This thesis describes two new phase-transfer catalysed processes, in which asymmetry is mediated via ion-pairing with a chiral cation. In the first chapter, an enantioselective method for N functionalization of pyrroles is described and a phase-transfer catalysed approach to axial chirality via a cation-directed SNAr reaction is discussed in Chapters 3, 4 and 5.

This study focused on the preparation and characterization of new indigo diimine (Nindigo) derivatives as a new atropisomeric scaffold. Trans- and cis- indigo diimines were studied and structure-property relationships were investigated regarding N-C atropisomerism using variable temperature 1H NMR studies and density functional theory calculations. Neutral trans- and protonated cis-Nindigos were prepared featuring a variety of mono ortho-substituted aryl imine groups with varying levels of steric bulk. The neutral trans-Nindigo derivatives generally have smaller N-C rotational energy barriers than their protonated cis-congeners. This finding is consistent with the latter having closer proximity of the N-aryl groups to each other, leading to steric repulsions between the two groups. The N-C rotational energy barriers are substituent dependent; the N-C rotational energy barriers of mono ortho substituted trans-Nindigos were in the range of 6.0 – 16.4 kcal/mol and can be classified as predominantly “Class 1’ atropisomers as defined by LaPlante, while the mono ortho substituted protonated cis-Nindigo analogs have N-C rotational barriers between 12.3 – 25.5 kcal/mol and are classified as “Class 1” and “Class 2” atropisomers. The introduction of additional substituents onto the other ortho position of the aryl imine subunit has significant consequences for the N-C rotational energy barriers of both the neutral trans- and protonated cis-Nindigos making them stable, or close to being, ‘Class 3’ atropisomers, having N-C rotational energy barriers between 31.5 – 276.9 kcal/mol and 29.3 – 32.6 kcal/mol respectively. Recognizing that the protonation state induced trans- to cis-isomerization process could have significant consequences regarding the potential applicability of these atropisomeric Nindigo derivatives, cis-Nindigo derivatives were synthesized that contained a tether (oxalyl or palladium (II) acetylacetonate) between the two indole type nitrogens of the Nindigo, which prevent the central -C=C- from isomerizing. The N-C rotational barriers of the tethered cis-Nindigos also displayed substituent dependent N-C rotational energy barriers. The protonation state of the N, N’-oxalyl bridged cis-Nindigos has a significant impact (higher in energy by a minimum of 5.1 kcal/mol) on the N-C rotational barriers; the neutral N, N’-oxalyl bridged cis-Nindigos have N-C rotational energy barriers ranging between 11.8 – 14.9 kcal/mol, classifying them as “Class 1” atropisomers, while their protonated congeners have N-C rotational energy barriers between 16.9 – 19.8 kcal/mol, which classifies them as “Class 1” atropisomers but are on the cusp of being “Class 2” atropisomers. The size of the tether influences the N-C rotational energy barriers of cis-Nindigos; the one-atom bridged palladium (II) acetylacetonate complexes have generally lower N-C rotational energy barriers than their protonated N, N’-oxalyl bridged cis-Nindigo congeners. The palladium acetylacetonate tethered cis-Nindigo complexes displayed substituent N-C rotational energy barrier dependence and the mono ortho substituted analogs have N-C rotational energy barriers between 12.4 – 20.2 kcal/mol and are predominantly “Class 1” atropisomers, while the bulkier analogs are “Class 2” atropisomers. The palladium (II) acetylacetonate cis-Nindigo complexes that have aryl imine groups with a 2,6-disubstitution pattern have N-C rotational energy barriers greater than 19.7 and 20.2 kcal/mol and are presumed to be stable “Class 3” atropisomers like their unbridged neutral trans- and protonated cis-Nindigo counterparts. / Graduate / 2023-09-12

Les macrocycles représentent une catégorie chimique unique en chimie organique et ils possèdent des applications dans les industries pharmaceutique et agrochimique, en parfumerie, et dans les matériaux. Une propriété importante des macrocycles est la possibilité de démontrer de la chiralité planaire menant à des atropoisomères distincts aux propriétés uniques. Très peu de techniques générales existent pour le contrôle de l’atropoisomérisme au sein des macrocycles, rendant leur synthèse un véritable défi. Nous avons accompli le premier exemple d’une synthèse biocatalytique énantio- et atroposélective de p-cyclophanes planaires chiraux. En utilisant une lipase immobilisée commercialement disponible (CALB) et des matériaux de départ pro-chiraux simples, nous avons été en mesure de générer 23 différentes structures avec des rendements entre 11 et 88 %. Des analyses SFC ont permis l’évaluation de l’énantioenrichissement des différents macrocycles, étant compris entre 96 et >99 % ee. Surtout, les macrocycles planaires chiraux ayant des substituants de type halogène ou borylé peuvent subir de la diversification moléculaire au-delà des limites tolérées par l’enzyme. Notre découverte ouvre la porte à l’utilisation de biocatalyseurs pour le contrôle de l’atropoisomérisme lors de la formation de structures macrocycliques. / Macrocycles represent a unique chemotype in organic chemistry, with applications ranging from pharmaceuticals, agrochemicals, aromachemicals and material science. An important property of macrocycles is the possibility of displaying planar chirality yielding distinct atropisomeric structures with unique properties. Very few generalized techniques capable of controlling atropisomerism in macrocycles exist, rendering their synthesis extremely challenging. We have achieved the first example of enantio- and atroposelective biocatalytic synthesis of planar chiral p-cyclophanes. Employing a commercially available immobilized lipase (CALB) and simple pro-chiral starting materials, we were able to generate 23 different structures with yields ranging from 11 to 88 %. SFC analysis permitted evaluation of the enantioenrichment of the different macrocycles, which ranged from 96 to >99 % ee. Importantly, planar chiral macrocycles having halogen or borylated substituents are capable of molecular diversification outside the boundaries of what may be tolerated by the enzyme. Our discovery paves the way for the use of biocatalysts in the control of atropisomerism during macrocycle formation.

Ce manuscrit présente la synthèse, la réactivité et les propriétés des amino(organo)boranes. Le diisopropylaminoborane a été utilisé dans le cadre de la formation de liaisons carbone-bore. La réactivité du diisopropylaminoborane en tant qu’agent de borylation a d’abord été mise à profit pour l’hydroboration des alcynes catalysée par le réactif de Schwartz. Une grande variété d’alcénylaminoboranes, -boronates et -diazaborolanes a ainsi été synthétisée. Leur transformation stéréosélective en bromoalcènes Z et E a également été optimisée. La borylation des alcynes vrais via un procédé tandem de déshydrogénation / couplage déshydrogénant a permis l’accès à une grande variété d’alcynylaminoboranes. Enfin, les différentes réactivités des aminoboranes ont été mises à profit dans la préparation d’acides boriniques comportant une fonction phosphine, ainsi que d’ une nouvelle classe de dérivés du bore chiraux par atropoisomérie autour de la liaison C-B. Ces aminoarylboranes chiraux ont été caractérisés par séparation des énantiomères complétée d’études spectroscopiques et de racémisation. / This manuscript presents the synthesis, reactivity and properties of amino(organo)boranes. The diisopropylaminoborane has been used for the formation of carbon-boron bonds. Its reactivity as a borylating agent was first explored for the hydroboration of alkynes catalyzed by Schwartz reageant. A large variety of alkenylaminoboranes, -boronates and -diazaborolanes was thus synthesized. Their stereoselective transformation into E and Z bromoalkenes was also optimized. The borylation of terminal alkynes via a tandem process of dehydrogenation/ dehydrogenative coupling allowed the access to a large scope of alkynylaminoboranes. Finally, the different reactivities of aminoboranes were used for the preparation of borinic acids bearing a phosphine group but also of a new class of chiral boron derivatives via a C-B atropisomerism. These chiral aminoarylboranes were fully characterized after separating the enantiomers and running spectroscopic analyses and racemization studies.

Les travaux présentés dans ce manuscrit ont eu pour but d’étudier le « couplage aryne », une technique de synthèse qui produit des biaryles sans l’intervention de métaux de transition, grâce à la réaction entre deux intermédiaires réactionnels générés in situ : un aryllithien nucléophile et un aryne électrophile. Les travaux réalisés ont consisté en l’optimisation de la version diastéréosélective du couplage, ensuite appliquée à la synthèse formelle de la (-)-stéganacine. Dans un second temps, les premières études sur la version énantiosélective du couplage ont été réalisées, en introduisant des ligands chiraux à la réaction et en évaluant l’influence de différents paramètres réactionnels. Les premiers excès énantiomériques ont ainsi été obtenus, parfois accompagnés de la formation de divers sous-produits, parmi lesquels des dérivés de biphénylène. Devant l’intérêt que représentent ces composés, une partie des travaux a été consacrée à leur synthèse par dimérisation des arynes. / This work consisted in the study of the “aryne coupling”, a transition-metal free process to access biaryl moieties, which involves the reaction between two in situ generated intermediates: a nucleophilic aryllithium derivative and an electrophilic aryne. This work resided in the optimization of the atropoenantioselective version of the aryne coupling and its application to the formal synthesis of (-)-steganacin. We then moved to the atropoenantioselective version of the reaction, by introducing chiral ligands in the reaction mixture, which aim was to coordinate the aryllithium species and to transfer their chiral information to the biaryl axis. After optimization of various reaction parameters, some enantiomeric excesses were obtained as well as various side products in some cases, among which biphenylene derivatives. According to the potential applications of these compounds, another part of this work was dedicated to their synthesis by means of aryne dimerization reactions.

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