Investigations into the conjugate addition of phenols and sp3-hybridized carbons bound to tin, boron and silicon by transition metal catalysts through novel transmetallation pathways were undertaken with limited success. An intramolecular Lewis acid-catalyzed tandem [1,5]-hydride shift / cyclization and Friedel-Crafts acylation reaction with alkylidene Meldrum’s acid derivatives has been accomplished. The use of metal phenolates as nucleophiles for transition metal catalyzed conjugate addition onto alkylidene Meldrum’s acids is explored, and the ambident nucleophilic property of metal phenolates allow for the C-alkylation and O-acylation with alkylidene Meldrum’s acids, producing substituted 3,4-dihydrocoumarins in modest yields. The transmetallation of rhodium complexes with alkyl boron, tin and silicon derivatives and subsequent conjugate addition onto alkylidene Meldrum’s acid derivatives is investigated without success. An intramolecular Lewis acid-catalyzed [1,5]-hydride shift / cyclization reaction promoted by electron-rich aromatic rings is employed with alkylidene Meldrum’s acid derivatives to furnish spiro Meldrum’s acids in excellent yields. These can subsequently be used as electrophiles in the Friedel-Crafts acylation reaction, and a tandem, one-pot variation of this reaction has been accomplished in moderate to good yields. Preliminary investigations into the scope and limitations of this transformation are outlined.

Investigations into the conjugate addition of phenols and sp3-hybridized carbons bound to tin, boron and silicon by transition metal catalysts through novel transmetallation pathways were undertaken with limited success. An intramolecular Lewis acid-catalyzed tandem [1,5]-hydride shift / cyclization and Friedel-Crafts acylation reaction with alkylidene Meldrum’s acid derivatives has been accomplished. The use of metal phenolates as nucleophiles for transition metal catalyzed conjugate addition onto alkylidene Meldrum’s acids is explored, and the ambident nucleophilic property of metal phenolates allow for the C-alkylation and O-acylation with alkylidene Meldrum’s acids, producing substituted 3,4-dihydrocoumarins in modest yields. The transmetallation of rhodium complexes with alkyl boron, tin and silicon derivatives and subsequent conjugate addition onto alkylidene Meldrum’s acid derivatives is investigated without success. An intramolecular Lewis acid-catalyzed [1,5]-hydride shift / cyclization reaction promoted by electron-rich aromatic rings is employed with alkylidene Meldrum’s acid derivatives to furnish spiro Meldrum’s acids in excellent yields. These can subsequently be used as electrophiles in the Friedel-Crafts acylation reaction, and a tandem, one-pot variation of this reaction has been accomplished in moderate to good yields. Preliminary investigations into the scope and limitations of this transformation are outlined.

The development of methods for site-selective derivatization of natural products to enable simultaneous arming and structure activity relationship (SAR) studies has shown great potential for the synthesis of pharmaceutical drug leads and cellular probes for mechanism of action studies. Herein, we describe a strategy to functionalize carboxylic acid and phenol containing natural products. This methodology relies on the in situ generation of diazoalkanes to form the corresponding carbonyl esters and phenolic ethers derived from natural products. We applied this process to several natural products, to begin demonstrating the utility of this methodology for the simultaneous arming and SAR studies of natural products. To expand our group’s nucleophile catalyzed aldol lactonization (NCAL) reaction for synthesizing highly substituted cyclopentane fused beta-lactones, we developed a nucleophile catalyzed, tandem Michael aldol lactonization (NCMAL) reaction. Herein, we show the synthetic utility of this reaction in varying the Michael donors and acceptors, developing a catalytic, enantioselective NCMAL, and synthesizing tricyclic-!-lactones. Furthermore, we initiated studies toward applying this new methodology to the synthesis of a lipase inhibitor, vibralactone.

The objective of this study was to synthesize new energetic, strained, saturated polycyclic compounds. For this purpose, new methodology has been developed, as follows: (i) Ketenes have been generated in situ via treatment of aldo-, keto- or alkenoic acid with either toluenesulfonyl chloride or 2-chloro-1-methylpyridfniurn iodide (Mulkaiyama's reagent). The reactive intermediates thereby generated have been found to undergo intramolecular [2+2] cycloaddition reactions in these systems.

An environmentally friendly, operationally simple copper-amine catalyst system is disclosed. Using this catalyst system, electron deficient alkenes and alkynes with diverse functional groups are borylated and silylated in high yields and with short reaction times. In the case of electron deficient alkynes the identity of the electron withdrawing group controlled diastereoselectivity. Esters and amides exclusively form E-product, while aldehydes and ketones favor Z-product. Mechanistic insights into the catalytic cycle as well as origin of diastereoselectivity are discussed. / Master of Science

The lithiation of 3-sulfolene followed by subsequent treatment with an alkyl halide electrophile has been previously established as a method to produce 2-substituted-3-sulfolenes. Tandem reactivity with bis-alkyl halides has been observed to afford relatively simple bicyclic products. We hypothesized that it may be possible to access more complex bicyclic systems through use of bis-vinyl ketones as the electrophilic component. Herein, we present the outcome and mechanistic insights for the reaction between a variety of 3-sulfolene and substituted-3-sulfolene anions with bis-vinyl ketones to afford a variety of stereochemically complex fused, bridged and spiro bicyclic archetypes. The potential of these bicyclic-sulfone frameworks to act as molecular scaffolds for the generation of conformationally-restricted enzyme inhibitors is explored. Potent monocyclic small molecules that inhibit influenza’s neuraminidase enzyme have been developed as commercially successful antivirals. Similarly potent inhibitors against prokaryotic or eukaryotic neuraminidases have yet to be described. Selective inhibitors of these latter neuraminidase isozymes may provide useful treatments for bacterial infections (such as cholera and pneumonia) as well as a variety of cancers and metabolic disorders. A conformationally-restricted scaffold may prove ideal for designing selective (and potent) inhibitors against these underexplored enzymes. As a proof of principle, one of our rigid bicyclic-sulfone archetypes is elaborated to a drug-like scaffold that is shown to inhibit viral, bacterial and human neuraminidase enzymes. / Graduate / mgbrant@uvic.ca

Au cours de ce travail, nous nous sommes intéressés à la préparation d'esters arylboroniques issus de l'hexylène glycol et porteurs de substituants électroattracteurs. Nous avons d'abord étudié la borylation catalysée au palladium d'halogénures d'aryle pauvres en électrons par MPBH, substitut économique du PinBH. Il s'est avéré que MPBH était moins performant sur ce type de substrats que le PinBH. Nous nous sommes alors tournés vers une borylation par un échange iode/magnésium avec piégeage in situ par le borate MPBOiPr. Cette méthode nous a permis de boryler des iodures d'aryle pauvres en électrons, porteurs de groupes fonctionnels sensibles, de manière propre et sécurisée (pas d'accumulation de magnésien). Elle s'avère applicable à grande échelle (kilogramme). Ces esters arylboroniques ont ensuite été engagés dans des réactions d'addition sur des nitrones, sans succès. Cela nous a amené à développer une nouvelle réaction : l'arylation directe de nitrones cycliques par des halogénures d'aryle. Au cours de l'étude, nous avons démontré l'effet d'accélération de deux additifs introduits en quantité catalytique : un sel de cuivre et l'acide pivalique. Les réactions sont ainsi rapides et propres, et s'appliquent à des iodures, bromures ou chlorures (hétéro)aromatiques très variés. Pour finir, nous avons effectué une étude mécanistique qui nous a permis de proposer deux mécanismes, selon l'additif mis en jeu. / The first part is focused on the preparation of arylboronic esters derived from hexylene glycol, and bearing electron withdrawing substituents. We studied the palladium catalyzed borylation of electron-poor aryl halides with MPBH, an economic substitute for PinBH. MPBH, however, was found less efficient than PinBH. Next, a borylation through iodine/magnesium exchange with in situ trapping by the borate MPBOiPr was developed. This method allowed the borylation of aryl iodides carrying electron withdrawing and sensitive substituents, cleanly and safely (no accumulation of organomagnesium species), and scale up was possible (kilogram scale). Our attempts to use these arylboronic esters in addition reaction onto nitrones were unsuccessful. This led us to develop a new reaction: the direct arylation of cyclic nitrones with aryl halides. The coupling is dramatically accelerated by catalytic amounts of either a copper salt or pivalic acid. The reactions are fast and clean, and various (hetero)aryl iodides, bromides and chlorides can be used. Last, a mechanistic study allowed us to propose a mechanism for each additive.

As they make up DNA and RNA, nucleosides are considered the key to life. Synthetic nucleosides also constitute many drugs that treat viral infections and cancer. As a result, more efficient methods to access these crucial molecules would have implications that extend beyond a synthetic chemist's benchtop and into medicinal chemistry and medical research. One of the most challenging steps in the synthesis of nucleosides is the glycosylation step between the acceptor heterocycle (nucleobase) and the saccharide-based donor. Often to obtain satisfactory yield of this step with good regio- and stereochemical control the extensive use of protecting groups must be employed to squelch reactivity at unwanted reactive groups. Consequently, this process of protection−glycosylation−deprotection is laborious, inefficient, and often requires the use of toxic reagents. It would be, therefore, highly welcomed if new methodology to effect this glycosylation step was designed that reduces or removes the need to use protecting groups, but would still provide nucleosides in good yield, regio- and stereoselectively. Herein, this thesis presents my efforts into achieving this end. By employing modified Mitsunobu conditions, I determined that it is possible to directly glycosylate a nucleobase with D-ribose to afford...

Cette thèse présente des travaux de méthodologie de synthèse et des études mécanistiques. Une approche complémentaire est utilisée, avec des résultats expérimentaux et des résultats théoriques issus de calculs DFT. Trois réactions ont été étudiées. La première réaction est l’alpha-arylation de cétones énolisables en l’absence de métal de transition. Elle se déroule en présence de DMF et de tBuOK. L’étude mécanistique met en évidence la formation d’une espèce riche en électrons par déprotonation du solvant. La deuxième réaction étudiée est la N-arylation de pyrazoles via la formation d’aryldiazoniums in situ. Cette réaction est catalysée au cuivre. Une évaluation de la méthode DFT la plus adaptée est présentée. Un double cycle catalytique est proposé, faisant intervenir le complexe de cuivre et l’acide acétique. La dernière réaction étudiée est la formation stéréoselective d’alkényl thioethers fluorés trisubstitués par catalyse au cuivre. La méthodologie de synthèse est présentée, suivie d’une étude mécanistique. Celle-ci révèle un mécanisme radicalaire qui peut être généralisé à d’autres substrats. / In this thesis, synthetic methodology development and mechanistic studies are presented. A complementary approach, using both experiments and theoretical outcomes from DFT, is used. Three reactions were studied. The first reaction is the transition-metal free alpha-arylation of enolizable ketones. It proceeds using DMF and tBuOK. The mechanistic study reveals the formation of an electron-rich species by deprotonation of the solvent. The second reaction studied is the copper-catalyzed N-arylation of pyrazoles with arenediazonium salts generated in situ. A benchmark is performed to evaluate the best DFT methodology. A double catalytic cycle is proposed, involving copper and acetic acid. The last reaction studied is the copper-catalyzed stereoselective access to trisubstituted fluorinated alkenyl thioethers. The development of the methodology is presented. Then a mechanistic study reveals a radical mechanism that can be generalized to other substrates.

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.