Les réactions multicomposants sont des réactions faisant intervenir au minimum trois composés pour la préparation d'un produit contenant la majeure partie des atomes de départ. Elles constituent l'un des procédés les plus performants en synthèse organique. En diminuant les coûts et les rejets par rapport aux réactions classiques de chimie organique, elles sont également plus économes et plus respectueuses de l'environnement. De plus, en permettant la formation rapide et efficace d'une large librairie de molécules complexes à partir de substrats simples, elles représentent un outil à forte valeur ajoutée dans le domaine pharmaceutique pour l'élaboration de chimiothèques. Face à ces enjeux, le laboratoire a développé en 2006 une réaction multicomposants de type Mannich entre des organozinciques, des amines et des aldéhydes. Cette réaction permet la synthèse efficace d'une variété importante de diarylméthylamines, dont la structure amine α,α-disubstituée est rencontrée dans de nombreux composés d'intérêt pharmacologique.A partir de ces travaux, il a été envisagé d'étendre la réaction multicomposants à la préparation de β-amino esters N-protégés. La réaction a été mise au point à partir d'un acrylate, d'une imine préformée et d'un organozincique aromatique formé in situ dans des conditions de type Barbier. Ces conditions opératoires présentent l'avantage d'éviter l'étape préliminaire de formation de l'organométallique.Par la suite, lors d'essais portant sur le développement d'une réaction à quatre composants entre un aldéhyde, un sulfonamide, un acrylate et un halogénure aromatique, nous avons observé, lorsque le manganèse est utilisé comme réducteur du bromure de cobalt, la formation majoritaire d'un diarylméthylsulfonamide résultant d'une nouvelle réaction à trois composants entre l'aldéhyde, l'amine primaire et le dérivé halogéné. Les conditions opératoires ont donc été optimisées afin de synthétiser de nombreuses diarylméthylsulfonamides.Enfin, en se basant sur la différence de réactivité des deux atomes de brome d'un composé dibromé, il a été envisagé la synthèse en deux étapes d'indolines en partant de bromure de benzyle ortho-bromé, par l'intermédiaire d'une réaction de Mannich benzylique puis une seconde étape d'amination aromatique intramoléculaire, catalysée au palladium. / Multicomponent reactions are processes in which at least three starting materials react together to form a product containing most of the starting atoms. They constitute one of the most efficient processes in synthetic organic chemistry. They are also more economical and environmentally friendly than classic organic reactions. Moreover, since they allow a straightforward access to large libraries of compounds containing the same core unit, they represent a valuable tool for pharmaceutical industries, especially for high-throughput screening. In 2006, the laboratory developed a Mannich-type multicomponent reaction between aromatic organozinc compounds, aldehydes and secondary amines allowing the efficient preparation of diarylmethylamines. These structures, and more generally the α,α-disubstituted amine core unit, are found in a large range of compounds displaying diverse pharmacological properties. On the basis of this work, it was planned to extend the reaction to other families of compounds, N-protected β-amino esters and diarylmethylsulfonamides. In the first part of this work, a range of β-amino esters have been prepared starting from in situ-generated aromatic organometal compounds (Barbier-like conditions), acrylates and preformed sulfonylimines. These conditions present the advantage to avoid the pre-formation of the organometallic compound. Thereafter, during tests pertaining to the development of a four component reaction between an aldehyde, a sulfonamide, an acrylate and an aromatic halide, it was observed the major formation of diarylmethylsulfonamide resulting from the three-component reaction between the aldehyde, the primary amine and the halide, when manganese is used as the reducer of cobalt bromide. The experimental conditions were thus optimized in order to synthesize many diarylmethylsulfonamides.Lastly, based on the difference of reactivity between benzylic and aromatic C-Br bonds, it was described the two-step synthesis of various 1,2-substituted indolines starting from ortho-brominated benzyl bromide by means of a benzylic Mannich-like reaction followed by palladium-catalyzed intramolecular amination of the aromatic ring

Mn-Mediated radical addition has been developed within the Friestad laboratory as a versatile method toward addition to C=N bonds. N-Acylhydrazones generated by condensation between an aldehyde and an N-acylamine serves as the substrate toward radical addition. A bulky directed group attached with the N-acyl moiety and restricted rotation around N-N bond due to a three point chelation with a Lewis acid differentiates the faces of the C=N bond of the N-acylhydrazones. Radical generation initiated by photolysis of Mn2(CO)10 causing homolysis of C-X bond in alkyl halide serves as the radical donor to the N-acylhydrazones. Radical addition thereafter occurs stereoselectively from the less hindered face of the C=N bond of the N-acylhydrazones. The product N-acylhydrazines can be effectively transformed to α-chiral amines. In this thesis, a new protocol toward generation of non-proteogenic γ-amino esters using Mn-mediated radical addition has been described. Moreover, the utility of the Mn-mediated radical addition has been demonstrated through studies toward synthesis of tubulysin U and V. Chapter 3 describes a new strategy for asymmetric synthesis of γ-amino esters starting from non-amino precursors. The α-substituted γ-amino esters are prevalent in drugs, drug candidates, and in peptidomimetics. As a part of progressing the Mn-mediated radical addition reaction, highly stereoselective reactions were devised for addition to N-acylhydrazonoesters in absence of Lewis acid. Spectroscopic investigations were carried out to decipher the Lewis acid chelation of N-acylhydrazones. Finally, a novel microwave mediated trifluoroacylation of N-acylhydrazinoesters facilitated the cleavage of N-N bond to liberate γ-aminoester. Chapter 4 describes application of Mn-mediated radical addition toward synthesis of tubulysin natural products. Tubulysins are natural products, isolated from myxobacteria, that have exhibited potent cytotoxicity toward cancer cells in the picomolar regime. The Mn-mediated radical addition was used to prepare two chiral amine subunits in highly diastereoselective fashion. The subunits were then assembled after required manipulations into the tetrapeptide structure characteristic of tubulysins. This strategy to synthesize tubulysins is the most stereoselective of all efforts toward the synthesis of this molecule. Synthesis toward tubulysin was achieved in 18 steps as the longest linear sequence with a 31% overall yield to tubulysin V in benzyl protected form. Chapter 5 describes a new strategy toward installation of N-hydroxymethyl unit into a peptide chain. N,O-Acetals are acid-base labile species that is present in some tubulysin natural analogs. This new approach exploits Fleming-Tamao oxidation and hence introduce the hydroxymethyl unit of the N,O-acetal in a masked form. Following peptide construction the masked hydroxy group is released to liberate the N-hydroxymethyl moiety. Acylation of the free hydroxy group furnishes the N,O-acetal moiety in a strategy that is potentially applicable toward synthesis of tubulysin D.

Currently, cancer is the second leading cause of death in the United States. Conventional cancer treatment includes chemotherapy, radiation, and surgical resection, but unfortunately, all of these methods have significant drawbacks. Hyperthermia, the heating of cancerous tissues to between 41 and 45°C, has been shown to improve the efficacy of cancer therapy when used in conjunction with irradiation and/or chemotherapy. In this work, a novel method for remotely administering heat is presented. This method involves heating of tumor tissue using hydrogel nanocomposites containing magnetic nanoparticles which can be remotely heated upon exposure to an external alternating magnetic field (AMF). The iron oxide nanoparticles contained in the hydrogel nanocomposites are able to heat via an AMF due to Brownian and Neel relaxation processes. The administration of hyperthermia via hydrogel nanocomposites allows for local delivery of heat to tumor tissue while also providing a drug depot to deliver chemotherapeutic agents. Both in vivo and in vitro studies have demonstrated that numerous chemotherapeutic agents, when used in conjunction with hyperthermia, show improved efficacy in treating cancer Various magnetic hydrogel nanocomposites were synthesized and characterized for this work including poly(ethylene glycol) (PEG)-based hydrogels, which were studied due to their inherent biocompatibility and “stealth” properties, as well as, poly(β-amino ester) (PBAE)-based hydrogels which have tailorable degradation properties. The PEG hydrogels were investigated for their temperature-responsiveness swelling, mechanical strength, heating capabilities, biocompatibility, ability to kill M059K glioblastoma cells via thermoablation, and the ability to deliver paclitaxel, a chemotherapeutic agent. PBAE hydrogels were also characterized for their degradation and swelling properties, ability to heat upon exposure to an AMF, biocompatibility, mechanical strength, and ability to deliver paclitaxel in a controlled fashion. Additionally, multiple cancer cell lines were exposed to a combination of paclitaxel and heat (at 42.5 °C) in vitro and it was shown that A539 lung carcinoma cells exhibit higher cytotoxicity when exposed to both heat and paclitaxel than either treatment alone. Overall, magnetic hydrogel nanocomposites are promising materials that can be utilized for the multi-modality treatment of cancer through the synergistic delivery of both heat and chemotherapeutic agents.

La fonctionnalisation C(sp3)-H catalysée par des métaux de transitions, ouvre de nombreuses perspectives en synthèse organique, permettant des voies d'accès plus économes en atomes, et en étapes à des molécules à forte valeur ajoutée. Dans cette optique, une méthode efficace permettant l'arylation des liaisons C(sp3)-H en position α d'un groupement attracteur, plus communément appelée α -arylation a récemment fait l'objet d'une attention toute particulière de la part de la communauté scientifique. Le travail détaillé dans ce manuscrit décrit les dernières avancées de cette méthodologie, ainsi qu'une variante «β-arylation » développée au laboratoire qui constitue une évolution significative dans le domaine de l'arylation regiosélective des liaisons C(sp3)-H non activées. Dans le cadre de ce projet de thèse nous nous sommes efforcés de développer cette nouvelle réaction que nous avons pu optimiser pour l'étendre à une famille plus étendue de substrats de type amino-esters. Dans la continuité de ce travail nous avons réalisé la première réaction d'arylation migratoire sélective d'amino-esters pouvant aller jusqu'à la position η d'une chaîne alkyle linéaire. Enfin, dans le but d'accéder à de nouvelles molécules à plus haute valeur ajoutée, nous avons pu appliquer notre méthodologie aux acetals de cétènes silylés permettant de dépasser certaines limitations du système existant. Dans ce cas précis, des conditions plus douces (sans base forte) ont permis l'arylation de substrats dits sensibles et par extension la synthèse de lactones fonctionnalisées / The transition metal catalysed functionalization of C(sp3)-H bonds unlocks numerous perspectives within organic synthesis in terms of atom economical access routes to otherwise difficult to synthesise molecules. One efficient method to exact such transformations involves the exploitation of an activated C-H bond situated adjacent to an activating electron withdrawing group, allowing facile insertion of a transition metal catalyst species and subsequent functionalization with a new species (normally an aryl group). This strategy is generally termed ‘α-functionalization’. The work detailed within this manuscript describes a diversion from the classic, and well documented α-functionalization reaction, in which rearrangement steps within the catalytic cycle give rise to β- and more remote substrate functionalization. The first new methodology to be described involves a fundamental extension to the in-house developed β-arylation reaction, in which, through careful substrate and ligand choice, this methodology could be applied to achieve the functionalization of simple ester enolates in remote γ- to η - positions. The developed strategy allowed the synthesis of a small range of interesting homophenylalanine analogues, and higher homologues. The second methodology to be described involves a necessary modified protocol for the β-arylation reaction, in which silyl ketene acetals were exploited as mild metal-enolate surrogates, allowing the coupling of base-sensitive substrates. The previously described reaction scope has been extended in terms of both the electrophile and nucleophile coupling partners through the development of mild reaction conditions, which subsequently allowed application of several products towards the synthesis of lactones

In this thesis a methodology to synthesize anti-β-hydroxy-α-amino esters possessing olefins has been investigated. The developed procedures originate from two already established procedures in which α-amido-β-keto esters, which do not contain olefins, has been stereoselectively reduced to the corresponding anti-β-hydroxy-α-amino alcohols via asymmetric transfer hydrogenation coupled with dynamic kinetic resolution. Both established methods, one solvent free and one emulsion procedure, have been investigated on the expanded substrate scoop. Four different α-amido-β-keto ester containing olefins were tested and it was found that the ketones were reduced to desired anti-β-hydroxy-α-amino esters in both procedures, but also side products were formed where the olefins were reduced. The ratio of the different products was dependent on the structure of the starting α-amido-β-keto ester, ligand used on the catalyst and reaction conditions such as number of equivalents of base and reaction temperature. The diastereoselectivity for the desired products was in favor of the anti stereoisomer, however, the dr was worse than in the established procedures. The usefulness of this methodology was then demonstrated by a formal total synthesis of Sphingosine.

Abdominal aortic aneurysms are a leading cause of death in the U.S. where 14,000 people die from aneurysm rupture and 178,000 are diagnosed each year. A novel alternative treatment for abdominal aortic aneurysms has been proposed, where a biodegradable polymer scaffold is photopolymerized in situ around the exterior of the aneurysm. This scaffold will mechanically constrain the aneurysm from further expansion, and will deliver a drug, doxycycline, to treat the underlying biological cause of the disease. In order for device development, a suitable polymer must be designed with appropriate mechanical properties, degradation rate, polymerization, and elution rate. Poly(β-amino ester) networks have been proposed as the material of choice; however, many of their structure-property relationships have yet to be determined. Therefore, the overall goal of this work is to determine the structure-property relationships of the poly(β-amino ester) networks in order to advance the design of the treatment, and has been divided into three objectives: (1) understand the structure-property relationships of poly(β-amino ester) networks, specifically the polymerization, degradation rate, and thermo-mechanical properties, (2) determine the impact of doxycycline incorporation on degradation rate and mechanical properties, (3) evaluate the effect of simulated physiological conditions on degradation rate and mechanical properties. In the initial chapters, the fundamental structure-property relationships are established between reactant chemical structure, step-growth polymerization, photopolymerization, thermo-mechanical properties, and degradation rate using a systematic approach of two homologous series of reactants. Further tailoring of degradation rate, water content, and modulus in vitro was performed by using a copolymer network. Doxycycline inhibited photopolymerization due to overlapping absorbance spectra with the photoinitiator, but full network formation occurred by increasing the photoinitiator concentration. Networks displayed varying controlled release rates, and the underlying release mechanism was determined for each network using established methods. In order to increase mechanical properties, a co-monomer, methyl methacrylate, was added to the network to increase the glass transition temperature, toughness, and deformation capacity. These co-networks displayed temporal-control of mechanical properties in simulated physiological conditions, since degradation caused a shift in the glass transition temperature, which changed the mechanical behavior of the network. The temporal-control of mechanical properties was further investigated under degradation conditions in vitro and in vivo. Due to the mechanically active loading environment in vivo, networks displayed a decrease in toughness, yet maintained mechanical properties similar to native biological tissues. These networks establish a multifunctional biomaterials platform with materials that can be easily synthesized, photopolymerized into various geometries, and sustain mechanical properties while undergoing degradation and therapeutic agent release.