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

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L’intérêt grandissant suscité par les propriétés thérapeutiques exhibées par les cannabinoïdes a motivé la naissance du projet décrit dans ce mémoire de maîtrise. La synthèse efficace de différents cannabinoïdes est devenue essentielle afin de pouvoir mieux comprendre les mécanismes régulant les propriétés médicales de ces composés ainsi que pour promouvoir le développement de nouveaux traitements médicamenteux. Le cannabidiol est d’intérêt particulier en raison des propriétés anti-inflammatoires, et anticancéreuses exhibées par cette molécule. Ce projet vise à explorer différentes routes permettant la fonctionnalisation du cannabidiol en phase avancée dans le but de faciliter l’accès aux dérivés de ce produit naturel. La première partie de ce mémoire se concentre sur le développement d’une voie de synthèse permettant la fonctionnalisation d’un précurseur du cannabidiol en utilisant le 1,3-diméthoxybenzène, un produit de départ abordable et commercialement disponible. L’approche proposée comporte six étapes et s’appuie sur une réaction de Diels-Alder pour générer l’adduit bicyclique du cannabidiol. Plusieurs routes ont été explorées pour obtenir la fonctionnalisation de ce précurseur, à savoir une borylation de Hartwig-Miyaura et une bromination du cycle aromatique. La deuxième partie de ce projet se concentre sur la fonctionnalisation du cannabidiol en phase avancée en s’appuyant sur la fonctionnalité de l’amide de Weinreb. Ces travaux ont abouti au développement d’une voie de synthèse efficace et durable pour la production de l’olivetol, un fragment clé pour la production à grande échelle de cannabidiol dans l’industrie pharmaceutique. Cette méthode se base sur une approche en quatre étapes s’appuyant sur un amide de Weinreb en utilisant un produit de départ abordable, l’acide 3,5-dimethoxy benzoïque. La synthèse de l’amide de Weinreb puis de la cétone correspondante, suivie d’une réduction de Wolff-Kishner, et enfin la démethylation du substrat ont permis d’obtenir le produit désiré. La versatilité de cette approche tolère une fonctionnalisation variée de la molécule, permettant la synthèse potentielle de divers dérivés de l’olivetol. / The increasing interest around the therapeutic possibilities offered by cannabinoids was the motivation for the project described in this Master’s thesis. The efficient synthesis of various CBs has become critical to deepen the understanding of the mechanisms behind the medical properties of cannabinoids as well as for the development of novel drug treatments. Cannabidiol is of particular interest as the molecule exhibits anti-inflammatory, and anticarcinogenic properties. This work aims to explore different routes to enable the late-stage functionalization of cannabidiol in order to easily access derivatives of the natural compound. The first part of this work focuses on developing a route enabling the functionalization of the cannabidiol precursor utilizing the affordable and commercially available starting material 1,3-Dimethoxybenzene. The proposed six-step approach relies on a Diels-Alder reaction to generate the bicyclic adduct of cannabidiol. Several routes were then explored to obtain the functionalization of the precursor namely a Hartwig-Miyaura borylation and a bromination of the aromatic ring. The second part of this project focuses on the functionalization of cannabidiol relying on the Weinreb amide functionality. This work led to the development of an efficient and sustainable route for the synthesis of olivetol, a key fragment for the large-scale production of cannabidiol within the pharmaceutical industry. The method relies on a four-step approach relying on a Weinreb amide synthesized using the affordable 3,5-Dimethoxybenzoic acid. The synthesis of the Weinreb amide followed by the formation of the corresponding ketone, subsequent Wolff-Kishner reduction, and finally demethylation of the substrate allowed to generate the desired product. The versatility of the approach allows for variations in functionalization, enabling potential formation of various olivetol derivatives.

The synthesis of benzo[e]dimethyldihydropyrene (BDHP) photoswitches with ter-27, quarter-36, and quinque-28 thiophene oligomers attached on the same side of the switch was achieved using Stille coupling reactions. BDHP photoswitches with bi-75, ter-76 and quinque-77 thiophene oligomers attached directly to the switch on one side, and via a carbonyl spacer on the opposite side of the switch were also synthesized. Dimethyldihydropyrene (DHP) photoswitches with a naphthoyl functional group in the 2 position were synthesized using a Friedel Crafts reaction, and ter-96, quinque-97 and septi-98 thiophene oligomers were attached on opposite sides of the switch using Stille coupling reactions. All compounds were characterized by NMR, IR UV-vis spectroscopy and mass spectrometry. The relative rates of the photo-opening reactions under excess light conditions and the UV closing reactions versus BDHP were measured. Improvements in the photo-opening properties of the oligothiophene functionalized switches compared to BDHP were observed. The most dramatic photo-opening improvement was found for the quinquethienyl substituted DHP switch 97 which photo-opened when irradiated with visible light over 100 times faster than BDHP. UV closing rates were virtually the same as that of BDHP. However the addition of oligothiophenes led to an increase in the thermal closing reaction rates. Compounds with the naphthoyl functional group in the 2 position of DHP were found to have dramatically increased thermal closing rates. The electrochemical properties of oligothiophene functionalized BDHP and naphthoyl functionalized DHP switches in the closed form were studied by cyclic voltammetry and spectroelectrochemistry. During the oxidation cycle, a closing reaction from the cyclophanediene (CPD) form to the DHP form of the switches occurred which prevented the study of the electrochemical properties of the switches in the open form. Conductivity testing was performed on the quinquethienyl substituted DHP switch 97 using a gold interdigitated micro electrode array. The conductivity of undoped 97 was greater in the closed DHP isomer than in the open CPD isomer. Irradiation with red or blue light allowed for repetitive switching between the more highly conducting closed form and the less conducting open form. When electrochemically doped, 97 showed improved conductivity over the undoped form but only the conductivity of the closed doped form could be measured due to electrochemically induced closing.