Copolymers that contain terminal or pendent functional groups have great potential in the biomedical area due to their biocompatibility and tunable properties.1-3 In this research, two vinyl functional epoxides, vinyldimethylsilylpropyl glycidyl ether (VSiGE) and ethoxy vinyl glycidyl ether (EVGE), were synthesized. These heterobifunctional monomers were polymerizable via the epoxide groups and can be functionalized via thiol-ene reactions through the pendent vinyl groups. A series of amphiphilic block copolyethers based on poly(ethylene oxide) and poly(1,2-butylene oxide) that incorporate VSiGE or EVGE were synthesized and characterized. The vinyl ether and vinyl silane functional groups were functionalized after polymerization and the functional polymers formed pH-sensitive micelles in aqueous medium. The copolyethers were loaded with ritonavir yielding well-controlled nanoparticles. Poly(L-glutamic acid) is comprised of naturally occurring L-glutamic acid repeating units that are linked together with amide bonds. In this research, we have prepared magnetic block ionomer complexes based on poly(ethylene oxide)-b-poly(L-glutamic acid) copolymers. This is of interest due to the biocompatibility and biodegradable nature of the poly(L-glutamic acid) component of the backbone. Allyl- and thiol-functional poly(ethylene oxide)-b-poly(L-glutamic acid) copolymers were also synthesized and coated onto the surface of iron oxide nanoparticles. Allyl- and thiol-tipped single particles were reacted with each other to prepare magnetic clusters. Transverse relaxivities of the clusters were found to be significantly higher than that of single particles. One major problem in commercial development of therapeutic proteins is their poor transport across cellular membranes and biological barriers such as the blood-brain barrier (BBB). One solution to this problem is to modify proteins with amphiphilic block copolymers such as PEO-b-PPO-b-PEO, Pluronics®. However, it isn't possible to independently tune the two PEO block lengths with commercial Pluronics® since a difunctional PPO macroinitator is utilized to grow both PEO blocks simultaneously (HO-EOn-b-POm-b-EOn-OH). Another challenge is introducing functional group which allows post-polymerization functionalization for specific applications. In this study, a series of heterobifunctional asymmetric amino-EOn1-b-POm-b-EOn2-OH block copolymers (APs) with different molecular weights of each block were synthesized and the amino terminal group was conjugated to an antioxidant enzyme, Cu/Zn superoxide dismutase (SOD1). The conjugates were characterized and their cellular uptake was investigated. / Ph. D.

Azaspiracid-1, a novel marine toxin that contains 9 rings and 20 stereogenic centers, has drawn considerable attention from synthetic groups worldwide due to its structural complexity, which includes a unique trioxabisspiroketal fused to a tetrahydrofuran ring (ABCD rings), a piperidine-tetrahydrofuran spiroaminal system fused to a 2,9-dioxabicyclo[3.3.1]nonane system (FGHI rings), a connecting six-membered cyclic hemiketal bridge (E ring) and a ��,��-unsaturated terminal carboxylic acid side chain. Our efforts toward the total synthesis of azaspiracid-1 led to the completion of both C1-C26 northern and C27-C40 southern halves of azaspiracid-1. Herein, our improved and scalable synthetic studies toward the total synthesis of azaspiracid-1 is described. In particular, an improved and scalable synthesis of sulfone 3.6 with a key one-pot ketalization and methylation of ketone 3.22 to methylated hemiketal 3.24 is illustrated. A total 19 mmol of sulfone 3.6 has been prepared by this approach. An improved and scalable synthesis of aldehyde 3.7 utilizing allyl bromide 3.31 to couple with Evans auxiliary 3.33 has been developed. A total of 10 mmol of aldehyde 3.7 has been prepared by this approach. An improved synthesis toward the ABC ring fragment 3.52 with a high yield Julia coupling step is shown. Large scale improved syntheses of the linkage fragment 3.2, the aldehyde fragment 4.9 and the azide fragment 4.10 of the southern portion of (���)-azaspiracid-1 have been described. With an abundant material prepared by this scalable improved approach, we are confident that completing the total synthesis of (���)-azaspiracid-1 will occur in the near future. / Graduation date: 2013

Dendrimers are highly branched macromolecules which are prepared by a stepwise procedure. The presence of a well-defined core, discrete generations and a large number of terminal groups in dendrimers make them structurally very interesting and potentially useful for a wide variety of applications.1 Hyperbranched polymers,2 on the other hand, do not possess a unique core or discrete generations and they contain a large number of statistically distributed defects. Despite the presence of structural imperfections, studies have indicated that hyperbranched polymers capture many of the essential features of dendrimers, such as adoption of a compact conformation and the presence of a large number of readily accessible terminal functional groups. The first chapter of this thesis provides a brief introduction to hyperbranched polymers, with an emphasis on different methods for synthesizing them, followed by a discussion of the various approaches to control their molecular structural features, such as molecular weight, polydispersity, degree of branching, branching density, terminal end-groups, etc. One of the main objectives of the present study is to develop a simple synthetic strategy to generate peripherally functionalized (or functionalizable) hyperbranched polymers (HBP) that could potentially exhibit core-shell type behavior; in other words, polymers that carry segments of distinctly different solubility preferences within the core-region and the peripheral shell. To this end, in chapter 2 we describe the use of the melt-transetherification process,3 using an AB2 monomer along with a mono-functional A-R type comonomer, to directly generate core-shell type hyperbranched structures in a single step.4 Given that an AB2 monomer carries one equivalent excess of B functionality, copolymerization with an A-R type molecule bearing a single A functional group, readily permits the decoration of the periphery of the hyperbranched structures with these R-units. Thus, hyperbranched polyethers having polyethylene glycol (PEG) segments at their molecular periphery were prepared by a simple procedure wherein an AB2 type monomer was melt-polycondensed with an A-R type monomer, namely heptaethylene glycol monomethyl ether (HPEG). The presence of a large number of PEG units at the termini rendered a lower critical solution temperature (LCST) to these copolymers, above which they precipitated out of an aqueous solution.5 In an effort to understand the effect of various molecular structural parameters on their LCST, the length of the hydrophobic spacer segment within the hyperbranched core and the extent of PEGylation, were varied. Increase in the size and hydrophobicity of the hyper-core resulted in a continuous lowering of its LCST, while an increase in the level of PEGylation, increases the LCST, for a given size of the hyper-core. Additionally, linear analogues that incorporates pendant PEG segments were also prepared and comparison of their LCST with that of the hyperbranched polymer clearly revealed that the hyperbranched topology leads to a substantial increase in the LCST, highlighting the importance of the peripheral placement of the PEG units as shown in figure 1.5 This observation also provided an indirect evidence for the development of core-shell type topology in these peripherally functionalized hyperbranched structures. Figure 1. Transmittance of a 0.4 wt % aqueous solution of the linear and hyperbranched polymers as a function of temperature, measured at 600 nm. Such core-shell type HBPs could be also exploited both as unimolecular micelles and reverse micelles by suitably modifying the nature of the AB2 and A-R type monomers4. In the third chapter, the preparation and dye-encapsulation properties of unimolecular micelles as well as reverse micelles based on core-shell HBPs have been presented. In case of micelle forming polymers, an AB2 monomer carrying a decamethylene spacer was used along with heptaethylene glycol monomethyl ether (HPEG) as the A-R type comonomer. One the other hand, for the preparation of reverse micelle forming polymers, an AB2 monomer containing an oligo(oxyethylene) spacer was used along with cetyl alcohol as the A-R type comonomer as shown in scheme 1. The former was readily soluble in water while the latter was soluble in hydrocarbon solvents, like hexane. NMR spectral studies confirmed that both the approaches generated highly branched structures wherein ca. 65-70 % of the terminal B groups were capped by the A-R comonomer. scheme1. Synthesis of the unimolecular micelle and reverse micelle forming polymers using a one step AB2 + A-R type copolymerization. (REFER PDF FILE) One of the approaches commonly used to demonstrate core-shell behavior is to examine the ability of such polymers to encapsulate appropriate dyes from a suitable medium. In the case of the micelle-forming polymer, an aqueous solution of the polymer (6 μM) was sonicated in the presence of excess pyrene for varying periods of time. From the UV-visible spectra (Figure 2) of the aqueous solution (after filtration), it is evident that the saturation uptake is attained in about 7 h. Similar studies were also carried out for reverse-micelle forming polymers in hexane, using methyl orange as the dye. These dye-uptake studies, in conjunction with dynamic light scattering, unequivocally confirmed the formation of unimolecular micelles/reverse micelles. Figure 2. Absorbance as a function of sonication time for micelle-forming polymers (A), and absorbance as a function of the amount of solid dye taken, for reverse micelle-forming polymers (B). (REFER PDF FILE) Another novel approach to generate core-shell systems, using A2 + B3 + A-R type terpolymerization, was also explored in an effort to simplify the synthesis even further. However, dye-uptake measurements revealed that the polymers prepared via the AB2 + A-R approach exhibited a significantly larger uptake compared to those prepared via the A2 + B3 + A-R approach. This suggests that the AB2 + A-R approach generates hyperbranched polymers with better defined core-shell topology when compared to polymers prepared via the A2 + B3 + A-R approach, which is in accordance with previous studies6 that suggest that A2 + B3 approach yields polymers with significantly lower branching levels and consequently less compact structures. In chapter 4, different strategies for functionalization of the core-region and periphery of core-shell type hyperbranched polymers (HBP) using the “click” reaction7 have been explored. For achieving peripheral functionalization, an AB2 + A-R1 + A-R2 type copolymerization approach was used (as depicted in scheme 2), where the A-R1 is heptaethylene glycol monomethyl ether (HPEG-M) and A-R2 is tetraethylene glycol monopropargyl ether (TEG-P). A very small mole-fraction of the propargyl containing monomer, TEG-P was used to ensure that the water-solubility of the core-shell type HBP is minimally unaffected. Scheme 2. Preparation of a hyperbranched polyether having a few percent of propargyl groups at the molecular periphery and further click reaction to place fluorophores at the periphery. Similarly, to incorporate propargyl groups in the core region, a new propargyl group bearing B2-type monomer was designed and utilized in an AB2 + A2 + B2 + A-R1 type copolymerization, such that the total mole-fraction of B2 + A2 is small and their mole-ratio is 1:1 (Scheme 3). Further, using a combination of both the above approaches, namely AB2 + A2 + B2 + A-R1 + A-R2, hyperbranched structures that incorporate propargyl groups both at the periphery and within the core were synthesized. Since the AB2 monomer carries a C-6 alkylene spacer and the periphery is PEGylated, all the derivatized polymers form core-shell type structures in aqueous solutions. In order to ascertain and probe the location of the propargyl groups in these HBP’s, a fluorescent azide, namely azidomethyl pyrene, was quantitatively clicked onto these polymers and their fluorescence properties were examined in solvents of different polarities. Fluorescence spectra in water was unable to differentiate between the fluorophores present at different locations suggesting that the tethered pyrene at the end of a flexible oligoethylene oxide unit is probably tucked within the core-region because of its intrinsic hydrophobic nature. Scheme 3. Preparation of a hyperbranched polyether bearing a few percent of the propargyl groups within the core and further click reaction to place fluorophores in the core-region. The conventional melt-transetherification polymerization proceeds by continuous removal of methanol as volatile by product.3 The fifth chapter describes the design and development of a new AB2 monomer that carries two propargyloxy benzyl groups and one hydroxyl group, which underwent melt-transetherification condensation by exclusion of propargyl alcohol (instead of methanol) to generate a hyperbranched polyether containing numerous propargyl ether groups located on their molecular periphery as shown in scheme 4. These propargyl groups were readily “clickable” under very mild conditions with a variety of azides using the copper (I) catalyzed Huisgen type dipolar cycloaddition, popularly known as click reaction,7 to generate a range of functionalized hyperbranched polymers. The simplicity of the monomer synthesis, the solvent-free melt polymerization process and the mild conditions under which quantitative peripheral derivatization is achievable, makes this process ideally suited for the generation of hyperscaffolds onto which a wide range of functionalities could be placed. This turned out to be a rather remarkable extension of the melt transetherification polymerization that permitted the direct generation of peripherally clickable hyperbranched scaffold that, in principle, could be used to generate a wide range of interesting structures. Scheme 4. Synthesis of the hyperbranched polyether with clickable surface in a single step. (For structural formula pl refer pdf file)

Well-defined heterobifunctional homopolyethers and amphiphilic block copolyethers containing a variety of functionalities were designed, synthesized, and characterized via GPC and 1H NMR. These have included controlled molecular weight cholesterol-PEO-OH, mono- and trivinylsilyl-PEO-OH, monovinylsilyl-PEO-PPO-OH, monovinylsilyl-PEO-PPO-PEO-OH, maleimide-PEO-OH, stearyl alcohol-PEO-OH, propargyl alcohol-PEO-OH, trivinylsilyl-PPO-OH, trivinylsilyl-PPO-PEO-OH, and benzyl alcohol-initiated poly(allyl glycidyl ether)-OH. The focus of polymers utilized in this study involved the mono- and trivinylsilyl polyethers. The vinylsilyl endgroups on these materials were functionalized with various bifunctional thiols through free radical addition of SH groups across the vinylsilyl double bonds. The resultant end-functional polyethers were adsorbed onto magnetite nanoparticles and the stabilities of the polymer-magnetite complexes were compared as a function of the type of anchoring moiety and the number of anchoring moieties per chain. Anchoring chemistries investigated in this work included carboxylates, alkylammonium ions, and zwitterionic phosphonates. The anchor group-magnetite bond stability was investigated in water and phosphate buffered saline (PBS). Through these studies, the zwitterionic phosphonate group was shown to be a better anchoring group for magnetite than either carboxylate or ammonium ions. Tri-zwitterionic phosphonate anchor groups provided stability of the complexes in PBS for a broad range of polymer loadings. Thus, investigations into the stability of polyether-magnetite complexes in PBS focused on hydrophilic zwitterionic phosphonate-PEO-OH and amphiphilic zwitterionic phosphonate-PPO-b-PEO-OH oligomer coatings on the surface of magnetite. Superparamagnetic magnetite nanoparticles are of interest as potential contrast-enhancement agents for MRI imaging. Thus, transverse NMR relaxivities of these complexes were studied as a function of chemical composition and nanostructure size and compared to commercial contrast agents. The amphiphilic polyether-magnetite nanoparticles were shown to be stable in both aqueous media as well as physiological media and have much higher transverse relaxation values, r2, than those of commercial contrast agents and other materials in the literature. / Ph. D.

Tetrahydrofuran (THF) and tetrahydropyran (THP) rings are commonly found in a wide range of natural products and biologically active compounds. In total synthesis, the formation of THF/THP motifs is often the key step but existing methods often involve numerous steps and low overall efficiencies. Part one of this thesis details the development of a practical method for the synthesis of THF rings by the controlled mono-addition/cyclisation of organolithium species to C2-symmetric diepoxides (Scheme A-1). This method can also be applied to the synthesis of bis-THF rings from triepoxides and has potential applications in more complex cascade reactions. A similar cyclisation process providing THF rings from epoxyaldehydes is also described. Part two of this thesis details our efforts towards the synthesis of the marine macrolide neopeltolide. Wright and co-workers reported the isolation of neopeltolide 211 from a deep-water sponge of the family neopeltidae off the north coast of Jamaica. The structure, which was assigned by NMR and HRMS studies and reassigned by total synthesis, contains a 14-membered macrolactone, a 2,6-cis THP ring and an unsaturated oxazole side-chain. Chapter four describes the synthesis of the C2-C8 and C9-C16 fragments (Scheme A-2). Chapter five details our initial attempts in the coupling of subunits 268 and 320, as well as a revised synthetic strategy that allowed us to successfully couple C2-C9 alkyne 347 with C10-C16 aldehyde 348 and the preparation of an advanced intermediate 364 (Scheme A-3).

This work examines the chemical and physical effects of a material treatment process on the biopolymers PEEK, POM-h, POM-c, PTFE and UHMWPE. The polymers are analyzed physically and chemically using atomic force microscopy, profilometry, scanning electron microscopy, optical microscopy, contact angle measurement, FT infra-red spectroscopy and energy dispersive X-ray spectrometry. PEEK is found to be the most suitable polymer and FT Infra-red spectroscopy an informative analytic tool.

This work examines the chemical and physical effects of a material treatment process on the biopolymers PEEK, POM-h, POM-c, PTFE and UHMWPE. The polymers are analyzed physically and chemically using atomic force microscopy, profilometry, scanning electron microscopy, optical microscopy, contact angle measurement, FT infra-red spectroscopy and energy dispersive X-ray spectrometry. PEEK is found to be the most suitable polymer and FT Infra-red spectroscopy an informative analytic tool.

Natural compounds have been the primary resource used to produce polymeric materials by humankind since the mid-1900s. Yet, progress in bio-based polymers from renewable feedstock has encountered some obstacles, mainly due to the low prices of petroleum-based monomers, compared to natural and sustainable materials. However, most commodity plastics are non-degradable materials, and solid plastic waste accumulation adversely affects the environment. As the world population is growing and demanding chemicals, energy, and plastics materials, polymer research is focusing on synthesizing bio-based and degradable polymers. Thus, biomass, a sustainable and inexpensive feedstock, is highly appropriate for designing alternative thermoplastics that are degradable to reduce the current environmental issues. In this dissertation, three different approaches were used to afford alternative thermoplastics to petroleum‐based commodities: bio-based poly(ether-amide)s, random aromatic copolyesters, and copoly(acetal triazole)s. In our first approach, two new lignin‐derived poly(ether‐amide)s (PEA)s were prepared. Their thermal properties showed high degradation temperature (Td) ranging from 330 °C to 380 °C, and glass transition temperature (Tg) between 100 °C and 120 °C. The chemical degradation studies revealed that the PEAs were degradable in 4 M H2SO4, HNO3, and TFA in 3 days. The second polymer group synthesized were semicrystalline bio-based aromatic copolyesters with tunable thermal properties. The thermal analysis of these copolyesters revealed high Td (413 °C to 446 °C) and Tg and Tm ranging from –36 °C to 67 °C and 60 °C to 267 °C, respectively. Their crystallization behavior showed a dependence on the comonomer composition, exhibiting a pseudo-eutectic region. Finally, furfural- and benzaldehyde-based copoly(acetal triazole)s (Td range 280–340 °C) were prepared by click polymerization at room temperature. Preliminary results showed that furfural-based copoly(acetal triazole)s were susceptible to hydrolytic degradation under neutral conditions after only 8 days at 40 °C. Overall, degradable and bio-based polymers were successfully synthesized as a potential thermoplastic alternative for packaging applications.

Ces travaux de thèse portent sur la valorisation de la biomasse oléagineuse, via la polymérisation de synthons, issus d’huiles végétales, en polymères hyper-ramifiés. Ces recherches ont conduit à la synthèse et à la purification d’un nouveau monomère biosourcé, le 10,11-epoxy undecan-1-ol (EUnd), dont la polymérisation par ouverture de cycle (ROMBP) a permis de générer des polyéthers hyper-ramifiés biosourcés. Les conditions de polymérisations ont été étudiées en laboratoire dans le but d’optimiser les rendements de synthèse mais aussi afin de contrôler la structure chimique, ainsi que leurs propriétés. La copolymérisation de l’EUnd avec le glycidol a permis d’atteindre de nouvelles propriétés, notamment en termes de solubilité. Une seconde partie fut consacrée à la fonctionnalisation de polyesters hyper-ramifiés biosourcés, développés au LCPO lors du projet HyPerBioPol. L’objectif étant de contrôler la solubilisation des composés dans différents milieux, polaires et apolaires, afin de créer des polymères pouvant être utilisés comme agents de réticulation. / The aim of this thesis is to valorize oilseed biomass through the polymerization of building block, stemming from vegetable oils, into hyperbranched polymers. This research involves the synthesis and purification of a new bio-based monomer, coined as 10,11- epoxyundecanol (EUnd), which ring-opening multibranching polymerization (ROMBP) has generated bio-based hyperbranched polyethers (hbPEUnd). Conditions of polymerization have been studied in order to maximize yields of reaction and control both the chemical structure and the properties of hbPEUnd. Copolymerization of EUnd with glycidol has also been implemented, yielding hyperbranched copolyethers with varied properties (e.g. solubility). The second part of this work has been dedicated to the functionalization of bio-based hyperbranched polyesters, developed in the frame of a former project. Appropriate derivatizations have provided these modified polyesters with solubility in polar solvents and made them employable as curing agents.

This work examines the chemical and physical effects of a material treatment process on the biopolymers PEEK, POM-h, POM-c, PTFE and UHMWPE. The polymers are analyzed physically and chemically using atomic force microscopy, profilometry, scanning electron microscopy, optical microscopy, contact angle measurement, FT infra-red spectroscopy and energy dispersive X-ray spectrometry. PEEK is found to be the most suitable polymer and FT Infra-red spectroscopy an informative analytic tool.