Le travail décrit dans ce manuscrit de thèse est consacré à l'utilisation du contre-ion chiral en catalyse asymétrique organométallique. Dans un premier temps, nous avons développé et optimisé une voie de synthèse du phosphate d'argent chiral Ag(S)TRIP de manière à pouvoir obtenir ce dernier avec des rendements reproductibles et de bons degrés de pureté. L'étude de la réactivité d'un complexe Ru/Au original présentant une plateforme organométallique a été entreprise et a montré une différence de réactivité notable de ce dernier comparée à celle de Ph3PAuCl dans le cas particulier des cycloisomérisations de  hydroxyallénynes. L'utilisation du phosphate d'argent Ag(S)TRIP en association avec ce complexe bimétallique a permis d'obtenir un excès énantiomérique prometteur de 25% dans la cycloisomérisation d'un allénol incorporant un lien gem diphényle. Nous avons rapporté le premier exemple de carbocyclisation énantiosélective d'énynes-1,6 métallocatalysée en présence d'un contre-ion chiral grâce au développement d'un système à l'iridium cationique généré in situ à partir du complexe de Vaska. Une étude DFT originale et inédite a permis de mettre en évidence la formation d'une paire d'ions séparée par le substrat et dans laquelle le phosphate établit des liaisons du type liaisons hydrogènes avec l'ényne. Nous avons également rapporté les premiers exemples de cycloadditions [2+2+2] catalysées par des complexes de rhodium cationiques générés in situ en présence du contre-ion chiral Ag(S)TRIP. Ces travaux nous ont permis de justifier pour la première fois l'utilisation originale d'un contre-ion comme inducteur de chiralité dans ces réactions de cycloaddition

Title from first page of PDF document. Includes bibliographical references (p. 55-57).

Part A: Synthesis of 5- and 6-Membered Camphor-Based Hydrazides as Organocatalysts for Cycloaddition Reactions The favorable environmental and reactivity qualities of organocatalysts are contributing to the popularization of this method for the acceleration of enantioselective reactions. Research in our group has been focused on the synthesis of camphor-derived hydrazide based organocatalysts for enantioselective cycloaddition processes. Recent results suggest that the presence of an exocyclic electron withdrawing group on the hydrazide moiety, as well as the incorporation of the hydrazide moiety into a 6-membered ring, may have a beneficial effect on the kinetics of the catalysts. A variety of camphor-based cyclic hydrazides have been synthesized and tested in Diels-Alder reactions, varying both the ring size and placement of the electron withdrawing group. Part B: Synthesis of Isocampholenic Acids by the Rearrangement of Camphor Derivatives A variety of substituted isocampholenic acid derivatives have been prepared by rearrangement of the camphor skeleton of a variety of tertiary alcohols derived from ketopinic acid. The reaction is highly reliable and retains the stereochemical information from the camphor scaffold. This rearrangement represents an efficient way to prepare synthetically useful isocampholenic acids. Mechanistic experiments show that the rearrangement does not involve exogenous water and that a short-lived carbocation is implicated in the reaction. Part C: Diastereoselective Formation of Quaternary Centers from Stereodefined Trisubstituted Alkenes Previous work in our laboratory has focused on the preparation of single-isomer tri- and tetra-substituted olefins. This methodology has been used in the construction of a variety of alkenyl esters in good to excellent yields. These alkenyl esters could then be transformed into the corresponding 3,3-disubstituted allyl boronates in a stereocontrolled fashion. There are a limited number of methods available to prepare single isomer 3,3-disubstituted allyl boronates, which can be important precursors in the stereoselective preparation of all-carbon quaternary centers. Our methodology has therefore been applied to the construction of single isomer 3,3-disubstituted allyl boronates and subsequently used in the stereoselective generation of all-carbon quaternary centers by the reaction of these allyl boronates with aldehydes.

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The use of ionic liquids (ILs) as both reagents and solvents is widely recognised. ILs offer a number of advantages compared to regular molecular solvents. These advantages include: chemical and thermal stability, no measurable vapour pressure, no or lower toxicity, non-flammability, catalytic ability, high polarity and they can be recycled. There are a number of research groups investigating the various applications of this reaction medium and most studies have focused on solvents derived from the imidazolium cation. The use of the imidazolium-based ILs in the Diels-Alder reaction has been studied in detail and higher yields compared to conventional methods have been reported. The IL affects the rate and interesting selectivities have been observed. However, not much attention has been paid to the scope and limitations of phosphonium ILs (PILs). Therefore the focus of this thesis is the synthesis and application of novel chiral PILs as environmentally benign, task-specific solvents for the Diels-Alder reaction. In addition, this research seeks alternative ways to eliminate the use of toxic heavy metal catalysts and to exploit methodologies which reduce the energy consumption of the Diels-Alder reaction. A series of CILs were synthesised from the chiral pool and they were characterised by thermogravimetric analysis, differential scanning calorimetry and spectroscopy. They were then investigated as solvents and catalysts in the Diels-Alder reactions of a series of dienes (cyclopentadiene, isoprene, 2,3-dimethylbuta-1,3-diene, furan, pyrrole, N-methyl pyrrole) and dienophiles (methyl acrylate, methyl vinyl ketone, acrylonitrile, dimethyl maleate, acrolein, dimethylacetylene dicarboxylate, maleic anhydride and maleimide). Investigation of the effect of PILs in the presence of three heterogeneous catalysts Al2O3, SiO2 and K-10 montmorillonite were studied. Ultrasound and microwave-assisted Diels-Alder reactions in the PILs, in the absence and presence of the catalysts, were also studied. The reactions of these prototypical substrates illustrated that the solvents are indeed task-specific. / University of Bradford

Dipolar (3+2) cycloadditions are extensively utilized by synthetic chemists for accessing important 5-membered heterocyclic structures. After the pioneering work by Rolf Huisgen in the early 1960s, the field greatly matured and found applications in a variety of fields of chemistry. Worthy of mention, the discovery by Meldal, Sharpless, and Folkin of copper-catalyzed azide alkyne cycloadditions (CuAAC), also referred to as a “Click” reaction, was awarded the Nobel Prize in 2022. The finding of this ideal CuAAC reaction originated from the reliability of dipolar (3+2) cycloaddition reactions, whose transformation was rendered extremely kinetically favorable and stereospecific with the use of copper-catalysis. It is therefore of high importance to continue finding novel (3+2) cycloadditions, despite the apparent maturity of the field. The research described in this thesis presents the efforts towards the synthesis of fused pyrroles and thiophenes by means of (3+2) cycloaddition cascades using ynamides and alkynyl sulfides as isoelectronic species to 1,3-dipoles. In Chapter 2, the exploration of different strategies to bridge the in-situ synthesis of alkyne tethered ynamide and our group’s previously described thermally induced (3+2) cycloaddition cascade was investigated. Many challenges were faced when attempting to design one-pot procedures including the unprecedented degradation of yne-ynamides under metal-containing reaction conditions. This impeded the use of copper-catalyzed cross-coupling reactions as a general retrosynthetic disconnection for the in-situ formation of the ynamide functionality. Even an attempt to functionalize an ynamide precursor containing a tethered terminal alkyne by a Sonogashira cross-coupling was unsuccessful. With the aim to find an efficient way of synthesizing these diynes while limiting the use of stoichiometric reagents, the use of a previously unreported ynamide substituted propynal building block was explored. These aldehyde synthons were easily synthesized from accessible ynamide substituted propargyl alcohols using Dess-Martin Periodinane as the oxidant. Upon mixing these propynal derivatives with primary propargyl amines, a rapid condensation reaction takes place as long as the removal of water is done. These in-situ formed yne-ynamides then undergo (3+2) cycloaddition cascades towards fully substituted fused pyrroles at temperatures ranging from 60 to 100 oC. While the method was found to be limited to [3.3.0] fused pyrroles and moderate yields were observed (22-55% yields, 8 examples), this one-pot method permitted an extremely rapid growth of molecular complexity. Collectively, the work described in this chapter further accentuates the utility of ynamides as building blocks for densely functionalized pyrrole heterocycles. In Chapter 3, the reactivity of analogous alkyne tethered alkynyl sulfides (thioalkynes) was investigated. Alkynyl sulfides are an important class of heteroatom-substituted alkynes, whose alkynyl carbons are weakly polarized in contrast to ynamines (N-alkynyl amines) derivatives. While thioalkynes display superior stability in contrast to ynamides, both X-alkynyl species share similar reactivities. Upon heating of S-ester substituted yne-alkynyl sulfides, fully substituted thiophenes were obtained indicating that the reactivity observed with ynamides (as 4 cycloaddition partner) was transferable to thioalkynes. When S-alkyl substituted yne-thioalkynes are used, 5-unsubstituted thiophenes are formed instead. The use of S-tert-butyl substituted alkynyl sulfides enabled a broad scope of 5-unsubstituted fused thiophenes to be obtained via an intramolecular (3+2) cycloaddition and dealkylation cascade. The transient thiophenium ylide cycloadducts formed as a result of (3+2) cyclization were also efficiently trapped with electrophiles generating complex functionalized thiophenes. The use of S-n-propyl substituted yne-alkynyl sulfide was necessary in this case to provide control over product selectivity and to permit the electrophilic trapping to occur before dealkylation. Collectively, the reactivity cascades of thermally formed thiophenium ylides cycloadducts were studied in detail revealing a modulable and controllable reactivity by judicious choice of alkynyl sulfide substitution and reaction condition. In Chapter 4 the use of coinage metals for catalyzing the (3+2) cycloaddition of yne-alkynyl sulfides at room temperature was presented. Our group established that metal-induced low-energy pathways are accessible when alkynyl sulfides are tethered with terminal alkynes. Application of the new set of reaction conditions to an S-phenyl substituted yne-thioalkyne substrate revealed the formation of a thiophenium cycloadduct intermediate. The screening of alternative reaction conditions enabled the successful isolation of this S-phenyl thiophenium cycloadduct by precipitation from the reaction crude enabling structure confirmation by NMR and X-ray crystallography. The reactivity of this previously undescribed S-phenyl thiophenium salt was also evaluated under thermolysis and (metallo)photoredox conditions. The synthesis of S-(hetero)aryl yne-thioalkynes derivatives was first tackled revealing an incompatibility of the current methods described in the literature for a broad range of (hetero)aryl substituted alkynyl sulfides. Despite the numerous challenges encountered, the synthesis of para-substituted electron-poor and rich phenyl derivatives was successfully achieved using sulfur umpolung methods. A one-pot strategy was applied to these S-phenyl derivatives involving the in-situ formation of thiophenium cycloadducts which readily underwent a [1,5]-sigmatropic rearrangement and aromatization upon mild heating (70 oC) towards 2-aryl substituted fused thiophenes. Lastly, the compatibility of the S-phenyl thiophenium cycloadduct in (metallo)photoredox transformations for new CPh-C bond formation was evaluated. In contrast to electrophilic S-aryl sulfonium reagents commonly employed, this first generation of thiophenium salt was not efficient in providing high yields for the desired cross-coupled products. It was postulated that undesired HAT side reactivity was detrimental to the reaction efficacy. These preliminary studies allowed us to gain crucial insight into the inherent reactivity of an S-phenyl thiophenium salt with the hope to guide the next generation of potentially useful electrophilic reagents.

The catalytic activation of enones in C-C bond forming processes represents a promising alternative to the prefabrication of chemically labile enols and enolates. Through the use of a (diketonato)cobalt/silane catalyst system, we have devised highly diastereoselective aldol and Michael cycloreductions (J. Am. Chem. Soc. 2001, 123, 5112). Modulation of the catalyst system has enabled the first intramolecular metal-catalyzed alkene (2+2)cycloaddition (J. Am. Chem. Soc. 2001, 123, 6716). Finally, the concept of catalytic nucleophilic enone activation embodied by the Morita-Baylis- Hillman and Rauhut Currier reactions has been utilized to develop an organic catalyst system for the cycloisomerization of bis-enones, i.e. an intramolecular Rauhut Currier reaction (J. Am. Chem. Soc. 2002, 124, 2402). Notably, this protocol allowed for the selective "crossed" cyclization of unsymmetrical bis-enone substrates. / text

The isolation and identification of the active constituents from an Allium sp. extract possessing antibacterial activity was undertaken. The plant material of interest was extracted, purified and screened for antibacterial activity against a Gram positive bacteria. Multiple trials were performed and the isolation was scaled-up repeatedly, overall three compounds potentially possess the observed activity. One compound was identified to yield the majority of activity, and a refined procedure for its purification was established. Initial characterization studies demonstrated the major isolate of interest is novel compared to other isolates from the Allium genus. A ruthenium-catalyzed homo Diels-Alder [2+2+2] cycloaddition between bicyclo[2.2.1]hepta-2,5-diene and alkynyl phosphonates was also studied. The observed reactivity was found to be dependent on the presence of the phosphonate moiety. The cycloaddition was compatible with a variety of aromatic and aliphatic substituted alkynyl phosphonates providing the corresponding phosphonate substituted deltacyclenes in low to good yields (up to 88%).

1-Aza-2-azoniaallene salts are reactive intermediates that undergo [3+2] cycloaddition with many different types of multiple bonds. For the past several years, the Brewer group has studied the reactivity of these intermediates in intramolecular reactions, and have discovered that these cationic heteroallenes can react through a variety of other, mechanistically distinct, pathways to give different classes of nitrogen heterocycles. For example, prior work in the Brewer group revealed that 1-aza-2-azoniaallene salts could react in an intramolecular [4+2] cycloaddition reaction to give protonated azomethine imine salts containing a 1,2,3,4-tetrahydrocinnoline scaffold. Further study of the scope and limitations of this Diels-Alder-like reaction are described herein. These studies primarily focused on how varying the N-aryl ring and alkene substituents affected the reaction. We discovered that in several instances, the metal mediated reaction did not facilitate the cycloaddition very well, so we searched for alternative ways to facilitate the reaction. We discovered that a non-metallic Lewis acid (TMSOTf) provided very clean products with α-chloroazo compounds. I hypothesized that changing the leaving group adjacent to the azo might further improve the reaction. With this in mind, I developed a technique to prepare α-trifluoroacetoxyazo compounds by treating aryl hydrazones with trifluoroacetoxy dimethylsulfonium trifluoroacetate. This technique is compatible with all types of functional groups including nitro aryl compounds, which gave low yields of the corresponding chloroazo derivatives. Importantly, these α-trifluoroacetoxyazo compounds gave even better cycloaddition results when treated with TMSOTf, and this method is more practical, more environmentally friendly, and greener than the metal mediated technique. This process even returned sterically hindered products in high yield, and provide a dearomatized non-protonated azomethine imine salt, which further verified the proposed mechanism of the [4+2] cycloaddition. Azomethine imines are well known to undergo 1,3-dipolar cycloadditions with alkenes. We wondered if the protonated azomethine imine salts generated by the [4+2] cycloaddition could be used in a subsequent base-mediated [3+2] cycloaddition to generate structurally complex tetra- or pentacyclic products. We were pleased to find that the protonated azomethine imines indeed reacted smoothly with a variety of π-system in the presence of triethylamine to give the corresponding cycloadducts in high yields with moderate to high diastereoselectivities. In an attempt to understand the diastereoselectivity of these [3+2] cycloadditions better, I modeled them computationally.

Ce manuscrit traite de la mise au point d’une méthode d’accès éco-compatible à des squelettes carbocycliques et hétérocycliques, présents dans de nombreux composés d’intérêt biologique. Cette méthode met en œuvre une réaction de cycloaddition [2+2+2] catalysée par un métal de transition. Dans un premier temps, une voie d’accès à des fluorénones hautement substituées, ainsi qu’à des analogues a été développée. Cette voie utilise une réaction de cycloaddition [2+2+2] de diynes-[alpha, omega] pontés par un groupe benzoyle, avec des alcynes, en présence de RuCl3·nH2O. Dans un deuxième temps, des dérivés 2-aminopyridines diversement fonctionnalisés ont été synthétisés via une catalyse au ruthénium neutre (RuCl3·nH2O) ou cationique (Cp*Ru(CH3CN)3PF6), et ce à partir de la cycloaddition [2+2+2] de diynes et de cyanamides. Dans le cas où Cp*Ru(CH3CN)3PF6 a été utilisé comme catalyseur, une excellente régiosélectivité a été observée, ce qui a permis d’isoler une grande variété de 2-aminopyridines, dont des halopyridines, des vinylpyridines, ou des amino-aza-fluorénones. Dans une dernière partie, la cycloaddition [2+2+2] énantiosélective de triynes prochiraux avec des mono alcynes a été examinée. Elle a été conduite en utilisant un catalyseur cationique au rhodium, le complexe [Rh(cod)2]BF4/(R)-BINAP, et a permis la préparation de dérivés de 1,3-dihydroisobenzofuranes énantiomériquement enrichis, contenant un carbone quaternaire stéréogène. / This manuscript focused on the development of eco-friendly and mild processes to access original carbocyclic and heterocyclic scaffolds of biological interest through transition-metal-catalyzed [2+2+2] cycloaddition reactions. Initially, an efficient and practical route for the preparation of highly substituted fluorenones and analogues via solventless RuCl3·nH2O-mediated [2+2+2] cycloaddition of benzoyl bridged [alpha, omega]-diynes and alkynes was developed. Secondly, various functionalized 2-aminopyridine derivatives were synthesized using both neutral RuCl3·nH2O and cationic Cp*Ru(CH3CN)3PF6 complexes to catalyze the [2+2+2] cycloaddition of diynes and cyanamides under solvent-free conditions. With Cp*Ru(CH3CN)3PF6 as catalyst, excellent regioselectivities were achieved to provide a wide range of 2-aminopyridines of high synthetic utility involving halopyridines, vinyl pyridines and amino-aza-fluorenones. Finally, the enantioselective rhodium-catalyzed [2+2+2] cycloaddition of prochiral triynes and monoalkynes was carried out in the presence of cationic [Rh(cod)2]BF4/(R)-BINAP complex to provide enantioenriched 1,3-dihydroisobenzofuran derivatives containing a quaternary carbon stereogenic center.