<p>  </p> <p>Seven-membered ring structures are one of the most important structural motifs found widely in natural products and bioactive molecules. Although several [5+2]-cycloaddition reactions have been developed to construct these seven membered cores, asymmetric cycloaddition reactions are less explored. Described in Chapter-1 is a base mediated intramolecular diastereoselective [5+2]-cycloaddition reaction that afforded highly functionalized seven membered rings in good yields and excellent diastereoselectivities. The high diastereoselectivity is controlled by the alkyl stereocenter and the chain length of the alkene tether. The existing chirality of the substrate can direct the stereochemical outcome of the [5+2]-cycloaddition reaction. Furthermore, this methodology has been applied to synthesize various potent HIV-1 protease inhibitors. </p> <p>COVID-19 pandemic has profoundly affected life around the globe and costed us 6 million lives. Therefore, there is an urgent need for rational design of new drug candidates to specifically target different SARS-CoV-2 proteins. Recently, Pfizer developed an FDA-approved antiviral therapeutic agent, Paxlovid, targeting SARS-CoV-2 3CLpro. Chapter-2 discusses a concise synthetic route to synthesize active component of Paxlovid, Nirmatrelvir, in 6-steps without any epimerization. We have also developed a series of potent covalent inhibitors targeting SARS-CoV-2 3CLprotease and compared the antiviral activities of these inhibitors with that of Nirmatrelvir. </p> <p>In the final chapter, a concise partial synthesis of the segment A of (-)-Rafonin is discussed. (-)-Rasfonin is an antitumor agent that induces apoptosis in <em>ras</em>-dependent cells. We have proposed an asymmetric chiron approach to install the α-pyranone ring of rasfonin. Our goal is to perform SAR studies on this natural product by designing various analogues. </p>

Development of therapeutics is an extensive process, consuming significant amounts of time and requiring herculean synthetic efforts. A new therapeutic is most often designed from a previously commercialized scaffold, to increase the chance of success. Designing new molecular scaffolds can be extremely high risk and time consuming, yet at the same time the reward can be substantial. Accessing new molecular scaffolds, with efficient and “green” methods, is important in modern medicinal chemistry to diversify chemical space for therapeutic targets. There may be significant quantities of therapeutic candidates that have been over-looked due to synthetic challenges. There is a need for methodologies to synthesize challenging molecular scaffolds that are underexplored in commercialized therapeutics. The work described herein employs two distinct methodologies to access complex molecular scaffolds: 1) by developing a titanium (II) mediated Kulinkovich de-Meijere reaction arrested by Bredt’s rule and a suitable aryl sulfonyl moiety to afford diverse molecular scaffolds with potential for medicinal chemistry applications and 2) utilizing a [4 + 4] photocycloaddition of 2-pyridone-enolynes to access functionally rich cyclooctanoids that are capable of further photochemical transformations into even more complex molecular scaffolds. The titanium (II) mediated Kulinkovich reaction traditionally yields cyclopropylamines and cyclopropanols from amides and esters, respectively. The reaction involves two consecutive carbon-carbon bond forming steps. The bridged tricyclic intermediates would violate Bredt’s Rule and prevent the final carbon-carbon bond formation. This transformation can access a wealth of cyclic amino-ketones from olefin-tethered lactams. In addition, appropriate selection of an electron withdrawing group on nitrogen achieves the same bond sequestration. Interception of the titanafuran intermediate allows for electrophilic trapping of the titanium-carbon bond. The electronically arrested second carbon-carbon bond forming step adds generality to the interrupted Kulinkovich de-Meijere reaction to access the challenging molecular scaffolds of trans-α,α’-disubstituted cyclic ketones. Intramolecular [4 + 4] photoreaction of 2-pyridones with silyl 3-enol-1-ynes yields a highly reactive 1,2,5-cyclooctatriene. In the presence of a silanol proton source the allene is converted into a 1,3-diene. Without the combination of silyl 3-enol-1-ynes and silanol, as previously reported with 1,3-enynes, complex mixture of products is observed. Use of more nucleophilic solvents results in near quantitative yield of the cyclooctadienone through loss of silicon. Further photochemical manipulations of the cyclooctanoids allows for rapid scaffold diversification into bullvalene-like structures through a di-π-methane rearrangement. / Chemistry

Chiral amines are ubiquitous in natural products and are found in many drugs and drug candidates. Enantiopure sulfinimines [RS(O)N=CHR1] are useful chiral building blocks for the stereoselective synthesis of amines and amine derivatives. The aim of this thesis research is to develop new methods to access chiral amine building blocks for applications in the synthesis of nitrogen-heterocycles including ring-substituted tropinones, tropanes, cyclic cis-beta-amino acid derivatives, and amino-cyclopentitols. / Chemistry

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Yes / An experimental and computational investigation is conducted into the role of substituents in retro Diels-Alder extrusion of CO2 from 2-oxa-bicyclo[2.2.2]oct-5-en-3-ones. We provide the first experimental evidence that loss of CO2 from the cycloadducts significantly depends on the nature and position of the substituents. For example, we show that whilst 5-carboethoxy-2-pyrone undergoes a more facile cycloaddition that 3-carboethoxy-2-pyrone, the cycloadduct from the latter pyrone undergoes a more facile loss of CO2 than the cycloadduct from the former pyrone. / EPSRC, Yorkshire Cancer Research, Yorkshire Enterprise Fellowships

Yes / Ynamide, is an understudied but attractive class of alkynes, activated by the donating ability of the nitrogen adjacent to alkynes. With the nucleophilicity on β-carbon and the electrophilicity on α-carbon of ynamides, this review summarizes the syntheses of ynamides and miscellaneous reactions - oxidation, rearrangement, cyclization, and cycloaddition to construct complicated heterocyclic rings. The synthetic methodologies were further applied into natural products synthesis, e.g. marinoquinolines A and C, aplidiopsamine A, rigidin A, and 7-azaserotonin derivative. / We thank National Science Foundation of China (NSFC) (21462004), State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources (CMEMR2014-A04), 2015 GXNSFBA (139032), GXNU, and Newton International Fellowship granted by Royal Society.

The purpose of this investigation was to provide a systematic study of the cycloaddition pf (N-alkyl-N-phenylamino)- methoxy-and dichloroketenes to various imines and to investigate the stereochemistry of these cycloadditions.

Les peptides aldéhydes sont connus comme inhibiteurs de protéases et précurseurs de différentes classes de composés biologiquement actifs. Les méthodes pour leur synthèse impliquent classiquement la transformation d'un précurseur (amide de Weinreb, ester, alcool, acétal) en aldéhyde en étape finale pour éviter l'épimérisation du stéréocentre en position α de l'aldéhyde. En revanche, les β-peptides aldéhydes, plus stables à l’épimérisation, ont été relativement peu explorés. Ils sont généralement obtenus par homologation de l'acide aminé correspondant malgré les faibles rendements, les problèmes d’épimérisation et de nombreuses étapes. Par conséquent, un nouvel accès synthétique aux β-peptides aldéhydes reste toujours un challenge difficile. Sur la base des travaux antérieurs dans notre équipe en hétérocycloaddition diastéréosélective [4+2] et [3+2], nous avons développé au cours de ce doctorat de nouvelles stratégies pour l'accès asymétrique à ces dérivés de β-aminoacides par deux voies complémentaires :1) Une voie utilisant les hétérocycles à six chaînons de type 6-ATO (6-alcoxytétrahydrooxazinone) qui ont été préparés par une réaction d’hétérocycloaddition hautement stéréosélective avec de bons rendements et ed. Ces cycloadduits ont été transformés par transacétalisation vers les aminoacétals intermédiaires «mixtes» ou «symétriques». Ces nouveaux acétals sont des intermédiaires parfaits pour la N-élongation par couplage peptidique, conduisant finalement aux aldéhydes peptidiques β3-C-terminaux monosubstitués. 2) Sur une autre approche, les hétérocycles à cinq chaînons 5-AISO (3,3'-disubstitué 5-alcoxy-isoxazolidines) ont été obtenus par cycloaddition dipolaire-1,3 entre des cétonitrones esters et des éthers vinyliques. Ces composés ont été utilisés avec succès en tant que précurseurs d'aminoaldéhydes β3-disubstitués après l’étape de transprotection de l'atome d'azote, suivie par la copure de la liaison N-O. L’extension asymétrique de l'étape de cycloaddition a été étudiée par des voies énantiosélective et diastéréosélective, ouvrant ainsi l'entrée vers les peptides aldéhydiques β3-disubstitués-C-terminaux énantioenrichis. / Peptide aldehydes are known as protease inhibitors and precursors for many biologically active compounds. Methods for their synthesis involve classically the transformation of a precursor (Weinreb amide, ester, alcohol, acetal) into an aldehyde as one of the final steps to prevent epimerization of the carbon α to the aldehyde. By contrast, β-peptide aldehydes, more stable to epimerization, have been relatively unexplored. They are usually obtained by homologation of the corresponding amino acid despite low yielding steps, an epimerization problem and low number of accessible amino acids. Therefore, new synthetic access to β-peptide aldehydes is still a challenging problem. On the basis of previous work in our team concerning [4+2] and [3+2] diastereoselective cycloadditions, we have developed during this PhD thesis new strategies for the asymmetric access of β-amino acid derivatives by two complementary ways :1) Original six-membered heterocycles 6-ATO (6-alkoxy-tetrahydrooxazinone ) were prepared by a highly stereoselective heterocycloaddition reaction with good yields and de. These cycloadducts were transformed via transacetalisation into both «mixed» and «symmetrical» aminoacetals. Moreover, these new acetals are ideal intermediates for further peptide coupling, leading ultimately to monosubstituted β3-C-terminal peptide aldehydes. 2) By another approach five-membered heterocycles 5-AISO (3,3’-disubstituted 5-alkoxy-isoxazolidines) were obtained via 1,3-dipolar cycloaddition between α-keto ester nitrones and vinyl ether. These compounds were successfully used as precursors of disubstituted β-amino aldehydes after transprotection of the nitrogen atom and N-O cleavage of the isoxazolidine ring. Asymmetric extension of the cycloaddition step was studied by enantioselective and diastereoselective pathways, thus opening unprecedented entry to enantioenriched disubstituted β3,β3-C-terminal peptide aldehydes.

Le système spirocyclique (7,5) est un motif récurrent dans un certain nombre de produits naturels tels que les Micrandilactones ou les Rubriflordilactones. Ces structures polycycliques représentent un réel défi synthétique pour les chimistes organiciens puisqu'elles présentent au moins neuf centres stéréogènes dont plusieurs sont quaternaires. L'objectif principal de ce travail était de développer de nouvelles réactions de cycloaddition [3+2] et de les utiliser comme étape clé afin d'obtenir rapidement et efficacement le squelette polycylique de ces composés. La première partie de ces travaux a été consacrée au développement d'une réaction de cycloaddition [3+2] intra- et intermoléculaire mettant un jeu un nouveau partenaire dipolarophile, les γ-alkylidènes-buténolides. Cette étape clé conduit à la formation de cycloadduits hautement fonctionnalisés de façon rapide et efficace avec d'excellents rendements et de façon hautement chimio-, régio- et diastéréosélective. De plus, des calculs théoriques ont permis d'appréhender le mécanisme réactionnel entre un 2-diazo-1,3-cétoester et la protoanémonine catalysé par un sel de rhodium mis en jeu dans ce type de processus et ainsi d'expliquer les résultats obtenus.Dans une deuxième partie, deux approches aux cœurs ABC et CD de la micrandilactone C ont été développées mettant respectivement en jeu une cycloaddition [3+2] formellement intermoléculaire utilisant un lien de type acétal de silicium et suivie par une réaction de Diels Alder. Ainsi, le motif tétracyclique devrait être rapidement accessible après quelques aménagements de la voie de synthèse initiale. / The spiro (7, 5) ring system is a recurring structural moiety in numerous natural products such as Micrandilactones and Rubriflordilactones. In term of complexity, these polycyclic structures represent a synthetic challenge for organic chemist. Indeed, these molecules present at least nine stereogenic centres including several quaternary ones. The main goal of this work was to use unprecedented partners in the [3+2] cycloaddition reaction to obtain quickly and efficiently the polycyclic core of those natural products. The first part of these studies was dedicated to the development of an intra- and intermolecular [3+2] cycloaddition using for the first time a γ-alkylidene-butenolide dipolarophile. This approach provides rapid and facile access to highly functionalised polycyclic molecules along with excellent regio-, chemo- and stereoselectivities. In addition, thanks to computational studies an overall picture of the mechanism of the intermolecular rhodium catalysed [3+2] cycloaddition between 2-diazo-1,3-ketoester and protoanemonin was apprehended, and experimental results have been rationalised.Finally, two approaches to the ABC and CD cores of Micrandilactone C were developed using respectively a formal intermolecular [3+2] cycloaddition reaction in presence of a silicon acetal linker followed by a Diels Alder reaction. The ACDE tetracyclic moiety should be quickly accessible after few modifications of the initial strategy.

Les carbènes N-hétérocycliques (NHC) sont très utilisés pour complexer les métaux de transition. Ils quittent rarement ce rôle de ligand ancillaire et trouvent, depuis une vingtaine d’années, des applications en catalyse ou, plus récemment, en chimie médicinale. Dans ce travail, nous discuterons d’une méthode de synthèse douce conduisant à la formation de complexes AgI – NHC via une source d’argent soluble. Cette méthode nous a permis d’obtenir des complexes bien connus mais également d’accéder à une nouvelle série de complexes NHC-Ag-phosphine. Nous présenterons également une nouvelle réaction où des NHC portant une fonction azoture à proximité du carbone du carbène quittent leur rôle de ligand ancillaire et conduisent à la formation d’hétérocycles azotés par cyclisation carbène-nitrène. Cette réaction sera présentée en détail, ainsi que la caractérisation spectroscopique concernant une sous-série de composés fluorescents obtenus par cette méthode. Enfin, nous présenterons une stratégie de post-fonctionnalisation de complexes développée dans notre équipe. Des complexes argent(I)-NHC portant un azoture proches du centre carbénique catalysent leur propre fonctionnalisation. De plus, des complexes de cuivre(I) portant des azotures en position éloignée du centre métallique seront greffés sur des nanoparticules magnétiques pour servir de catalyseur recyclables. / N-heterocyclic carbenes (NHC) are widely used to complex transition metals. They rarely leave their role as ancillary ligand and find, since 20 years, applications in catalysis or, more recently, in medicinal chemistry. In this work, we will discuss a mild synthetic method leading to the formation of AgI – NHC complexes via a soluble silver species. This method allowed us to obtain well known complexes but also to access a new series of NHC-Ag-phosphine complexes. We will also present a new reaction where NHC ligands bearing an azide function close to the carbenic center leave their role as ancillary ligand and lead to the formation of nitrogen rich heterocycles by a carbene-nitrene cyclization. This reaction will be presented in detail, along with the spectroscopic characterization regarding a sub-series of fluorescent compounds obtained by this method. Finally, we will present a post-functionalization strategy of complexes developed in our team. Silver(I)-NHC complexes tagged by an azide close to the carbenic center catalysed their own functionalization. Moreover, copper(I) complexes tagged by an azide function in a distant position from the metallic centre will be grafted on magnetic nanoparticles to act as recyclable catalysts.