In the first part of the thesis, the aim was to devise a new simple catalytic system based on palladium to allow insertion of carbon monoxide in the presence of an alcohol into unsaturated systems with retention of the double bond to give an unsaturated ester. The process is known as oxidative carbonylation. To allow the process to become catalytic, the palladium needs to be reoxidised in situ. Optimal conditions for the catalytic system were developed and a wide range of substrates have been examined. Simple terminal alkenes and alkenes bearing functional group have been successfully carbonylated (yield 16%-87%). The method was applied to the synthesis of a known pharmaceutical intermediate. The aim of the second part was to develop an efficient system for the intramolecular oxidative amination of unsaturated hydrazine carboxylates to form novel vinyl oxazolidines. After optimisation of the reaction conditions, the scope and limitations of the reaction were established. Attempts were also carried out to develop an enantioselective version of the cyclisation. The method was applied to the synthesis of a known intermediate in a sequence towards (-)-kainic acid thus accomplishing a formal total synthesis of this compound.

Intracellular protein-protein interactions (PPIs) play a vital role in many biological processes. Although they are viewed as of high biological interest they prove difficult to explore as potential targets for drug discovery. Numerous studies have shown α- helical peptides 'locked' in their respective bioactive structure can greatly increase their performance by increasing their target affinity, resistance to proteolysis as well as facilitating cellular uptake. A striking feature of literature to date is how few studies utilise different stapling techniques when developing inhibitors for PPIs. Current methods generally exploit ruthenium catalysed ring closing metathesis (RCM) or copper catalysed alkyne/azide click (CuAAC) chemistry to generate geometrically constrained peptides. Even though these methods have shown great potential they both share a fundamental limitation as the chemistry can only be employed on small synthetic peptides and cannot be extended to larger proteins. Thiol-ene coupling (TEC) chemistry (Chapter 1) which is often described as a 'click' reaction due to its fast reaction rates, high yields, wide functional group tolerance and insensitivity to ambient oxygen and water has the potential to solve this challenge. Thiol-ene chemistry was investigated as an alternative stapling strategy by employing the naturally occurring amino acid L-cysteine (Cys) as a source of the thiyl radical and L-homoallylglycine (Hag), a non-natural amino acid shown to act as a methionine surrogate in protein synthesis to act as a source of an alkene functionality to form a potentially expressible thioether tether in Chapter 2. However, due to unsatisfactory results from the intramolecular thiol-ene cyclisation at the molar concentrations required for peptide or protein modification, and a promising new lead, the closely related thiol-yne reaction was investigated as an alternative in Chapter 3. Using a small library of peptides (14 mers) derived from α-Synuclein (αSyn), a protein mainly found in the presynaptic terminals in the brain and is believed to be key to the pathological progress of Parkinson's disease, a successful macrocyclisation was achieved between the side chains of cysteine (Cys) and homopropargylglycine (Hpg). Although the vinyl-thioether tether did not confer any helical conformation on the stapled peptides, the results clearly demonstrate a potential route for the development of expressible staples. Electron paramagnetic resonance (EPR) spectroscopy in combination with site-directed spin labelling (SDSL) of biomolecules has become a powerful tool for studying the structure and conformational dynamics of biomolecules. Typically, proteins are modified in a site-specific manner by utilising the side chains of cysteine residues to form disulphide bonds with spin active compounds, however, this strategy has its limitations. In Chapter 3 thiol-ene chemistry was investigated as an alternative biorthogonal method to spin label proteins and peptides. The newly synthesised sulfhydryl bearing nitroxide spin label was found to degrade upon exposure to radical promoting conditions, however, an alternative strategy was explored using more classical thiol-Michael chemistry to spin label dehydroalanine (Dha) modified peptides giving the desired spin labelled complex.

Polymer nanocomposite technology has had significant impact on material design. With the environmental advantages of photopolymerization, a research has recently focused on producing nanocomposites utilizing inexpensive clay particles based on in situ photopolymerization. In this research, novel polymerizable organoclays and thiol-ene photopolymerization have been utilized to develop advanced photopolymer clay nanocomposites and to overcome several limitations in conventional free radical photopolymers. To this end, factors important in nanocomposite processes such as monomer composition, clay dispersion, and photopolymerization behavior in combination with the evolution of ultimate nanocomposite properties have been investigated. For monomer-organoclay compositions, higher chemical compatibility of components induces enhanced clay exfoliation, resulting in photopolymerization rate increases due to an amplified clay template effect. Additionally, by affecting the stoichiometric ratio between thiol and acrylate double bond in the clay gallery, thiolated organoclays enhance thiol-ene copolymerization with increased final thiol conversion while acrylated organoclays encourage acrylate homopolymerization. In accordance with the reaction behavior, incorporation of thiolated organoclays makes polymer chains more flexible with decreased glass transition temperature due to higher formation of thio-ether linkages while adding acrylated organoclays significantly increases the modulus. Photopolymer nanocomposites also help overcome two major drawbacks in conventional free radical photopolymerization, namely severe polymerization shrinkage and oxygen inhibition during polymerization. With addition of a low level of thiol monomers, the oxygen inhibition in various acrylate systems can be overcome by addition of only 5wt% thiolated organoclay. The same amount of polymerizable organoclay also induces up to 90% decreases in the shrinkage stress for acrylate or thiol-acrylate systems. However, nonreactive clays do not reduce the stress substantially and even decreases the polymerization rate in air. Additionally, the clay morphology and polymerization behavior are closely related with evolution of ultimate nanocomposite performance. Use of polymerizable organoclay significantly improves overall toughness of nanocomposites by increasing either modulus or elongation at break based on the type of polymerizable organoclay, which demonstrates the promise of this technology as a modulation and/or optimization tool for nanocomposite properties.

Aim of this thesis was to combine the versatility of sulfur-chemistry, regarding redox-sensitivity as well as chemo- and site-specific conjugation, with multifunctionality of poly(glycidol)s as an alternative to poly(ethylene glycol). First the homo- and copolymerizations of EEGE and AGE were performed with respect to molar-mass distribution and reaction kinetics. A detailed study was given, varying the polymerization parameters such as DP, counter ion, solvent and monomer influence. It can be concluded that in general the rates for all polymerizations are higher using K+, in contrast to Cs+, as counter ion for the active alkoxide species. Unfortunately, K+ as counter ion commonly leads to a reduced control over polymer dispersity. In this thesis it was shown that the broad molar-mass distributions might be reduced by adding the monomer in a step-wise manner. In experiments with a syringe pump, for continuously adding the monomer, a significant reduction of the dispersities could be found using K+ as counter ion. In analogy to the oxyanionic polymerization of epoxides, the polymerization of episulfides via a thioanionic mechanism with various DPs was successful with thiols/DBU as initiator. In most experiments bimodality could be observed due to the dimerization, caused by oxidation processes by introduced oxygen during synthesis. Reducing this was successful by modifying the degassing procedure, e.g. repeated degassing cycles after each step, i.e. initiation, monomer addition and quenching. Unfortunately, it was not always possible to completely avoid the dimerization due to oxidation. Thiophenol, butanethiol, mercaptoethanol and dithiothreitol were used as thiol initiators, all being capable to initiate the polymerization. With the prediction and the narrow molar-mass distributions, the living character of the polymerization is therefore indicated. Homo- and copolymers of poly(glycidol) were used to functionalize these polymers with side-chains bearing amines, thiols, carboxylic acids and cysteines. The cysteine side-chains were obtained using a newly synthesized thiol-functional thiazolidine. For this, cysteine was protected using a condensation reaction with acetone yielding a dimethyl-substituted thiazolidine. Protection of the ring-amine was obtained via a mixed-anhydride route using formic acid and acetic anhydride. The carboxylic acid of 2,2-dimethylthiazolidine-4-carboxylic acid was activated with CDI and cysteamine attached. The obtained crystalline mercaptothiazolidine was subjected to thiol-ene click chemistry with allyl-functional poly(glycidol). A systematic comparison of thermal- versus photo-initiation showed a much higher yield and reaction rate for the UV-light mediated thiol-ene synthesis with DMPA as photo-initiator. Hydrolysis of the protected thiazolidine-functionalities was obtained upon heating the samples for 5 d at 70 °C in 0.1 M HCl. Dialysis against acetic acid lead to cysteine-functional poly(glycidol)s, storable as the acetate salt even under non-inert atmosphere. An oxidative TNBSA assay was developed to quantify the cysteine-content without the influence of the thiol-functionality. A cooperation partner coupled C-terminal thioester peptides with the cysteine-functional poly(glycidol)s and showed the good accessibility and reactivity of the cysteines along the backbone. SDS-PAGE, HPLC and MALDI-ToF measurements confirmed the successful coupling. / Ziel der Arbeit war es die Vielseitigkeit der Schwefelchemie, hinsichtlich der Redoxsensitivität und chemo- und seitenspezifischer Konjugation, mit der Funktionalisierbarkeit von Poly(glycidol)en, als multifunktionale PEG-Alternative zu kombinieren. Zunächst wurden die Homo- und Copolymerisationen von EEGE und AGE hinsichtlich der Molmassenverteilung und der Reaktionskinetik untersucht. Durch die Variation der Polymerisationsparameter, wie angestrebter Polymerisationsgrad, Gegenion, Lösungsmittel und Monomer, wurde der Einfluss dieser untersucht. Allgemein konnte gezeigt werden, dass die Polymerisationen schneller ablaufen, wenn K+, im Gegensatz zu Cs+, als Gegenion zum aktiven Alkoxidkettenende verwendet wird. Nachteilig bei der Verwendung von K+ als Gegenion ist der Kontrollverlust der Polymerisation, welcher mit einer Erhöhung der Dispersität einhergeht. Es konnte gezeigt werden, dass die Breite der Molmassenverteilung durch die Geschwindigkeit der Monomerzugabe kontrolliert werden kann. Tatsächlich konnte die Dispersität durch die Verwendung einer Spritzenpumpe verbessert werden, da das Monomer mit einer konstanten angepassten Flussrate hinzugefügt wurde. Analog zur oxyanionischen Polymerisation von Epoxiden, war die Polymerisation von Episulfiden mittels thioanionischer Polymerisation ebenfalls möglich. Hierzu wurden verschiedene Polymerisationsgrade von EETGE und ATGE angestrebt und mittels Thiol/DBU als Initiator auch erreicht. In den meisten Fällen war jedoch eine Dimerisierung der Polymere zu beobachten, welche durch die Oxidation der aktiven Thiolatspezies verursacht wurde. Eine Möglichkeit zur Dimerisierungsunterdrückung war die wiederholte Durchführung von Entgasungszyklen nach jedem Arbeitsschritt, z.B. nach Zugabe des Initiators, des Monomers oder nach dem Quenchen. Trotz dieses experimentellen Aufwandes konnte nicht immer ein vollständiger Ausschluss der Dimerisierung erreicht werden. Thiophenol, Butanthiol, Mercaptoethanol und Dithiothreitol wurden als Thiolinitiatoren (in Kombination mit DBU) verwendet und waren alle in der Lage die Polymerisation zu starten. Die Kontrolle des Polymerisationsgrades und die enge Molmassenverteilung der Polymere verdeutlichen, dass die thioanionische Polymerisation ebenfalls lebend verläuft. Glycidol Homo- und Copolymere wurden verwendet und die Seitenketten mit Amin-, Thiol-, Carbonsäure- und Cysteingruppen funktionalisiert. Die Cysteinseitenketten wurden durch ein neues thiolfunktionales Thiazolidin erhalten. Ausgehend von Cystein und Aceton wurde zunächst das Dimethyl-substituierte Thiazolidin erhalten, welches daraufhin am Ring-Amin mit Essigsäureanhydrid und Ameisensäure formyliert wurde. Die Carbonsäurefunktion des Thiazolidins wurde mittels CDI aktiviert und anschließend mit Cysteamin umgesetzt. Hierbei bildete sich das niedermolekulare kristalline thiolfunktionale Thiazolidin, welches mittels Thiol-En-Click Chemie an allyl-funktionales Poly(glycidol) geknüpft werden konnte. Eine systematische Untersuchungen der thermischen und UV-induzierten Thiol-En-Click Chemie zeigte, dass wesentlich höhere Umsätze und Geschwindigkeiten bei der photoinduzierten Reaktion erhalten werden. Mittels 0.1 M HCl konnte bei 70 °C innerhalb von 5 d die Hydrolyse der Thiazolidine im Anschluss erreicht werden. Nach der anschließenden Dialyse der Polymere gegen 0.1 M Essigsäure wurde erfolgreich das Acetatsalz der cysteine-funktionalen Poly(glycidol)e erhalten. Diese waren hinsichtlich der Thioloxidation unter atmosphärischen Bedingungen stabil. Ein oxidativer TNSBA-Assay wurde entwickelt, um die Menge der Cysteine zu quantifizieren und gleichzeitig den störenden Einfluss der Thiole zu unterbinden. Ein Kooperationspartner setzte die cysteinfunktionalisierten Poly(glycidol)e mit C-terminalen Thioestern um und konnte die gute Zugänglichkeit und Aktivität der Cysteine entlang des Polymerrückgrats nachweisen. SDS-PAGE, HPLC und MALDI-ToF Messungen bestätigten die erfolgreiche Konjugation im Anschluss.

The research presented herein explores three aspects of asymmetric catalysis: (1) the development of new catalytic enantioselective reactions, (2) the application of stereoselective catalysis to natural product total synthesis, and (3) the design and synthesis of new chiral catalysts. / Chemistry and Chemical Biology

Advancements in the biomedical field are driven by the design of novel materials with controlled physical and bio-interactive properties. To develop such materials, researchers rely on the use of highly efficient reactions for the assembly of advanced polymeric scaffolds that meet the demands of a functional biomaterial. In this thesis two main strategies for such materials have been explored; these include the use of off-stoichiometric thiol-ene networks and dendritic polymer scaffolds. In the first case, the highly efficient UV-induced thiol-ene coupling (TEC) reaction was used to create crosslinked polymeric networks with a predetermined and tunable excess of thiol or ene functionality. These materials rely on the use of readily available commercial monomers. By adopting standard molding techniques and simple TEC surface modifications, patterned surfaces with tunable hydrophobicity could be obtained. Moreover, these materials are shown to have great potential for rapid prototyping of microfluidic devices. In the second case, dendritic polymer scaffolds were evaluated for their ability to increase surface interactions and produce functional 3D networks. More specifically, a self-assembled dendritic monolayer approach was explored for producing highly functional dendronized surfaces with specific interactions towards pathogenic E. coli bacteria. Furthermore, a library of heterofunctional dendritic scaffolds, with a controllable and exact number of dual-purpose azide and ene functional groups, has been synthesized. These scaffolds were explored for the production of cell interactive hydrogels and primers for bone adhesive implants. Dendritic hydrogels decorated with a selection of bio-relevant moieties and with Young’s moduli in the same range as several body tissues could be produced by facile UV-induced TEC crosslinking. These gels showed low cytotoxic response and relatively rapid rates of degradation when cultured with normal human dermal fibroblast cells. When used as primers for bone adhesive patches, heterofunctional dendrimers with high azide-group content led to a significant increase in the adhesion between a UV-cured hydrophobic matrix and the wet bone surface (compared to patches without primers). / <p>QC 20140116</p>

SUMMARY The moenomycin-type compounds are known to inhibit selectively the enzyme penicillin binding protein 1b (PBP 1b) that catalyses the transglycosylation reaction in the biosynthesis of bacterial cell wall peptidoglycan. The moenomycins (see moenomycin A12) have been shown to interfere with this biosynthetic step interacting with the enzyme(s). The moenomycins do not induce resistance readily. A weak point in this respect may, however, be the phosphate bond to unit F. Its cleavage by a yet poorly characterized enzyme is the only enzymatic degradation reaction of the moenomycins that is known to-date. With this in mind we started a programme aimed at synthesizing trisaccharide analogues of moenomycin A12 in which the phosphate oxygen at C-1 of unit F is replaced by a CH2 group. It seemed important to retain all other functional groups in ring F as present in moenomycin since they are known to be of major importance as far as antibiotic activity is concerned. It appeared that the commercially available and cheap b-D-galactose-pentaacetate 30 would be an interesting starting material for this synthesis. In this work, the synthesis began with the introduction of the C-glycoside appendage at position 1 according to Giannis et al., thus forming the allyl C-galactopyranoside 34, a substance that represents the first C-glycosyl backbone for the synthesis of the glycosyl acceptors. The total synthesis of the glycosyl acceptors is shown in Scheme 6.1. We wanted to convert the C-allyl glycoside 34 into its propenyl analogue. Attempts to achieve this with singlet oxygen and palladium-mediated reaction proved fruitless. On the other hand, ene reaction of 34 with 4-phenyltriazolin-3,5-dione in CH2Cl2 provided 56 in 83 % yield. Ozonolysis of this alkene (-70 °C, MeOH-CH2Cl2) and subsequent quenching with dimethyl sulfide, followed by reduction of the crude aldehyde with sodium acetoxyborohydride (prepared from NaBH4 and AcOH in THF) furnished the primary alcohol 35 (85 %). This alcohol was converted into the mesylate 60 (60 %), and this in turn into the bromide 61 (80 %) by heating it at 80 °C with tetrabutylammonium bromide in toluene. The acetate groups were hydrolysed using Zemplén conditions to furnish 62 quantitatively. The primary hydroxyl group in 62 was protected as a tBuPh2Si ether 63 (85 %) on reaction with TBDPSCl in DMF at 0 °C, and as a tBuMe2Si ether 94 (87 %) on reaction with TBDMSCl in DMF at 0 °C in the presence of imidazole. PTScatalysed isopropylidenation of the 3,4-diols 63 and 94 with 2,2-dimethoxypropane in dry acetone gave the 3,4-O-acetonide derivatives 53 (88 %) and 95 (90 %), respectively. On the other hand, the glycosyl acceptor 53 was converted into the glycosyl acceptor 92. The free hydroxyl group in compound 53 was protected as an acetate group on reaction with acetic anhydride in pyridine in the presence of DMAP giving 89 (88 %). The silyl ether in 89 was cleaved with a molar solution of TBAF in THF affording compound 90 in 87 % yield. The free hydroxyl group in 90 was then subjected to an oxidation using the TEMPO method affording the aldehyde which was in turn oxidised with sodium chlorite to the corresponding acid. The acid was converted to the amide 91, making use of Staab's method, in which the acid was activated with CDI in dichloromethane to give the imidazolide, which upon reaction with ammonia furnished the amide 91 in an overall yield of 95 %. The required glycosyl acceptor 92 was obtained in quantitative yield by cleavage of the ester bond at position 5 under Zemplén conditions. Disaccharide formation was achieved employing the Jacquinet and Blatter method, which involves the use of glycosyl donor 67 and TMSOTf. No reaction was observed between this donor and acceptor 92, which may reflect the low nucleophilicity of the acceptor. On the contrary, glycosylation with acceptor 53 gave 68 (79 %). Deprotection of the silyl group in the disaccharide 68 was easily accomplished on treatment with a molar solution of TBAF in THF at RT affording 71 (89 %). Synthesis of the uronamide 72 was achieved after three major steps, in an overall yield of 98 %. Oxidation of the primary hydroxyl group in unit F to the corresponding aldehyde was accomplished with sodium hypochlorite and TEMPO. Oxidation of the crude aldehyde to the carboxylic acid with sodium chlorite followed by amide formation according to Staab gave 72. Removal of the isopropylidene group from 72 with trifluoroacetic acid (TFA) at RT furnished the diol 73 (89 %). Introduction of the carbamoyl group at C-4F position was achieved in two steps. Conversion of the diol 73 into the cyclic carbonate 76 with CDI in CH2Cl2 (84 %) and subsequent ring opening of this carbonate by bubbling a stream of gaseous ammonia into the CH2Cl2 solution at 0 °C gave 74 (62 %) as well as its isomer 77 (21 %). Dehalogenation of the N-trichloroacetyl group was intensively studied, but interactions of other functional groups in the studied substances could not be avoided. The base-labile carbonate in 76 and the carbamoyl group in urethane 74 were cleaved under the reaction conditions. Hydrolysis of 76 with 0.5 M LiOH in MeOH-THF (1:1) followed by acetylation gave 80 (73 %), while its reduction with NaBH4 in ethanol followed by acetylation gave 82 (60 °C, 85 %; RT, 83 %). On the other hand, reduction of 74 with NaBH4 in ethanol at 60 °C followed by acetylation gave 82 (78 %), while performing the reduction step at 5 °C (THF-MeOH 4:1) or at RT (ethanol or isopropanol) gave 80 in an average yield of 65 %. In a non reproducible reaction (NaBH4, EtOH, RT, then Ac2O, pyridine, RT), the desired compound 83 (42 %) was obtained accompanied by 82 (46 %) The reaction between the N-trichloroacetyl group and NaBH3CN was also fruitless. The phosphonate grouping was installed making use of Arbuzov reaction furnishing 85 (70 %). Trisaccharides could not be obtained from the oxazoline donor 42 (prepared from chitobiose octaacetate 86) through its reaction with acceptor 53. There was also no coupling product between the recently synthesized donor 88 and the acceptor 92. However, in this work, trisaccharide formation was achieved through the glycosylation reaction of donor 88 and acceptor 95 in 50 % yield (-30 °C, 1,2-dichloroethane, 3 Å, TMSOTf-TEA). Selective deprotection of the TBDMS group in compound 96 was accomplished at -10 °C with 1 eq of a molar solution of TBAF in THF. The free hydroxyl group of 97 was subjected to an oxidation using the TEMPO method affording the aldehyde. After oxidation of the aldehyde with sodium chlorite, the resulting carboxylic acid was converted according to Staab's method into the amide 93 in an overall yield of 95 % (based on 96). There were difficulties in converting the N-phthalimido group in 93 to the N-acetyl group which is necessary for biological activity of moenomycin-type compounds, since the reactions were accompanied by elimination of HBr. In conclusion, the synthetic methods employed in this work allow to prepare the di- and trisaccharides C-phosphonate analogues of moenomycin A12. / Synthese von Phosphonat-Analoga des Antibiotikums Moenomycin A12 Universität Leipzig, Dissertation Diese Arbeit enthält 130 Seiten, 73 Abbildungen, 1 Tabelle, 156 Literaturangaben Referat: Im Rahmen der vorliegenden Arbeit wurden C-Glycosid-Di- und Trisaccharid-Bausteine des Antibiotikums Moenomycin A12 ausgehend von b-D-Galactose-pentaacetat hergestellt. Das Ausgangmaterial wurde in D-Galactoheptonamid übergeführt. Die Einheit F des Disaccharidbausteins hat alle Substituenten, die die Einheit F des Moenomycins A12 hat. Der ausgearbeitete Syntheseweg sollte zur Synthese anderer Analoga geeignet sein.

Thesis advisor: Masayuki Wasa / Thesis advisor: Amir H. Hoveyda / This dissertation describes the development of cooperative catalyst systems that contain an achiral Lewis acid and a chiral Lewis acid that may have overlapping functions but play their independent roles to promote enantioselective C–C bond formations. Chapter 1 provides a summary of recent advances made in the field of enantioselective cooperative catalysis that served as intellectual foundations for this dissertation research. As it will be discussed in the first chapter, key limitations of cooperative catalysis are: (1) undesirable catalyst deactivation which occurs due to acid/base complexation, (2) requirement for base sensitive pronucleophiles and acid sensitive electrophiles, and (3) poor reaction efficiency. In an effort to overcome these fundamental limitations, we have developed “frustrated” Lewis pair (FLP)-based catalyst systems that consist of potent and sterically encumbered Lewis acids used in pair with bulky N-containing Lewis bases. To demonstrate the potential of the novel FLP catalyst system, we describe our work involving the enantioselective Conia-ene-type cyclization (Chapter 2). In the subsequent chapter (Chapter 3), we discuss the application of the FLP catalysts for enantioselective β-amino C–H functionalization reactions. / Thesis (PhD) — Boston College, 2021. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

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