxyquinols formed through dearomatisation of p-substituted phenols, following the methodology developed in Chapter 3, were converted into 2-substituted-1,4-benzoquinones via acid- catalysed 1,2-alkyl shift of p-peroxyquinols. Optimisation of reaction conditions was initially carried out in batch, and the best conditions were then transferred to the continuous flow system. Several packed bed reactor designs were investigated in order to optimise the reaction yields. Chapters 6 and 7 present studies for the telescoped synthesis of 1,2,4-dioxazinanes and 1,3-oxazolidines, respectively. For both target compounds, an aminalisation/aza-Michael addition step using either a N-sulfinyl imine or N-sulfonyl imine was involved in the process. In Chapter 6, the synthesis of 1,2,4-dioxazinanes was investigated as this scaffold has been shown to have antimalarial activity, but synthetic methodologies to produce these compounds are scarce in the literature. The reaction conditions for both the asymmetric and racemic synthesis of 1,2,4-dioxazinanes were attempted in batch using a p-peroxyquinol and N-sulfonyl/sulfinyl imines previously synthesised. In Chapter 7, a synthetic route was designed for the asymmetric synthesis of 1,3-oxazolidines in four steps starting from the dearomatisation of p-substituted phenols. The reduction of p-peroxyquinols was examined in batch, and subsequent experiments were carried out to make 1,3-oxazolidines from p- quinols and N-sulfinyl imines. In Chapter 8, a summary of the work developed in this Thesis is outlined, highlighting the main findings and challenges in exploring the continuous flow photooxidation of p- substituted phenols in telescoped syntheses. The discussion is guided by the Thesis aims defined in the introduction chapter. Ideas for potential future work are also presented. Author name: Bruna Abreu Millard and Bruna Millar

Model studies of the cub-histidine-tyrosine centre in cytochrome c oxidase

This thesis reports the synthesis and copper coordination chemistry of covalently-linked aryl-imidazole derivatives designed as models for the crosslinked imidazole-phenol sidechains of the His-Tyr cofactor in the CcO. Three new imidazole- (HL1 - HL3) and three new indole- (HL4 - H2L6) containing tripodal ligands were synthesised. The conjugate addition of an imidazole to activated quinone derivatives was developed as a new route to organic models for the Tyr His cofactor. Two monodentate imidazole-aryl, Im-hq(OH)2 and Im-ArOH, and an imidazole-quinone, Im bq were obtained using this route. The X-ray crystal structure of Im-hq(OH)2.EtOH was determined. The route was also used to give new chelating ligands, H2L10 and HL12, containing a cross-linked imidazole-phenol surrogate for the Tyr244-His240 cofactor. Copper complexes of Im-hq(OH)2, Im-bq, Im-ArOH, H2L10-HL12, and HL1-H2L6 were prepared, and the X-ray crystal structures of [Cu(terpy)(Im-bq)][BF4]2 and five other copper complexes were determined. The physiochemical properties of the copper complexes were characterized by FT-IR, UV-Vis-NIR, EPR and (spectro)electrochemical studies. Key results include: the oxidation of Im-ArO- anion affords the semiquinone radical, Im-sq(4OH)(1O�), in a hydrous solvent. However, the oxidations of neutral Im-ArOH and [Cu(tpa)(Im-ArOH)]2+ produce the corresponding phenoxy radical species that rapidly and reversibly dimerise to give quinol cyclohexadienone, QCHD, dimers. Significantly [Cu(tpa)(Im-sq(4OH)(1O�))]2+ was EPR silent, perhaps due to antiferromagnetic coupling between the Cu(II) (S=1/2) and semiquinonyl radical (S=1/2) centres. Deprotonation of the hydroquinone in [Cu(tpa)(Im-hq(OH)2]2+ produces the hydroquinone dianion which reduces the Cu(II) centre. The semiquinone radical is coordinatively labile and dissociates from the Cu(I) centre. The biological implications of these results are mentioned