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Thesis advisor: Amir H. Hoveyda / Chapter One: Development of a New Catalytic Click Reaction Involving Nitriles and Allenes (CuPDF)Catalytic click reactions, although small in number, have made a profound impact on chemistry research, including the fields of drug discovery, biological chemistry, and materials science. What is much needed are additional catalytic reactions that bring about the union of commonly occurring and robust functional groups, are mutually orthogonal to those that exist and offer a function other than connecting two fragments. We have developed a catalytic click process that connects a nitrile and a monosubstituted allene in the presence of commercially available B2(pin)2 and a readily accessible Cu(I) complex. The modification stage involves alkene isomerization by base and condensation with a hydrazine and both processes are performed in situ. The resulting linkages contain a robust diazaborinine that is fluorescent. We demonstrate that the click process, which we have named copper(I)-catalyzed phenoxydiazaborinine formation (CuPDF) is mutually orthogonal to copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) as well as sulfur-fluorine exchange (SuFEx). These click reactions can therefore be used for efficient synthesis of sequence-defined oligomers that may contain modifiable linkages and peptide-drug conjugates. For applications in aqueous media, we have also developed, copper(I)- and palladium-catalyzed quinoline formation (Cu/PdQNF). These latter processes generate fluorescent connectors as well. Chapter Two: Development of a Catalytic Click Reaction Involving Ketones and Allenes (CuAKA) We have developed another click reaction, this time bringing about the union of a ketone and, similar to CuPDF, a monosubstituted allene and B2(pin)2. We label this click reaction copper(I)-catalyzed allene–ketone addition or CuAKA. As a consequence of shared reactants, identifying catalysts that would allow CuAKA and CuPDF to be mutually orthogonal was at the center of our investigations. Our studies resulted in the identification of copper(I) complexes that can be used to perform a click reaction on a nitrile or a ketone. Furthermore, we found that mutual orthogonality can be achieved between CuAKA and CuAAC using an amino phosphine–Cu(I) catalyst. Computational and kinetics studies were performed that shed light on the origins of catalyst-controlled chemoselectivity. Importantly, similar to CuPDF, CuAKA can be performed in aqueous media. Chapter Three: Preparation of Multi-drug Conjugates with Mutually Orthogonal Click Reactions We show that with CuAAC, CuPDF and CuAKA, three mutually orthogonal click processes can be efficiently merged to assemble complex molecules efficiently with no protection/deprotection needed. With CuAKA, similar to CuAAC and CuPDF, being also orthogonal to SuFEx, a four-armed core molecule may be used in a similar fashion. A central finding in this part of study was the discovery that CuAKA, similar to CuAAC but unlike CuPDF, can be used to link molecules that contain acidic protons, such as phenol or a carboxylic acid moieties. Chapter Four: Controlled Rupture of CuAKA-Generated Linkages A distinct attribute of CuAKA is that it forms a linkage that is cleavable under mild aqueous oxidative conditions. We show that the tertiary hydroxy group accelerates the oxidation of the nearby C–B bond within the connector to generate a -hydroxy ketone that undergoes a retro-aldol reaction to effect rupture. We show that an aryl linker between the ketone and the carrier molecule, such a bile acid or a cell-penetrating peptide (CPP) may be used to achieve the steric and electronic parameters that are needed for optimal clicking and clipping rates. To demonstrate applicability, we used CuAKA was used for efficient linking of camptothecin, an anti-cancer agent with low selectivity, to a ketone attached to unprotected penetratin, a CPP. The ensuing release of the payload proceeded readily in a 68 mM aqueous solution of hydrogen peroxide at 37 °C with control experiments indicating that a proximal lysine residue accelerates the retro-aldol reaction. / Thesis (PhD) — Boston College, 2024. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

This thesis is concerned with the asymmetric conjugate addition reactions of a range of chiral nucloeophiles. Chapter 1 introduces the conjugate addition reaction as a valuable carbon-carbon and carbon-heteroatom bond forming reaction in organic chemistry, and explores the asymmet- ric conjugate addition of a range of chiral and achiral carbon and nitrogen nucleophiles to a range of acceptors. Chapter 2 explores the use of the N-benzyl-N-(α-methylbenzyl)amino group as a chi- ral auxiliary, by employing the attempted conjugate additions of both N-benzyl-N-(α- methylbenzyl)hydrazine and N -benzyl-N -(α-methylbenzyl)hydroxylamine as chiral ammo- nia and water equivalents respectively. Chapter 3 describes the asymmetric and stereoselective preparation of a range of 4,4- disubstituted isoxazolidin-5-ones from the conjugate addition of lithium (S)-N-tert-butyl- dimethylsilyloxy-N -(α-methylbenzyl)amide. The isoxazolidin-5-ones are then globally de- protected via hydrogenolysis, giving rise to the corresponding β^2,2,3-amino acids. Chapter 4 focuses on the development of a protocol to effect the conjugate addition of a chiral aniline equivalent. The scope of the reaction is delineated by varying both the nu- cleophile and the α,β-unsaturated ester. Finally, cyclisation of the β-N-arylamino esters to the corresponding tetrahydroquinolines is explored, and an application to the synthesis of the natural product (−)-angustureine is presented. Chapter 5 contains full experimental procedures and characterisation data for all com- pounds synthesised in Chapters 2, 3 and 4.

<p>2,6-Disubstituted spiro[3.3]heptanes were synthesized to investigate and develop synthetic methods for preparation of these compounds. Possibilities for introducing different functionalities like nitriles and sulfonamides were also investigated.</p><p> </p><p>Synthetic routes presented describe successive [2+2] cycloadditions between dichloroketene and olefins to give the sought after spiro compounds with low to moderate yields throughout the multi-step synthesis. [2+2] Cycloadditions offered low turnovers and chromatography was required for purification.</p><p> </p><p>A synthetic route with cyclisations through double substitution reactions between di-electrophiles and di-nucleophiles resulting in a 2,6-disubstituted spiro[3.3]heptane is also described. This multi-step synthesis offered higher turnover and yields and often there was no need for purification through chromatography.</p>

During infections, bacterial microorganisms initiate profound interactions with mammalian host cells. Usually defense mechanisms of the host destroy intruding bacteria in rapid manner. However, many bacterial pathogens have evolved in a way to avoid these mechanisms. By use of effector molecules, which can be small organic molecules or proteins with enzymatic activity, the host is manipulated on a molecular level. Effectors mediating post-translational modifications (PTMs) are employed by many pathogens to influence the biological activity of host proteins. In the presented thesis, two related PTMs are investigated in detail: Adenylylation, the covalent transfer of an adenosine monophosphate group from adenosine triphosphate onto proteins, and phosphocholination, the covalent transfer of a phosphocholine moiety onto proteins. Over the past years, enzymes mediating these modifications have been discovered in several pathogens, especially as a mechanism to influence the signaling of eukaryotic cells by adenylylating or phosphocholinating small GTPases. However, the development of reliable methods for the isolation and identification of adenylylated and phosphocholinated proteins remains a vehement challenge in this field of research. This thesis presents general procedures for the synthesis of peptides carrying adenylylated or phosphocholinated tyrosine, threonine and serine residues. From the resulting peptides, mono-selective polyclonal antibodies against adenylylated tyrosine and threonine have been raised. The antibodies were used as tools for proteomic research to isolate unknown substrates of adenylyl transferases from eukaryotic cells. Mass spectrometric fragmentation techniques have been investigated to ease the identification of adenylylated proteins. Furthermore, this work presents a new strategy to identify adenylylated proteins. Additionally, small effector molecules are involved in the regulation of infection mechanisms. In this work, the small molecule LAI-1 (Legionella autoinducer 1) from the pathogen Legionella pneumophila, the causative agent of the Legionnaire’s disease, was synthesised together with its amino-derivatives. LAI-1 showed are a clear pharmacological effect on the regulation of the life cycle of L. pneumophila, initiating transmissive traits like motility and virulence. Furthermore, LAI-1 was shown to have an effect on eukaryotic cells as well. Directed motility of the eukaryotic cells was significantly reduced and the cytoskeletal architecture was reorganised, probably by interfering with the small GTPase Cdc42.

The research presented in this study demonstrates the critical role that organic synthesis plays in natural product chemistry. The biological activity demonstrated by 2-methyl-6-(3-methyl-2- butenyl)benzo-1,4-quinone prompted an investigation into the synthesis of this compound. This natural product showed significant activity against Staphylococcus epidermidis. Therefore the aim of this study was to synthesise 2-methyl-6-(3-methyl-2-butenyl)benzo-1,4- quinone and structural analogues. The regioselective synthetic route formulated for the synthesis of 2-methyl-6-(3-methyl-2- butenyl)benzo-1,4-quinone involved five steps. Different strategies towards the synthesis of this compound were investigated. The regioselective C-alkylation step was proving to be the most challenging. The synthetic strategies investigated included carbon alkylation of a phenoxide, directed-o-metallation, metal-halogen exchange and copper(II) Grignard-type metal halogen exchange. Problems were encountered with regioselectivity when carbon alkylation of a phenoxide was employed for the o-prenylation of o-cresol. The C-prenylated isomer was formed along with the O-prenylated isomer. When the reaction temperature was lowered, the yield of the desired C-prenylated isomer improved, whereas the yield of O-prenylated isomer declined. Although the reaction was performed under different conditions, the formation of the O-prenylated isomer could not be prevented. Therefore, another synthetic strategy was considered. The directed-o-metallation reaction was subsequently employed because of the associated regioselectivity. Unfortunately the desired product was not obtained when this method was employed. The reaction was attempted using different conditions, but the product could not be isolated. Since the directed-o-metallation protocol did not yield the desired results, another method was considered. Therefore, a metal-halogen exchange reaction was employed. The metal-halogen exchange transformation was preceded by the preparation of the o-brominated precursor. Regioselectivity-related problems were initially encountered during the synthesis of the obrominated precursor. The o-brominated isomer was formed in a 1:1 ratio with the pbrominated isomer. Further investigation led to a synthetic protocol that afforded the desired o-brominated isomer in a better yield. The metal-halogen exchange transformation was subsequently attempted, but the product was obtained in an unsatisfactory yield. Therefore, another method was employed in an effort to achieve regioselective C-alkylation with a better yield. Copper(II) Grignard-type metal-halogen exchange was successfully employed to achieve regioselective C-alkylation in good yield. The subsequent step was the deprotection, although problems were encountered, it was eventually achieved. The final step was the oxidation to obtain the desired compound, 2-methyl-6-(3-methyl-2-butenyl)benzo-1,4- quinone. The same procedure was successfully applied in the synthesis of structural analogues 2-isopentyl-6-methylbenzo-1,4-quinone, 2-(3,7-dimethylocta-2,6-dienyl)-6-methyl-1,4- benzoquinone and 2-(3,7-dimethyl-octyl)-6-methyl-1,4-benzoquinone. / Thesis (M.Sc.)-University of KwaZulu-Natal, Pietermaritzburg, 2010.

This thesis is concerned with investigations into applications of double asymmetric induction and parallel kinetic resolution in asymmetric synthesis. Chapter 1 introduces enantiorecognition phenomena as a significant field in asymmetric synthesis. The main approaches in this field are described: double asymmetric induction, kinetic resolution, parallel kinetic resolution and dynamic kinetic resolution. Chapter 2 describes investigations into the use of double asymmetric induction as a mechanistic probe to elucidate the reactive conformation of enantiopure α,β-unsaturated esters (derived from Corey’s 8-phenylmenthol auxiliary) and hydroxamates [derived from (S)-N-1-(1'-naphthyl)ethyl-O-tert-butylhydroxylamine] upon conjugate addition. Chapter 3 describes investigations into the doubly diastereoselective organocatalytic intramolecular Michael cyclization of enantiopure enamides (derived from a 4-substituted-5,5-dimethyl-oxazolidin-2-one auxiliary) and α,β-unsaturated esters (derived from Corey’s 8-phenylmenthol auxiliary) using α-methylbenzylamine and its derivatives as the chiral catalysts. Chapter 4 describes investigations into parallel kinetic resolution of acyclic γ-amino-α,β-unsaturated esters utilising a 50:50 pseudoenantiomeric mixture of lithium amides. To highlight the synthetic utility of the resultant β,γ-diamino esters, their elaboration to a range of 5-substituted-4-amino-pyrrolidin-2-ones is demonstrated and a concise synthesis of natural product (±)-absouline is performed. Chapter 5 contains full experimental procedures and characterisation data for all compounds synthesised in chapters 2, 3 and 4.

The main electrophilic source used in radiolabelling is [18F]F2, which is highly reactive, toxic and requires specialist equipment for safe handling. The Gouverneur group has initiated a research programme focused on the preparation of new stable and easy-to-handle N-18F reagents. In the development of [18F]radiolabelling reactions it would be extremely valuable to develop a library of selective N-18F reagents possessing reactivity tailored to the desired chemical transformation. The aim of this thesis is to further assess the scope of electrophilic N- 18F reagents in new transformations for the construction of C-18F bonds.

This thesis documents the development of novel synthetic methodologies for the incorporation of sulfur dioxide into organic molecules employing the amine-sulfur dioxide complex DABSO (vide infra). These developed processes serve to access a range of sulfonyl-containing (-SO₂-) compounds including sulfones and sulfonamides, via sulfinic acid precursors. <b>Chapter 1</b> provides an overview of the synthesis and applications of sulfonyl-containing compounds and the organic chemistry of sulfur dioxide. A comprehensive introduction to the developed uses of sulfur dioxide surrogates in organic chemistry is given. The synthetic utility of metal sulfinates towards accessing sulfonyl-containing compounds is also discussed. <b>Chapter 2</b> details the development of a one-pot sulfone synthesis via metal sulfinates generated from organometallic reagents and DABSO. Alkyl, alkenyl and (hetero)aryl sulfinates prepared from organolithium and Grignard reagents can be efficiently coupled with a range of electrophiles to access a range of products including diaryl, aryl-heteroaryl and &beta;-hydroxy sulfones. <b>Chapter 3</b> describes an array-compatible, one-pot sulfonamide synthesis employing metal sulfinates and N-chloroamines as in situ-generated intermediates. This employs DABSO and sodium hypochlorite (bleach) as simple reagents and organolithium, organozinc and Grignard reagents along with amines as readily-accessible building blocks. The robust nature of this methodology and its potential application in discovery chemistry is demonstrated with a 65-compound array synthesis. <b>Chapter 4</b> documents the development of a palladium-catalysed sulfination reaction of boronic acids to access a range of sulfonyl-containing compounds. This involved the establishment of a one-pot/one step synthesis of sulfones leading to the discovery of a redox-neutral, ligand-free sulfination procedure using DABSO and palladium(II) catalysis. Sulfinic acid derivatives can be generated and subsequently trapped in situ with a variety of electrophiles to furnish sulfones and sulfonamides. <b>Chapter 5</b> summarises the research and the potential future work. <b>Chapter 6</b> provides experimental details and data.

Small molecule synthesis has become a valuable tool in the study of biological systems. Biologically active compounds can be designed based on well-characterized endogenous systems or they can be found through the screening of large libraries of small molecules. This work involves the development of a small library of cyclic thiourea-based small molecules by use of an unreported synthetic pathway. Briefly, parent thioureas were cyclized by reaction with bromoacetyl bromide, and one or two isomeric heterocycles were found to form. Further studies indicated that the reaction could be easily manipulated by temperature or solvent to effectively control the product distribution. These iminothiozolidinones were characterized by single crystal x-ray analysis. The new reaction was explored in an effort to uncover the factors influencing the control of the isomer formation. Furthermore, these iminothiozolidinones underwent a novel decyclization reaction that resulted in the loss of the parent thiourea connectivity and incorporation of an external nucleophile to yield an aminooxoethylcarbamothionate. The reaction proceeds through a termolecular mechanism. These reactions can be combined to a one-pot reaction series. These compounds share similarities with a class of compounds reported to be known HIV-1 reverse transcriptase inhibitors94. In addition to these new synthetic reactions, work was conducted with a previously developed cyclen thiourea receptor for the anionic dye HPTS and its derivatives50-52. This system was used to develop a cell labeling assay that led to the amplification of fluorescent labeling of target cells through the use of liposomes. Briefly, a dye-ligand conjugate for the glycine receptor was synthesized. Liposomes functionalized with the cyclen receptor were prepared encapsulating Rhodamine B. Confocal microscopy studies demonstrated the binding of the HPTS-ligand to the cell membranes. Addition of the liposomes resulted in quenching of the green fluorescence, indicating binding of the cyclen to HPTS. Subsequent excitation of Rhodamine B showed red fluorescence associated with the cells. The intensity of the red signal was demonstrably higher than for the signal resulting from the binding of the ligand-dye to the receptor. Together, these projects increase the synthetic usefulness of thiourea based small molecules and demonstrate the potential biological applications of related compounds.