This thesis is concerned with the development of methodology for the regioselective ring-opening of aziridines and aziridinium intermediates and its subsequent application to the asymmetric synthesis of β-substituted-α-amino acids and 1,2,3,4-tetrahydroisoquinolines. Chapter 1 introduces methods for the formation of aziridines and aziridinium ions and focusses on their utility as intermediates in synthesis. Chapter 2 describes studies into the synthesis of aziridines from enantiopure α-hydroxy-β-amino esters and their subsequent conversion to the corresponding β-hydroxy-α-amino acids via either a regioselective ring-opening with Cl₃CCO₂H, or a rearrangement promoted by Cl3CCO2H. Application of this procedure to both syn- and anti-configured substrates enabled the syntheses of (S,S)-allo-threonine, (2R,3S)-threonine, (R,R)-3-hydroxyphenylalanine and (2S,3R)-3-hydroxyphenylalanine. Chapter 3 details attempts to truncate the synthesis described in Chapter 2 by investigating the synthesis of enantiopure anti-β-hydroxy-α-amino acids via the intermediacy of aziridinium ions. These studies culminated in the development of a regioselective and stereospecific one-pot aziridinium formation and ring-opening protocol, leading to the synthesis of a range of C(3)-aryl and C(3)-alkyl substituted anti-β-hydroxy-α-amino acids. Chapter 4 discusses the conversion of enantiopure anti-α-hydroxy-β-amino esters to anti-β-fluoro-α-amino esters via the regioselective and stereospecific ring-opening of an aziridinium intermediates in situ. The subsequent development of a one-pot deprotection strategy leads to a concise and expedient synthesis of anti-β-fluorophenylalanines. The extension of this methodology to access a representative anti-α,β-diamino acid is also demonstrated. Chapter 5 describes the development of a one-pot diastereoselective rearrangement of enantiopure α-hydroxy-β-amino esters to 1,2,3,4-tetrahydroisoquinolines. The substrate scope of this reaction manifold is examined and application to the asymmetric synthesis of enantiopure 1,2,3,4-tetrahydroisoquinolines also discussed. Chapter 6 contains full experimental procedures and characterisation data for all compounds synthesised in Chapters 2, 3, 4 and 5.

Thesis (Ph.D.)--Ohio University, March, 2008. / Abstract only has been uploaded to OhioLINK. Includes bibliographical references (leaves 115-125)

The traditional reagent for H• transfer in organic chemistry is 𝓃-Bu₃SnH, which has a Sn–H bond dissociation energy (BDE) of 78.5 kcal/mol. There are, however, many disadvantages of employing 𝓃-Bu₃SnH in radical reactions. The transfer of H• from tin is necessarily stoichiometric, with 𝓃-Bu₃Sn–X being the eventual product. Overall, the tin reactions have poor atom economy; n-Bu3SnH cannot be regenerated from 𝓃-Bu₃Sn• or 𝓃-Bu₃Sn–X with hydrogen, and no general methods of regenerating the tin hydride with other hydride sources have been reported. Standard purification methods leave unacceptable levels of residual tin in the products of n-Bu3SnH reactions. Alternatives are clearly needed. Transition metal hydrides represent a class of promising reagents to replace 𝓃-Bu₃H. Due to their typically weaker M-H bonds, transition metal hydrides are often able to transfer H• to C=C and generate radicals — a reaction that 𝓃-Bu₃SnH cannot do. Furthermore, many transition-metal hydrides can be regenerated from hydrogen gas, an event that requires that the M–H BDE be over 56 kcal/mol. By combining this reaction with the H• transfer, metalloradicals can often catalyze the formation of radicals from H₂. Over the years, the Norton group has studied several transition metal hydride systems and demonstrated their applications in different scenarios. The kinetics and thermodynamics of these systems have been studies in detail, and they are shown be competent hydrogen atom donors to unsaturated organic substrates and to organic radicals. Some of these metal hydrides can be made catalytic under hydrogen pressure, thus providing an atom-economical way to effect radical reactions. Specifically, the thermodynamic properties of the chromium hydride HCpCr(CO)₃ have been carefully studied. Based on this information, I developed a Ti/Cr cooperative catalytic system featuring multiple interactions between the two metal systems. Herein are described three applications of this Ti/Cr catalytic system: anti-Markovnikov hydrogenation of epoxides (Chapter 2), reductive cyclization of epoxy enones under H₂ (Chapter 3), and aziridine isomerization to allyl amines (Chapter 4). I have also explored new hydrogen atom acceptors. I was able to catalyze hydrodefluorination of CF₃-substituted olefins with a nickel hydride (Chapter 5). The reaction was demonstrated to be initiated by a hydrogen atom transfer from the Ni(II)-H to the olefin substrates. This also expands our toolbox of metal hydrides for transferring hydrogen atom to olefin substrates. With a different cobaloxime catalyst, I was able to catalyze the cycloisomerization of CF₃-substituted dienes (Chapter 6). In Chapter 7, I developed a method to achieve a broad range of hydrofunctionalizations of olefins with hydrogen atom transfer from metal hydrides in situ. Hydrogen atom transfer to olefins was followed by TEMPO trapping to form TEMPO adducts. A subsequent photocatalytic substitution on those TEMPO adducts with different nucleophiles affords various hydrofunctionalized products.

Thesis advisor: X. Peter Zhang / Highly strained three membered heterocycles are a common motif in many biologically relevant molecules and represent a versatile building block for organic synthesis. Of special interest for asymmetric synthesis is the construction of enantioenriched aziridines and epoxides, which are often used as chiral synthons to introduce heteroatoms in a stereoselective fashion. Among different elegant strategies, the direct aziridination and epoxidation of the ubiquitous alkene functionality represents one of the most powerful methods to access these motifs. Given the synthetic importance of the enantioenriched smallest aza- and oxaheterocycles, the focus of this dissertation is centered on the design and use of chiral cobalt porphyrins as catalysts to develop new methodologies for the asymmetric radical aziridination and epoxidation of alkenes.In the first part of this dissertation, we focused on using carbonyl azides as nitrogen source for the enantioselective radical aziridination of alkenes. Despite its high functionality and versatility for further derivatization, carbonyl azides have never been reported as nitrogen source for intermolecular asymmetric alkene aziridination. In the second part of this dissertation, we focused on opening up a new area of research, which involves the generation and characterization of the unprecedented cobalt porphyrin-supported oxygen-centered radical species. Finally, we demonstrated the synthetic utility of these new radical species by developing a new system for the asymmetric epoxidation of alkenes through the design and development of a novel family of catalyst named “JesuPhyrin”. / Thesis (PhD) — Boston College, 2021. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

New imidazotetrazinones have been synthesised that possess features in their structures to release aziridinium ions upon ring opening. Unstable 2-aminoethylisocyanates were required in this preparation, which were synthesized with BOC-protection of the amino group to counteract the reactivity of the amine towards the isocyanate group in the case of aliphatic amines; in contrast, anilinoethylisocyanates were synthesized unprotected. Substituents with a range of electron-withdrawing and electron-releasing properties were introduced at the p-position of the aniline ring. A 13C-labelled study confirmed the release of the aziridinium ion by these imidazotetrazinones in neutral pH buffer solution. Furthermore the kinetics of the hydrolysis in neutral aqueous solution of some these new tetrazines were similar to temozolomide, in addition to useful acid stability. Other imidazotetrazinones were synthesised for the purpose of releasing alcohols and phenols. Their synthesis was performed with a one-carbon linker between the imidazotetrazinone 3-position and the alcohols or phenols to be released. The release of alcohol and phenol through the hydrolysis of the intermediate diazonium ions to the unstable hemiacetals that decomposed to the alcohol and phenol was confirmed by 1H NMR. The kinetics of the hydrolysis of these tetrazines in neutral aqueous solution showed a faster reaction rate compared with temozolomide (t1/2 = 0.53 and 0.36 h compared with temozolomide 1.4 h). / Full text was made available at the end of the embargo period, 1st Feb 2016.

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L’objectif de cette thèse est d’élargir la gamme des composés issus des aziridine-2-carboxylates, obtenues par leur utilisation comme matière première pour la synthèse d’azahétérocycles ciblés diversement substitués, via des réactions d’ouvertures nucléophiles et d’expansions de cycle. La synthèse d’hétérocycles azotés fluorés originaux sera abordée à partir d’aziridines-2-carboxylates trifluorométhylées ainsi que d’aminoalcools et aminoacides trifluorométhylés enantiopures. Les aziridines-2-carboxylates trifluorométhylées dont la synthèse à déjà été décrite dans la littérature conduiront à des hétérocycles fluorés variés selon des réactions d’ouverture et d’agrandissement de cycles faisant intervenir les méthodologies mise au point en série non fluorée par le partenaire Tunisien. Les aminoalcools et aminoacides trifluorométhylés conduiront également à des hétérocycles de type oxazolidinones. Les nouveaux hétérocycles synthétisés trouveront des applications en tant qu’unités pseudo-peptidiques utiles en chimie des peptides. / Our purpose in this thesis is to widen the range of compounds from aziridine-2-carboxylate, which obtained by its use as a feedstock for the synthesis of new hétérocycles through nucleophilic reactions openings and expansions cycle.The synthesis of fluorinated heterocycles will be approached from aziridine-2-carboxylate trifluorométhylées and amino alcohols and amino acids trifluoromethylated enantiopure.Fluorinated aziridines whose synthesis has already been described in the literature will lead to various fluorinated heterocycles according reactions and opening cycles of expansion methodologies involving setting the nonfluorinated series developed by the Tunisian partner.The new synthesized heterocycles find applications as chiral pseudo-peptide units useful in peptide chemistry.

Ce manuscrit expose différents développements méthodolgiques et leurs applications pour la synthèse de composés à visée anticancéreuse.Le premier chapitre décrit les travaux ciblant l’obtention d’analogues du TMC-95A, produit naturel inhibiteur du protéasome dont l’activité antitumorale a été démontrée. La formation de ces analogues passe par la synthèse d’intermédiaires tryptophanes hautement oxydés fonctionnalisés en position 7. Une première stratégie mettant en jeu une réaction d’insertion C-H nous a permis d’obtenir des oxindoles fluorés avec de bons rendements. Cependant, les difficultés rencontrées lors des étapes de déprotection et de réduction nous ont amenés à revoir notre approche synthétique. Une hétéroannulation de Larock a ensuite été envisagée pour la synthèse de tryptophanes fonctionnalisés, sans plus de succès. En revanche, nous avons été capables de mettre au point une réaction de fluoration oxydante régio- et chimiosélective du noyau indolique du tryptophane incorporé dans des tripeptides linéaires. Ainsi, des précurseurs avancés d’analogues du TMC-95A ont pu être obtenus.Dans un deuxième chapitre, nous nous sommes intéressés à la réactivité d’aziridines bicycliques dérivées de sulfamates, obtenues par aziridination intramoléculaire catalysée au cuivre en présence de réactifs de l’iode hypervalent. Nous avons ainsi pu montrer qu’il était possible d’en réaliser l’ouverture à l’aide de nucléophiles carbonés. Puis, les sulfamates cycliques à 7 chaînons obtenus peuvent également réagir avec des nucléophiles carbonés pour conduire à des amines polysubstituées. Enfin, des études préliminaires nous ont permis d’évaluer ces aziridines bicycliques comme précurseurs de dipoles-1,3 et ont conduit à la formation de composés à haute valeur ajoutée.Enfin, le dernier chapitre de ce manuscrit décrit les résultats obtenus pour la synthèse totale de produits naturels. Grâce à la méthodologie développée précédemment, nous avons pu synthétiser la spisulosine ES-285, produit naturel issu des palourdes comestibles de l’océan atlantique nord et dont l’activité antitumorale a été démontrée. La voie de synthèse mise au point permet de moduler la nature des nucléophiles introduits, permettant donc un accès rapide à de nouveaux composés, potentiellement plus actifs. Un analogue fluoré original de la spisulosine a ainsi pu être obtenu. Cette méthodologie a également été mise en œuvre pour la synthèse de molécules plus complexes, comme la monanchorine, un alcaloïde à guanidine polycyclique d’origine marine. Un précurseur avancé a ainsi pu être obtenu, mais il n’a malheureusement pas été possible de conclure la synthèse. / This manuscript exposes several synthetics methods and their applications for the preparation of new anti-cancer compounds.The first part describes our efforts toward the obtention of new analogs of TMC-95A, natural proteasome inhibitor, which antitumoral activity has already been shown. The formation of these compounds requires the synthesis of highly oxidized tryptophane substituted in position 7. An initial strategy involving a C-H insertion allowed us to obtain fluoro oxindoles in good yields. However, the encountered difficulties for the reduction and deprotection steps prompted us to rethink our strategy. A Larock heteroannulation has been considered for the synthesis of functionalized tryptophanes and was, unfortunately, unsuccessful. Nevertheless, we have been able to develop a regio- and chemoselctive oxidative fluoration of the trypthophane indolic core incorporated in tripeptides. Therefore, advanced precursors of TMC-95A analogs have been obtained.In the second part, the reactivity of bicyclic aziridines derived from sulfamates has been studied. These aziridines were obtained by copper catalyzed intramolecular aziridination in the presence of hypervalent iodine reagent. We were then able to demonstrate the possibility to perform nucleophilic ring opening of these bicyclic aziridines with carbon nucleophiles. The obtained 7 membered ring sulfamates were also submitted to nucleophilic ring opening with carbon nucleophiles to give acces to polysubstituted amines. Finally, preliminary studies allowed us to test these bicyclic aziridines as dipole-1,3 precursors and have led to the the formation of high value compounds.Finally, the last chapter describes the results we obtained for the total synthesis of natural products. Thanks to the methodology developed above, we were able to synthesize the spisulosine ES-285, natural product extracted from the north Atlantic clams and known to display antitumoral activity. The synthetic path allows us to change the nature of the nucleophile and gives rapidly access to new compounds, potentially more active. A new fluoro analog of the spisulosine has been obtained. This methodology has also been applied for the total synthesis more complex molecules, such as monachorin, a marine polycyclic guanidine alcaloïd. An advanced precursor has been synthesized, but we unfortunately weren’t able to finish the synthesis.

La catalyse organométallique est l'un des piliers de la synthèse chimique moderne. Elle permet notamment la formation rapide de liaisons carbone-carbone et carbone-hétéroatome, processus les plus importants pour la fabrication des milliers de composés nécessaires à la vie contemporaine. Elle répond également aux critères d'économie d'atomes et d'énergie, et de réduction des déchets, des risques et des coûts de mise en oeuvre d'une réaction chimique.Parmi les thématiques les plus récentes de la synthèse organique, la catalyse homogène à l'or s'est imposée en seulement quelques années comme un outil synthétique très puissant. Elle autorise la génération rapide de complexité moléculaire à partir de substrats simples par l'activation d'insaturations carbonées. Durant ces études, nous avons tenté de tirer profit du caractère carbophile des complexes d'or (1) et (Ill) mais aussi de leur affinité pour certaines fonctions polaires pour transformer des hétérocycles acétyléniques en composés hétéropolycycliques dans des réactions en cascade. La réactivité complémentaire des complexes d'argent (1) a également été exploitée, ces derniers présentant de surcroît une sélectivité remarquable pour la déprotection d'éthers de méthoxybenzyle. / Organometallic catalysis is a key tool of modern chemical synthesis. lts use is ubiquitous in the preparation of bulk or fine chemicals, in particular for the assembly of carbon-carbon and carbon-heteroatom bonds. Besides its overall efficiency, it responds to the responsible criteria of energy and atom economy, the reduction of waste, risk, and financial costs needed to perform a chemical reaction.ln just a few years, homogenous gold catalysis has emerged as an invaluable tool for the fast generation of molecular complexity. lndeed, it allows the strong electrophilic activation of unsaturated hydrocarbon moieties (e.g. alkynes or alienes). During this PhD thesis, we focused our studies on the use of gold's pi acidity as weil as its "classical" - but less discussed - Lewis acid character for the triggering of cascade reactions.Starting from acetylenic heterocycles, we targeted the synthesis of polycyclic compounds. The milder reactivity of silver complexes was also found useful in these reactions, as weil as in the deprotection of methoxybenzyl ethers.