Thesis advisor: Amir H. Hoveyda / Chapter 1. A Review of Sulfonate-Containing NHC Ligands in Copper-Catalyzed Enantioselective Transformations—Maneuvering Selectivities in Tight Space. A comprehensive review of enantioselective copper-catalyzed transformations, which are promoted by a chiral N-heterocyclic carbene metal complex that features a unique sulfonate motif, is provided in this chapter. Reactions have been categorized into four sets: allylic substitutions conjugate additions, Cu-B additions alkenes and multicomponent reactions. The mechanistic scenarios provided by DFT calculations accounts for their uniquely reaction profile in enantioselective allylic substitutions (EAS), enantioselective conjugate additions (EAS) and enantioselective Cu-B additions to alkenes. Mechanistic investigations (density functional theory calculations and deuterium labeling) point to a bridging function for an alkali metal cation connecting the sulfonate anion and a substrate’ s phosphate group to form the branched addition products as the dominant isomers via Cu(III) π -allyl intermediate complexes in EAS reactions. Sulfonate-bearing NHC ligand with different substitution patterns promote EAS reactions with different reactivity and enantioselectivity. We also developed a guideline to follow to choose the proper sulfonate-based NHC ligands according to the combination of the substrates and the nucleophiles. Chapter 2. NHC–Cu-Catalyzed Enantioselective Allylic Substitutions with Silyl-protected Propargyl Boron Reagent to Generate Tertiary and Quaternary Carbon Stereogenic Centers. Catalytic allylic substitution reactions involving a propargylic nucleophilic component are presented; reactions are facilitated by 5.0 mol % of a catalyst derived from a chiral N-heterocyclic carbene (NHC) and a copper chloride salt. A silyl-containing propargylic organoboron compound, easily prepared in multi-gram quantities, serves as the reagent. Aryl- and heteroaryl-substituted disubstituted alkenes within allylic phosphates and those with an alkyl or a silyl group can be used. Functional groups typically sensitive to hard nucleophilic reagents are tolerated, particularly in the additions to disubstituted alkenes. Reactions may be performed on the corresponding trisubstituted alkenes, affording quaternary carbon stereogenic centers. Incorporation of the propargylic group is generally favored (vs allenyl addition; 89:11 to >98:2 selectivity); 1,5-enynes can be isolated in 75−90% yield, 87:13 to >98:2 SN2′:SN2 (branched/linear) selectivity and 83:17−99:1 enantiomeric ratio. Utility is showcased by conversion of the alkynyl group to other useful functional units. Application to stereoselective synthesis of the acyclic portion of antifungal agent plakinic acid A, containing two remotely positioned stereogenic centers, by sequential use of two different NHC–Cu-catalyzed enantioselective allylic substitution (EAS) reactions further highlights utility. Chapter 3. NHC–Cu-Catalyzed Enantioselective Allylic Substitutions with Methylenediboron to Generate Tertiary and Quaternary Carbon Stereogenic Centers. A catalytic EAS method for the site- and enantioselective addition of commercially available di-B(pin)-methane to disubstituted allylic phosphates is introduced. Transformations are facilitated by a sulfonate-containing NHC–Cu complex and products are obtained in 63–95% yield, 88:12 to >98:2 SN2’/SN2 selectivity, and 85:15–99:1 enantiomeric ratio. The utility of the approach is highlighted by its application to the formal synthesis of the cytotoxic natural product rhopaloic acid A, in an all-catalytic-method synthesis route. Catalytic EAS methods of the di-B(pin) methane to Z-trisubstituted allylic phosphates are also disclosed and DFT calculations provide insights to the stereochemical models for those transformations and rationales for the choice of Z-trisubstituted allylic phosphates as the starting materials. Chapter 4. Enantioselective NHC–Cu-Catalyzed Prenyl Conjugate Additions to Enoates to Generate Tertiary Carbon Stereogenic Centers. An efficient catalytic protocol for generation of prenyl-bearing tertiary carbon stereogenic centers from aryl-substituted enoates was achieved in the presence of a chiral alkoxy-based NHC–Cu complex. A range of aryl and heteroaryl-substituted substrate were suitable substrates, the corresponding prenyl conjugate addition products were generated in up to 94% yield and 95:5 enantioselectivity. The utility of the current method has been shown in the application to the synthesis of a selective integrin antagonist. DFT calculations provided a stereochemical model for the ECA reaction employing alkoxy-containing NHC–Cu catalyst. / Thesis (PhD) — Boston College, 2017. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

<p>The wide presence of C-N bonds in biologically and pharmaceutically important compounds continues to drive the development of new C-N bond-forming transformations. Among the different strategies, electrophilic amination is an important synthetic approach for the direct formation of C-N bonds. Compared to electrophilic amination of organometallic reagents, direct amination of C-H bonds will provide a potentially more effective route towards C-N bond formation. Towards this, we proposed an electrophilic amination of C-H bonds via their reactive organometallic surrogate intermediates. Specifically, we are interested in organozinc intermediates and their in situ formation from C-H bonds. </p><p>This dissertation reports our development of direct amination of various C-H bonds using a H-Zn exchange/electrophilic amination strategy as a rapid and powerful way to access a variety of functionalized amines. We were able to achieve C-H zincation using strong and non-nucleophilic bases Zn(tmp)2 or tmpZnCl*LiCl and subsequent electrophilic amination of the corresponding zinc carbanions with copper as a catalyst and O-benzoylhydroxylamines as the electrophilic nitrogen source. With such a one-pot procedure, the synthesis of various amines from C-H bonds has been achieved, including alpha-amination of esters, amides, and phosphonates. Direct amination of heteroaromatic and aromatic C-H bonds has also been developed in good to high yields. It is important to note that mild reactivity of organozinc reagents offers a good compatibility with different functional groups, such as esters, amides, and halides. </p><p>Success in developing direct and efficient syntheses of these various amines is highly valuable. These new amination methods will greatly expand the chemical diversity and space of available amine skeletons, and will contribute to future advances in material science, medicinal chemistry and drug discovery.</p> / Dissertation

Thesis advisor: Amir H. Hoveyda / Chapter 1. Catalytic SN2”-Selective and Enantioselective Substitution Reactions. The first broadly applicable strategy for SN2”-selective and enantioselective catalytic allylic substitution will be presented. It will be shown that transformations can be promoted by 5.0 mol% of a sulfonate-containing NHC–Cu complex (NHC = N-heterocyclic carbene), and may be carried out by the use of a commercially available allenyl–B(pin) (pin = pinacolato) or a readily accessible silyl protected propargyl–B(pin). Products bearing a 1,3 diene, a silyl allenyl or a propargyl moiety were obtained in high efficiency and selectivities. Also provided is insight regarding several of the unique mechanistic attributes of the catalytic process, obtained on the basis of kinetic isotope effect measurements and DFT studies. These investigations indicated that cationic π-allyl–Cu complexes are the likely intermediates, clarifying the role of the s-cis and s-trans conformers of the intermediate organocopper species and their impact on E:Z selectivity and enantioselectivity. It will also be shown we were able to highlight the utility of the approach by chemoselective functionalization of various product types, through which the propargyl, allenyl, or 1,3-dienyl sites within the products can be converted catalytically and chemoselectively to several synthetically useful derivatives. Chapter 2. NHC–Copper–Hydride-Catalyzed Enantioselective Processes with Allenyl Boronates and its Application in Natural Product Synthesis. Here, the development of a catalytic process that delivers otherwise difficult-to-access organoboron compound will be detailed. These processes involve the combination of a hydride, an allenyl–B(pin) and an allylic phosphate. As will be discussed, two unique selectivity problems were solved: avoiding rapid Cu–H reduction of an allylic phosphate, while promoting its addition to an allenylboronate as opposed to the commonly observed Cu–B exchange. We were able to underscore the considerable utility of the approach by applications to preparation of the linear fragment of pumiliotoxin B (myotonic, cardiotonic) and the first enantioselective synthesis of netamine C (anti-tumor), which also served to confirm its stereochemical identity. Chapter 3. Catalytic Enantioselective Prenyl Conjugate Addition Reactions. In this final section, studies leading to the development of the first class of catalytic enantioselective strategies for prenyl conjugate additions will be detailed. At the core of these investigations was finding ways to overcome two problems. One challenge originated from the fact that highly activated allylmetal species often deliver product with low enantioselectivity. The other was that regioselectivity was difficult to control owing to a strong preference for γ-selective additions. As will be described, we were able to address these difficulties by the use of a hydroxy NHC-copper complex and 3,3-dimethyl allyl–B(pin) as a reagent. In the end, we were able to use acyclic as well as cyclic enoates as substrates. The results of DFT studies that provide insight regarding varying selectivity profiles with different chiral ligands will be discussed as well. / Thesis (PhD) — Boston College, 2020. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

In molecular transition metal catalyst architectures, ligand design plays a crucial role in enhancing the efficiency of catalytic reactions. Selected ligands can play a bifunctional role in ligand-assisted catalysis, providing first coordination sphere basic sites and facilitating formation of multinuclear species through monomer bridging, as well as through their electronic and steric effects. This research addresses the underutilization of SNS complexes in various catalytic cycles. Our aim is to expand their activity in different cycles, unlocking untapped reactivity. Specifically, we focus on SNS ligands with soft thiolate and hard amido donors, comparing their catalytic performance in diverse coupling reactions. This comparative study provides insights into the suitability of these ligands with different transition metals, contributing to the understanding of ligand-assisted catalysis. Chapter 1 introduces these concepts and outlines the relevant catalytic reactions studied herein. To gain a deeper understanding of the chemistry involved, a comparative analysis of the reactivity differences between transition metal complexes with similar coordination structures is conducted. This investigation is crucial as it provides valuable insights into the design of suitable ligands for transition metal catalysts. Specifically, Chapters 2 and 3 of this thesis delve into a comparison of the reactivity of coordination complexes with identical metal centers and similar ligands, or even the same molecular formula, in catalysis. In the second chapter, we introduce a new cobalt (II) complex bearing an (SNS) amido ligand for the bifunctional hydroboration of carbonyls. Following an unsuccessful attempt to mono-protonate the amido donor in the bis(amido) complex Co(SᴹᵉNSᴹᵉ)₂ (2.1) treatment with 1 equivalent of 1,3-bis(1-adamantyl)imidazolium chloride (IAd•HCl) resulted in the liberation of one protonated ligand, affording CoᴵᴵCl(SᴹᵉNSᴹᵉ)(a-IAd) (2.2) with an "abnormally" coordinated IAd ligand, i.e., specifically bound through C4 instead of C2 of the imidazole ring. Compound 2.2 exhibited excellent catalytic activity in the hydroboration of aldehydes, displaying high substrate tolerance under mild reaction conditions and short reaction times. Stoichiometric reactions of 2.2 with pinacolborane (HBpin) revealed a bifunctional catalyst activation step, generating free SNS-amine, ClBpin and the active cobalt dihydride catalyst. Generation of an analogous catalyst with a normally coordinated IAd ligand showed poor reactivity in the hydroboration of aldehydes and was unable to effect ketone hydroboration. In Chapter 3, two tetranuclear copper(I) complexes bearing thiolate [Cu(SNSᴹᵉ)]₄ (3.1) and amido [Cu(SNSᴹᵉ)]₄ (3.2) SNS ligands are synthesized and their catalytic activity in a base-free azide-alkyne cycloaddition is compared. Complex 3.1 (1 mol%) demonstrated excellent reactivity for performing this 'click' reaction in water, exhibiting a broad substrate scope and enabling the production of various triazole compounds, including bioactive compound 3.16, which holds potential as an anti-cancer drug. DFT calculations suggested a proton shuttle role for the thiolate donor in conversion of the Cu-coordinated terminal alkyne to the key Cu-alkynyl intermediate. On the other hand, complex 3.2 exhibited reactivity similar to copper chloride. This observation was attributed to the basic nature of the amido ligand, which undergoes protonation by the coordinated alkyne C-H bond, with subsequent dissociation of the SNS-amine from the copper. Without a ligand to stabilize the copper in the less stable +1 oxidation state, a disproportionation reaction occurs, leading to catalyst deactivation. Chapter 4 introduces two palladium(II) thiolate complexes: PdI(κ³-SNSᴹᵉ) (4.1) exhibits catalytic activity in promoting the Heck cross-coupling reaction, while Pd(κ²-SNSᴹᵉ)₂ (4.2) affords no coupling product. In concert with triethylamine base, catalyst 4.1 efficiently produces olefin products with excellent yields, even at low catalyst loadings, and exhibits broad substrate tolerance over a 5 h reaction period. In contrast, the limited catalytic activity of 4.2 can be rationalized by proposing the formation of a Pd(N₂S₂) complex through ligand imine coupling at elevated temperatures, a reaction reported previously for Ni and Co analogs. The tetra-coordinated ligand formed through this isomerization occupies critical coordination sites around the metal, thereby preventing oxidative addition of the organohalide substrate, a key step in the Heck reaction mechanism. This work sheds light on the divergent catalytic behaviors of these two intriguing complexes. Finally, in Chapter 5 we assess what has been learned and identify relevant implications for further work.

The major directions of this dissertation involve (1) the syntheses and characterization of molecular polygons incorporating sp1hybridized carbon linkers and L2Pt corners (L2 = cis-1,3-diphosphine), (2) the development of protected carbon chain complexes featuring fluorous phosphine ligands and (3) click reactions of metal terminal polyynyl complexes and further metallations of the resulting triazole rings. A brief overview is provided in Chapter I. Chapter II details the syntheses of molecular squares containing bidendate diphosphine ligands of the formula R2C(CH2PPh2)2 where R = Me, Et, n-Bu, n-Dec, Bn, and p-tolCH2 (general designation dppp*), in which the R2 groups are intended to circumvent the solubility issues encountered by others. Their syntheses involve double substitutions of the dimesylate compounds R2C(CH2OMs)2 using KPPh2. Building blocks of the formulae (dppp*)PtCl2 and (dppp*)Pt((C≡C)2H)2 are synthesized and characterized, including one crystal structure of the latter. The target complexes are accessed by reactions of (dppp*)PtCl2 with (dppp*)Pt((C≡C)2H)2 under Sonogashira type conditions. Six new squares of the formula [(R2C(CH2PPh2)2)Pt(C≡C)2]4 are characterized including two crystal structures. Further topics include approaches to higher homologues and cyclocarbon synthesis. Chapter III focuses on carbon chain complexes bearing fluorous phosphine ligands of the formula P((CH2)mRfn)3 (Rfn = (CF2)n-1CF3; m/n = 2/8, 3/8, and 3/10). Precursors of the formula trans-(C6F5)((Rfn(CH2)m)3P)2PtCl are synthesized and characterized, including one crystal structure, which reveals phase separation of the fluorous and non-fluorous domains. Reactions with butadiyne give trans-(C6F5)((Rfn(CH2)m)3P)2Pt(C≡C)2H. Oxidative homocouplings afford the target complexes trans,trans-(C6F5)((Rfn(CH2)m)3P)2Pt(C≡C)4(C6F5)(P((CH2)mRfn)3)2Pt. Cyclic voltammetry indicates irreversible oxidations of the title compounds, in contrast to partially reversible oxidations of non-fluorous analogues. Chapter IV focuses on multimetallic complexes achieved by click reactions in metal coordination spheres. The copper catalyzed click reaction between trans-(C6F5)(p-tol3P)2Pt(C≡C)2H (1) and (η5-C5H4N3)Re(CO)3 affords the bimetallic 1,2,3-triazole trans-C6F5)(p1tol3P)2PtC≡CC=CHN((η51C5H4)Re(CO)3)N=N. Further reactions with Re(CO)5OTf and Re(CO)5Br give trimetallated adducts, which represent the first species of this type. An alternative route to a trimetallic complex involves the twofold cycloaddition of the diazide (η5-C5H4N3)2Fe and 1, giving (η5-C5H4NN=N-C(trans-(C≡C)Pt(Pp-tol3)2(C6F5)=CH)2Fe. The crystal structures of the di and trimetallic complexes are compared, but attempts to achieve a fourth metallation involving the =CH groups are unsuccessful. However, when the triazolium salt [trans-(C6F5)(p-tol3P)2PtC≡CC=CHN(CH2C6H5)N=N(Me)]+ I– is treated with Ag2O and [Rh(COD)Cl]2, a =CRh adduct is obtained. The success of =CH metallation is correlated to the 1H NMR chemical shift, indicative of an electronic effect.

Vu l’importance des molécules fluorées dans différents domaines et vu la réactivité engendrée par le 4,4,4-trifluorobut-2-ynoate d’éthyle 1 lors des travaux antérieurs réalisés au laboratoire, nous avons décidé d’étudier le comportement de dérivé fluoré 1 vis-à-vis d’hydrure tributylétain sans l’emploi de catalyseurs ou d’additifs. Le but est d’accéder à de nouveaux synthons fluorés par voies originales.Après une étude préliminaire pour effectuer cette réaction d’hydrostannation dans les meilleures conditions, nous avons réalisé pour la première fois la synthèse totalement régio- et stéréosélective des vinylétains (Z)-2α et (Z)-2β par un simple choix de solvant et sans l’utilisation d’aucun additif. Ces résultats inédits et très encourageants, nous ont conduis à étendre cette stratégie à d’autres hydrures comme l’hydrure de diphénylphosphine et l’hydrure de triphénylgermane..Les vinylétains (Z)-2α et (Z)-2β- de configurations bien définies sont des réactifs de choix pour élaborer de nouvelles structures fonctionnelles trifluorométhylées. En effet, le couplage cupro-catalysé de ces vinylétains en présence d’une quantité catalytique de CuI (10 moles%) avec une variété de bromures d’allyles, de propargyles, d’aryles, de benzyles et d’alcynyles conduisent à une grande variété de composés fluorés jamais décrits dans la littérature.Les méthodes de synthèse développées dans ce travail sont originales et permettent la synthèse d’une grande famille de composés fluorés avec un moindre coût. / The development of a simple method to obtain perfluoroalkylated building blocks for their subsequent utilization in the synthesis of Rf-containing compounds is therefore essential to organofluorine chemistry. Perfluoroalkylated vinyl metals constitute an important class of these building blocks.In order to prepare a new perfluoroalkylated bulding blocks, we investigated transition metal-catalyzed-free hydrostannylation of ethyl 4,4,4-trifluorobut-2-ynoate 1. The hydrostannylation took place smoothly in the absence of additive, providing regioselectively high yields of the corresponding α or β stannylated alkenoates depending on the nature of the solvent used. Indeed, we have demonstrated that the hydrostannylation of 1 in hexane provided the β-stannylated product with high regioselectivity (>95%) and excellent yield (>97%). Using methanol as solvent, total α-regioselectivity of the hydrostannylation of 1 was observed, providing α -tributylstannylacrylate as the sole regioisomer in a nearly quantitative yield.Theses new vinyltins reagents readily undergo copper (I) catalyst coupling reactions with various electrophiles as allyl, propargyl, benzyl and alkynyl bromides to provide good yields of the new corresponding acrylates esters bearing a β-trifluoromethyl group.This method provided a new efficient entry to this important class of compounds

Cette thèse est constituée de trois parties : 1) Le contexte bibliographique, 2) le développement de réactions domino cupro-catalysées et 3) une approche vers la synthèse totale des raputindoles.La première partie introduit d’abord le concept de réactions domino ainsi que leurs applications, puis les réactions catalysées par du cuivre permettant de former des liaisons C-N sont passées en revue en incluant les couplages de Ullmann, Goldberg et de Chan-Lam, les séquences d’activation oxydante de liaisons C-H/formation de liaison C-N, l’insertion de nitrènes et l’hydroamination de liaisons C-C multiples. En se basant sur ces réactions élémentaires permettant de former une liaison C-N unique, les développements récents de réactions domino sont ensuite détaillés.La deuxième partie peut être subdivisée en 3 sections : 1) la synthèse de benzimidazoles, 2) la synthèse d’imidazoles and 3) la synthèse de guanidines. Un rappel des méthodes existantes pour la synthèse de ces motifs est proposé dans chaque section. Notre travail, basé sur la formation de liaisons C-N multiples selon une séquence cupro-catalysée domino, est ensuite détaillé. Celui-ci nous a permis d’aboutir au développement de voies d’accès aux benzimidazoles, en utilisant une réaction séquentielle catalysée par du cuivre en présence d’oxygène à partir d’acides boroniques et d’amidines, à la synthèse d’imidazoles par une réaction de di-amination d’alcynes vrai par des amidines et à l’obtention de guanidines et de 2-aminobenzimidines par une réaction à 3 composant. Ces réactions domino montrent une bonne efficacité et permettent d’assembler des hétérocycles à partir de précurseurs aisément accessibles.La dernière partie est consacrée à la synthèse des raputindoles. La structure, les activités et les réactions clé pour la construction de ces alcaloïdes sont discuté d’abord, nous amenant à proposer une rétrosynthèse pour accéder à ces molécules. Les réactions qui ont retenues notre attention pour construire ces molécules sont une annelation [3+2] irido-catalysée d’acides o-formylarylboronique et de 1,3-diènes, la synthèse de Leimgruber-Batcho pour obtenir des indoles et une séquence d’alkylboration-protodéboration. A partir de cela 3 stratégies ont été évaluées, montrant que l’accès à ce type de composé naturel est envisageable en combinant ces étapes. / This thesis consists in three parts: bibliographic background, copper-catalyzed reactions for synthesis of N-containing compounds, approach to the synthesis of raputindoles.The first part introduces the domino reactions and their applications, then, copper-mediated reactions for construction of C-N bond formation are reviewed including Ullmann, Goldberg and Chan-Lam coupling, oxidative C-H activation/C-N formation, insertion of nitrenes and carbenoids, and hydroamination of multi-C-C bonds. This can be used as guides to design domino reaction. Following these copper-mediated single C-N bond formation reactions, recent developments of copper-catalyzed domino reactions for synthesis of heterocycles are described.The second part can be divided into three sections: 1) synthesis of benzimidazoles, 2) synthesis of imidazoles and 3) synthesis of guanidines. Each section summarizes the existing methods used for their synthesis. Following it, our synthetic work involving copper-catalyzed C-N bond formation domino reactions is discussed in detail. Our objectives include the synthesis of benzimidazoles through copper-catalyzed sequential reaction of benzamidines and boronic acids, synthesis of imidazoles via copper-catalyzed domino reaction of benzamidines and acetylenes, and synthesis of guanidines and 2-aminobenzimidazoles by Cu-catalyzed three-component reaction of cyanamides, boronic acids and amines. These copper-catalyzed domino reactions show high efficiencies from readily available and simple starting materials.The last part is about the total synthesis of raputindoles. The structure and bioactivities of raputindoles and key reactions for the total synthesis of raputindoles are introduced first, the synthetic strategies are then proposed on basis of relative synthetic methods. The key reactions we use for the synthesis of raputindoles are iridium catalyzed [3+2] annulation of o-formylarylboronic acids and 1,3-dienes, Leimgruber-Batcho indole synthesis, transition-metal catalyzed SN2 substitution and alkylborylation-protondeborylation. According to the three strategies we proposed, lots of relative reactions were investigated. The results show that it is possible to synthesize the raputindole molecules based on the iridium catalyzed [3+2] annulation of 2-formylarylboronic acids and 1,3-dienes.

In bacteria, protein synthesis can occur tightly coupled to transcription. In eukaryotes, it is believed that translation occurs solely in the cytoplasm; I test whether some occurs in nuclei and find: (1) L-azidohomoalanine (Aha) – a methionine analogue (detected by microscopy after attaching a fluorescent tag using ‘click’ chemistry) – is incorporated within 5 s into nuclei in a process sensitive to the translation inhibitor, anisomycin. (2) Puromycin – another inhibitor that end-labels nascent peptides (detected by immuno-fluorescence) – is similarly incorporated in a manner sensitive to a transcriptional inhibitor. (3) CD2 – a non-nuclear protein – is found in nuclei close to the nascent RNA that encodes it (detected by combining indirect immuno-labelling with RNA fluorescence in situ hybridization using intronic probes); faulty (nascent) RNA is destroyed by a quality-control mechanism sensitive to translational inhibitors. I conclude that substantial translation occurs in the nucleus, with some being closely coupled to transcription and the associated proof-reading. Moreover, most peptides made in both the nucleus and cytoplasm are degraded soon after they are made with half-lives of about one minute. I also collaborated on two additional projects: the purification of mega-complexes (transcription ‘factories’) containing RNA polymerases I, II, or III (I used immuno-fluorescence to confirm that each contained the expected constituents), and the demonstration that some ‘factories’ specialize in transcribing genes responding to tumour necrosis factor α – a cytokine that signals through NFκB (I used RNA fluorescence in situ hybridization coupled with immuno-labelling to show active NFκB is found in factories transcribing responsive genes).

Dans ce mémoire, je présente mes études sur une stratégie efficace développée pour la synthèse de cétones homoallyliques substituées à partir de l’addition en cascade de réactifs de Grignard vinyliques substitués sur des α-amino esters catalysée par des sels de cuivre. L’utilisation de ces cétones homoallyliques a permis d’obtenir des mimes peptidiques comprenant un isostère de type hydroxyéthylène du lien amide. L’étape clé de cette stratégie repose sur la synthèse de cétones homoallyliques substituées intermédiaires à partir de la réaction d’additions en cascade catalysée au cuivre, de bromure de β,β-diméthylevinyle magnésium sur des analogues d’esters de la phénylalanine et de la sérine. Les cétones homoallyliques résultantes sont réduites sélectivement en alcool, la liaison double est clivée oxydativement et l’acide carboxylique résultant est couplé à un acide aminé. Afin d’évaluer l’effet qu’ont le remplacement du lien amide central dans un coude β par un hydroxyéthylène et de la présence d’un gem diméthyle sur la chaîne carbonée sur la conformation tridimensionnelle adoptée par les tripeptides générés, des analyses à l’état solide par diffraction aux rayons X, des analyses en solution par la spectroscopie RMN et des expériences de type NOESY ont été réalisées. Ces études ont permis de définir un nouveau type de coude β. La présence de pont hydrogène intramoléculaire et l’effet de restriction de conformation induit par le gem diméthyle, généralement appelé effet Thorpe-Ingold, favorisent la formation d’un coude β. / In this thesis, I discuss my studies toward the synthesis of substituted homoallylic ketones from the copper-catalyzed cascade addition of substitued vinyl Grignard reagents to carboxylic esters. The homoallylic ketones were used to provide different peptidomimetics containing a hydroxyethylene isostere instead of an amide bond. The methyl ester of phenylalanine and serine derivatives were reacted in copper-catalyzed cascade additions of substitued vinylmagnesium bromide to provide substitued homoallylic ketone intermediates. Selective reduction of the ketone to an alcohol, oxidative cleavage of the double bond, followed by peptide coupling with amino acid lead to the desired peptidomimic. The influence of changing the central amide bond for a hydroxyethylene isostere in a β-turn and the effect of a gem dimethyl group on the backbone conformation adopted by the newly synthesized tripeptides, were studied by X-ray diffraction and solution NMR spectroscopy using NOESY experiments. From these studies, it was revealed that the iso-butyric acid hydroxyethylene isomer induced a β-turn-like conformation, and may serve as a novel scaffold for peptide mimicry.

Dans ce mémoire, je présente mes études sur une stratégie efficace développée pour la synthèse de cétones homoallyliques substituées à partir de l’addition en cascade de réactifs de Grignard vinyliques substitués sur des α-amino esters catalysée par des sels de cuivre. L’utilisation de ces cétones homoallyliques a permis d’obtenir des mimes peptidiques comprenant un isostère de type hydroxyéthylène du lien amide. L’étape clé de cette stratégie repose sur la synthèse de cétones homoallyliques substituées intermédiaires à partir de la réaction d’additions en cascade catalysée au cuivre, de bromure de β,β-diméthylevinyle magnésium sur des analogues d’esters de la phénylalanine et de la sérine. Les cétones homoallyliques résultantes sont réduites sélectivement en alcool, la liaison double est clivée oxydativement et l’acide carboxylique résultant est couplé à un acide aminé. Afin d’évaluer l’effet qu’ont le remplacement du lien amide central dans un coude β par un hydroxyéthylène et de la présence d’un gem diméthyle sur la chaîne carbonée sur la conformation tridimensionnelle adoptée par les tripeptides générés, des analyses à l’état solide par diffraction aux rayons X, des analyses en solution par la spectroscopie RMN et des expériences de type NOESY ont été réalisées. Ces études ont permis de définir un nouveau type de coude β. La présence de pont hydrogène intramoléculaire et l’effet de restriction de conformation induit par le gem diméthyle, généralement appelé effet Thorpe-Ingold, favorisent la formation d’un coude β. / In this thesis, I discuss my studies toward the synthesis of substituted homoallylic ketones from the copper-catalyzed cascade addition of substitued vinyl Grignard reagents to carboxylic esters. The homoallylic ketones were used to provide different peptidomimetics containing a hydroxyethylene isostere instead of an amide bond. The methyl ester of phenylalanine and serine derivatives were reacted in copper-catalyzed cascade additions of substitued vinylmagnesium bromide to provide substitued homoallylic ketone intermediates. Selective reduction of the ketone to an alcohol, oxidative cleavage of the double bond, followed by peptide coupling with amino acid lead to the desired peptidomimic. The influence of changing the central amide bond for a hydroxyethylene isostere in a β-turn and the effect of a gem dimethyl group on the backbone conformation adopted by the newly synthesized tripeptides, were studied by X-ray diffraction and solution NMR spectroscopy using NOESY experiments. From these studies, it was revealed that the iso-butyric acid hydroxyethylene isomer induced a β-turn-like conformation, and may serve as a novel scaffold for peptide mimicry.