This thesis deals with the copper-catalyzed substitution of allylic substrates. In the first part of this thesis, the synthesis of a series of metallocenethiolates is described. The thiolates were examined as ligands in the enantioselective copper(I)-catalyzed γ-substitution of allylic acetates. The second part describes a study on copper-catalyzed α-substitution of enantiomerically pure secondary allylic esters. It was observed that the degree of chirality transfer is strongly dependent on the reaction temperature. The loss of chiral information is consistent with an equilibration of the allylCu(III) intermediates prior to product formation, which is essential in order to realize a copper-catalyzed dynamic kinetic asymmetric transformation process. The third part describes a study on copper-catalyzed stereoselective α-substitution of enantiopure acyclic allylic esters. This method, when combined, with ruthenium and enzyme catalyzed dynamic kinetic resolution of allylic alcohols, provides a straightforward route to pharmaceutically important α-methyl carboxylic acids. The fourth part is a mechanistic study on the reaction of perfluoroallyl iodide with organocuprates. Experimental studies as well as theoretical calculations were used to explain the contrasting reactivity of perfluoroallyl iodide vs. allyl iodide in cuprate allylation reactions. In the fifth part, the development of a practical and useful method for the preparation of pentasubstituted acylferrocenes is presented.

The antiviral or anticancer activities of C-5 modified pyrimidine nucleoside analogues validate the need for the development of their syntheses. In the first half of this dissertation, I explore the Pd-catalyzed cross-coupling reaction of allylphenylgermanes with aryl halides in the presence of SbF5/TBAF to give various biaryls by transferring multiple phenyl groups, which has also been applied to the 5-halo pyrimidine nucleosides for the synthesis of 5-aryl derivatives. To avoid the use of organometallic reagents, I developed Pd-catalyzed direct arylation of 5-halo pyrimidine nucleosides. It was discovered that 5-aryl pyrimidine nucleosides could be synthesized by Pd-catalyzed direct arylation of N3-free 5-halo uracil and uracil nucleosides with simple arenes or heteroaromatics in the presence of TBAF within 1 h. Both N3-protected and N3-free uracil and uracil nucleosides could undergo base-promoted Pd-catalyzed direct arylation, but only with electron rich heteroaromatics. In the second half of this dissertation, 5-acetylenic uracil and uracil nucleosides have been employed to investigate the hydrogermylation, hydrosulfonylation as well as hydroazidation for the synthesis of various functionalized 5-vinyl pyrimidine nucleosides. Hydrogermylation of 5-alkynyl uracil analogues with trialkylgermane or tris(trimethylsilyl)germane hydride gave the corresponding vinyl trialkylgermane, or tris(trimethylsilyl)germane uracil derivatives. During the hydrogermylation with triphenylgermane, besides the vinyl triphenylgermane uracil derivatives, 5-[2-(triphenylgermyl)acetyl]uracil was also isolated and characterized and the origin of the acetyl oxygen was clarified. Tris(trimethylsilyl)germane uracil derivatives were coupled to aryl halides but with decent yield. Iron-mediated regio- and stereoselective hydrosulfonylation of the 5-ethynyl pyrimidine analogues with sulfonyl chloride or sulfonyl hydrazine to give 5-(1-halo-2-tosyl)vinyluracil nucleoside derivatives has been developed. Nucleophilic substitution of the 5-(β-halovinyl)sulfonyl nucleosides with various nucleophiles have been performed to give highly functionalized 5-vinyl pyrimidine nucleosides via the addition-elimination mechanism. The 5-(β-keto)sulfonyluracil derivative has also been synthesized via the aerobic difunctionalization of 5-ethynyluracil analogue with sulfinic acid in the presence of catalytic amount of pyridine. Silver catalyzed hydroazidation of protected 2'-deoxy-5-ethynyluridine with TMSN3 in the presence of catalytic amount of water to give 5-(α-azidovinyl)uracil nucleoside derivatives was developed. Strain promoted Click reaction of the 5-(α-azidovinyl)uracil with cyclooctyne provide the corresponding fully conjugated triazole product.

Les réactions de couplage croisé catalysées par des métaux de transition permettant la formation de liaisons C-C et C-hétéroatome sont à la base de la synthèse d’intermédiaires clefs pour la chimie pharmaceutique, la chimie supramoléculaire et la chimie des matériaux. Cependant, certains catalyseurs métalliques utilisés sont reconnus comme étant assez coûteux ou toxiques. Le développement de catalyseurs alternatifs peu coûteux et écologiques, tels que les catalyseurs à base de cobalt qui ont déjà montré leur efficacité pour la formation de liaisons C-C, fait donc l’objet d’études. Nous avons décidé d’utiliser des organozinciques aromatiques fonctionnalisés, obtenus facilement à l’aide d'une réaction catalysée par CoBr2, dans des réactions de couplage catalysées par CoBr2 avec des chloro-diazines et -triazines aboutissant à la synthèse d’aryldiazines et -triazines. Des organozinciques benzyliques ont également pu être utilisés dans ces réactions permettant la synthèse de benzyltriazines. Nous avons également envisagé l’utilisation d’autres types de substrats. Des réactions de couplage catalysées par CoBr2 entre des organozinciques aromatiques et des méthylthiopyrimidines ou le 2- méthylthiobenzo[b]thiazole ont ainsi été réalisées, conduisant à la synthèse de 2,4- diarylpyrimidines ou de 2-arylbenzo[b]thiazoles. Nous avons également étudié la réactivité des dérivés du benzonitrile dans les couplages directs catalysés par CoBr2 avec des halogénures aromatiques basés sur l’activation de la liaison C-CN pour former des biaryles. Enfin, des réactions de couplage croisé C-N entre des halogénures aromatiques et l’aniline conduisant à la synthèse de diarylamines ont été étudiées / Transition metal-catalyzed cross-coupling reactions allowing the formation of C-C or C-Heteroatom bonds underlie the synthesis of key intermediates for pharmaceutical, supramolecular chemistry and material sciences. Thereby, the development of these methodologies is prominent and an increasing number of studies are devoted to these processes. However, some metallic catalysts are known to be rather expensive or toxic. Consequently, the development of alternative sustainable catalysts such as cobalt or ironbased catalysts has been studied over the past few years. Cobalt-catalysts have been little-used although they have shown to be effective for various C-C bond forming reactions. Functionalized arylzinc reagents can be readily obtained from the corresponding arylhalides using a CoBr2-catalyzed reaction. First we envisioned using these arylzinc reagents in CoBr2-catalyzed cross-coupling reactions with chlorodiazines and chlorotriazines leading to aryldiazines and aryltriazines. Benzylzinc reagents had also been used in these reactions and we synthesized various benzyltriazines in this manner. We also studied whether we can use other kind of substrates in these reactions. Thus, we performed CoBr2-catalyzed cross-coupling reactions between arylzinc reagents and methylthiopyrimidines or methylthiobenzo[b]thiazole derivatives leading to 2,4-diarylpyrimidines and 2- arylbenzo[b]thiazole. Then, we studied the reactivity of benzonitrile derivatives in direct cross-coupling reactions with arylhalide based on C-CN bond activation using CoBr2 as catalyst. Finally, we also carried out the study of CoBr2-catalyzed C-N cross-coupling reactions for the synthesis of diarylamines

The Bull-Hutchings-Quayle (BHQ) reaction is a novel method for the synthesis of 1-(bromo/chloro)napthalenes from 2-allyphenyl-2’,2’,2’-tri(bromo/chloro)acetates. The reaction is also known as Atom Transfer Radical Cyclisation-Benzannulation (ATRC-Benzannulation). The ATRC-Benzannulation of structurally diverse 2-(cyclohex-1-en-1-ylmethyl)phenyl 2’,2’,2’-trichloroacetates in the presence of 1,3bis-(2,6diisopropylphenyl)imidazolium copper(I) chloride [“Nolan NHC-CuCl”] complexes, using microwave or thermolytic methods, afford a range of 9-chloro-1,2,3,4-tetrahydroanthracenes. Efficient ATRC-Benzannulation has been restricted to microwave conditions so a thermolytic method has been developed as an alternative. Application of BHQ methodology toward the synthesis of the core structure of lactonamycin are reported. Stille, Suzuki and Sonogashira cross-coupling methods were used for the synthesis of diene precursors of a lactonamycin analogue. [4+2] Diels-Alder cycloadditions have been investigated with the diene precursors and various dienophiles. 1-Chloroquinone has been displaced with para-methoxyphenol to generate 1-para-methoxyquinone. CAN mediated oxidation of 1-para-methoxyquinone has yielded 1-hydroxyquinone.

Thesis advisor: James P. Morken / This dissertation details three main projects that focus on stereoselective synthesis of organoboron reagents and their application to total synthesis studies. The first chapter describes the development of an enantioselective palladium-catalyzed conjuntive cross-coupling of bis(alkenyl)borates to access chiral allylboron reagents. These reagents are of high synthetic value that is demonstrated through various applications. The second chapter describes the development of a diastereoselective amine-modified boron-Wittig reaction with ketone electrophiles to access trisubstituted alkenyl boronic esters. The synthetic utility of these trisubstituted alkenyl boronic esters is demonstrated through a novel palladium-catalyzed cross-coupling reaction. The third chapter encompassess studies toward the total synthesis of natural products amphidinolides C and F. It highlights the application of methods developed in the Morken laboratory in the context of challenging total synthesis. It also highlights the potential for newly developed conjunctive cross-coupling and boron-Wittig reactions to solve problems in total synthesis. / Thesis (PhD) — Boston College, 2020. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

With a few exceptions, all organisms are restricted to the 20 canonical amino acids for ribosomal protein biosynthesis. Addition of new amino acids to the genetic code can introduce novel functionalities to proteins, broadening the diversity of biochemical as well as chemical reactions and providing new tools to study protein structure, reactivity, dynamics and protein-protein-interactions. The site directed in vivo incorporation developed by P. G. SCHULTZ and coworkers, using an archeal orthogonal tRNA/aaRS (aminoacyl-tRNA synthase) pair, allows site-specifically insertion of a synthetic unnatural amino acid (UAA) by reprogramming the amber TAG stop codon. A variety of over 80 different UAAs can be introduced by this technique. However by now a very limited number can form kinetically stable bonds to late transition metals. This thesis aims to develop new catalytically active unnatural amino acids or strategies for a posttranslational modification of site-specific amino acids in order to achieve highly enantioselective metallorganic enzyme hybrids (MOEH). As a requirement a stable protein host has to be established, surviving the conditions for incorporation, posttranslational modification and the final catalytic reactions. mTFP* a fluorescent protein was genetically modified by excluding any exposed Cys, His and Met forming a variant mTFP*, which fulfills the required specifications. Posttranslational chemical modification of mTFP* allow the introduction of single site metal chelating moieties. For modification on exposed cysteines different maleiimid containing ligand structures were synthesized. In order to perform copper catalyzed click reactions, suitable unnatural amino acids (para-azido-(L)-phenylalanine, para-ethynyl-(L)-phenylalanine) were synthesized and a non-cytotoxic protocol was established. The triazole ring formed during this reaction may contribute as a moderate σ-donor/π-acceptor ligand to the metal binding site. Since the cell limits the incorporation of boronic acids, an aqueous protocol for Miyaura borylation using a highly active palladacycle catalyst was established and can be transferred to a selective borylation of proteins. It allows subsequent Suzuki cross coupling and therefore broadens the possibilities for chemical modifications and the establishment of new metalloenzymes. Different metal chelating amino acids were investigated, such as Hydrochinolin-Alanine, Bipyridyl-Alanine, Dipyridine-Lysines and phosphorous containing amino acids.

This thesis is centered around the use of flow chemistry to enable cycles in order to increase reaction or process efficiency. Chapter two describes the development of a pseudo-catalytic cycle in space; a strategy to achieve formal sub-stoichiometric loading of a chiral auxiliary. By telescoping auxiliary attachment, asymmetric transformation and auxiliary cleavage into one continuous flow process, coupled with separation of product and recovery of auxiliary, the reuse of the auxiliary can be automated by returning the recovered auxiliary back to the start of the process to achieve ‘turn-over.’ An asymmetric hydrogenation mediated by Oppolzer’s sultam is used to demonstrate this concept. In order to achieve cycles such as the one discussed in Chapter two, the ability to telescope reactions in flow is paramount. However, solid handling challenges are frequent when transitioning to flow, leading to limitations in potential solvents or conditions in order to achieve homogeneity. This complicates the ability to telescope reactions, and to address this challenge the work in Chapter three focuses on the development of a general and simple solution to negate precipitation problems arising from precipitation of base·HX salts, a frequent reaction by-product of common reactions. By using bases that form low- to moderate-melting salts upon protonation, precipitation is precluded while reactions are performed above the melting point of the base·HX salt. This is shown to be applicable for a wide variety of substitution reactions and allow facile reaction telescoping. Chapter four focus on overcoming severe scope limitations in palladium catalyzed transformations that result when rapid background reactions deplete the nucleophilic coupling partner faster than catalyst turnover. This work starts with real-time MS investigations to investigate why slow addition of Grignard or organolithium nucleophiles facilitates substantial scope expansion in Kumada-Corriu or Murahashi cross-couplings, and then uses the information gleaned from these studies to significantly expand the accessible scope of palladium catalyzed aryl halide–diazo cross-coupling, through controlled addition of the diazo reagent at a rate that approximates aryl halide oxidative addition, in combination with on-demand flow synthesis of non-stabilized diazo reagents. Chapter five focuses on improving efficiency in the collection of kinetic data in flow, by developing a reaction cycling reactor. Conversion over time data is obtained by passing a discrete reaction slug back-and-forth between two residence coils, with analysis performed each time the solution passes from one coil to the other. In contrast to a traditional steady state flow system, which requires >5 X the total reaction time to collect data, this reactor design collects all the data during a single reaction. Multiple reactions can also be monitored at the same time by performing multiple reactions as sequential slugs in the reactor. The reactor is demonstrated by application to a wide variety of transformations and different methods of kinetic analysis.

Ce travail de thèse présente de nouvelles réactions catalysées au cobalt de couplages croisés entre un arylzincique et divers électrophiles. Après une introduction générale sur la catalyse au cobalt et les arylzinciques, le premier chapitre est consacré à la formation de biaryles cétones. La réaction entre un arylzincique et le chloroformiate d’éthyle en présence du bromure de cobalt et du ligand bipyridine conduit à la formation de biaryles cétones symétriques avec de très bons rendements dans des conditions simples. Il a été démontré que ce chloroformiate d’éthyle se décompose en monoxyde de carbone au cours de la réaction. Les premiers essais pour étendre cette méthode à la synthèse de biaryles asymétriques sont également décrits à partir d’arylzinciques et de diverses molécules carbonylées. Le deuxième chapitre est quant à lui porté sur le couplage de Negishi entre un arylzincique et un bromure d’aryle ou unchlorure d’hétéroaryle. L’avantage de cette méthode est que le cobalt présent pour former l’arylzincique sert également à former le biaryle, il n’y a donc pas ajout d’un autre catalyseur dans la seconde étape de la réaction. Les premiers résultats obtenus pour la formation de biaryles sont encourageants mais ont besoin d’être approfondis. Une méthode similaire a été utilisée pour la synthèse de nouvelles molécules à fluorescence retardée pour obtenir des diodes électro luminescentes organiques de troisième génération. Le troisième chapitre décrit la réaction catalysée au cobalt entre un arylzincique et des sources électrophiles de soufre, les sels de Bunte. Cependant, ces sulfures d’aryles s’oxydent facilement dans le milieu réactionnel et donnent des sulfoxydes et des sulfones, ce qui limite l’utilisation de cette méthode. Enfin, le dernier chapitre est consacré à des travaux préliminaires sur la trifluorométhylation d’aryl zinciques à partir de sources électrophiles ou nucléophiles trifluorométhylées. / This thesis presents new cobaltcatalyzed cross-coupling reactions between arylzinc derivatives and various electrophilic reagents. After a general introduction on cobalt-catalysis and arylzinc compounds, the first chapter is dealing with the formation of diaryl ketones. Reaction between arylzinc bromides and ethyl chloroformate in presence of cobalt bromide and bipyridine ligand leads to the formation of symmetrical diaryl ketones with very good yields under simple conditions. It has been shown that ethyl chloroformate decomposes into carbon monoxide during the reaction. First attempts to extend this method to the synthesis of unsymetrical diaryl ketones are also described from arylzinc bromides and various carbonyl containing substrates. As for the second chapter, it is focused on the Negishi coupling between arylzinc bromides and an aryl bromide or an heteroaryl chloride. The advantage of this method is that the cobalt used to form the arylzinc bromide also serves to form the biaryl, hence there is no addition of another catalyst in the second step of the reaction. Results about the formation of biaryls are promising, but this reaction needs to be thorough. A similar methodology was used for the synthesis of new delayed fluorescence molecules to obtain highly efficient organic light emitting diodes. The third chapter describes the cobalt-catalyzed reaction between an arylzinc bromide and an electrophilic source of sulfur, a Bunte salt. However, these aryl sulfides can be easily oxidized in the reaction mixture and give sulfoxides and sulfones, which limit the use of this method. Finally, the last chapter is about preliminary works on the trifluoromethylation of arylzinc bromides from electrophilic or nucleophilic trifluoromethyl sources.

Ces travaux de thèse se partage en deux parties distinctes : d’une part, les travaux concernant l’insertion du cobalt dans la liaison C(O)–N d’amide non-planaire, et les réactions de catalyse qui en découlent, et d’autre part, le développement d’une nouvelle famille de complexes de cobalt, basé sur ligand 5-(4-pyridyl)dipyrrométhène et ses dérivés. Dans la première partie, qui concerne la catalyse au cobalt avec les dérivés d’amides, la réactivité de différents sels et complexes de cobalt avec les amides non-planaires a été étudiés. L’insertion du cobalt se fait en présence de bipyridine en tant que ligand, dans le DMF, avec du manganèse métallique en tant que système réducteur. L’optimisation des réactions de conversion des amides secondaires en esters et les couplages réducteurs entre amides et iodoaryles est ensuite décrite.Dans la seconde partie, concernant la chimie de coordination du cobalt, le développement de complexes cobalt-dipyrrométhène est présenté. Dans un premier temps, l’optimisation de la synthèse des 5-(4pyridyl)dipyrrométhène décrite, suivi de tests de complexation avec différents précurseurs de cobalt. Le ligand ayant deux sites de coordination, la coordination sélective d’un métal de transition sur un des sites dépends principalement de l’encombrement du site "dipyrrométhène”. Si ce site est suffisamment encombré, le cobalt se chélate préférentiellementsur la partie pyridine. Pour forcer la coordination du cobalt dans la partie dirpyrrin, il est nécessaire de bloquer la partie pyridyl. En coordinant un précurseur de ruthénium photosensible sur la pyridine avant le cobalt, il est possbile d’obtenir un complexe bimétallique cobalt-ruthenium, permettant la photoréduction du cobalt, et donc potentiellement le développement d’une catalyse au cobalt sans réducteur métallique. / This thesis is divided in two distinct part: on one side, the works concerning the cobalt insertion into the C(O)–N bond of non-planar amides, and the resulting reactions, and on the other side, the development of a new family of cobalt complexes, based on the 5-(4-pyridyl)dipyrromethene ligand and its derivatives.In the first part, concerning cobalt catalysis with amide derivatives, the reactivity of different cobalt precursors and complexes toward non-planar amides has been studied. The insertion of the cobalt can be realized in presence of bipyridine as ligand, en DMF, with manganese powder as reductant system. The otpimization of the amide-to-ester conversion and the reductive cross-coupling between amides and iodo-aryl is then described.In the second part, concerning the coordination chemistry of cobalt, the development of cobalt-dipyrromethene complexes is presented. Firstly, the optimization of the 5-(4-pyridyl)dipyrromethene synthesis is described,followed by complexation tests with different cobalt precursors. With two coordination sites on the ligand, the selective coordination of a transition metal on one of the sites depends mainly on the dipyrrin hindrance. If this part is hindered enough, cobalt chelate preferentially on the pyridyl part. To force the cobalt coordination on the dipyrrin part, it is necessary to occupied the pyridyl part. By coordinating a photoensitive ruthenium precursor on the pyridine, it is possible to obtain un bimetallic cobalt-ruthenium complex, allowing the cobalt photoreduction, and potentially the development of a cobalt catalysis without metallic reductant.

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第19183号 / 工博第4060号 / 新制||工||1626(附属図書館) / 32175 / 京都大学大学院工学研究科合成・生物化学専攻 / (主査)教授 吉田 潤一, 教授 杉野目 道紀, 教授 松原 誠二郎 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM