Thesis advisor: Masayuki Wasa / This dissertation describes the development of novel catalyst systems that could promote the regio- and enantioselective transformations of C-H bonds contained in N-alkylamines and ethers through Lewis acid-mediated hydride abstraction processes. The progress made in C-H functionalization of N-alkylamines and ethers that served as the intellectual foundation of this dissertation research are summarized in Chapter 1. Despite notable advances, the development of broadly applicable, enantioselective, and catalytic protocols to functionalize C-H bonds in N-alkylamines and ethers with high regio- and stereo-selectivity was regarded as an unsolved problem when we started this dissertation research. In an effort to overcome these fundamental limitations, we first identified a B(C6F5)3/Cu-PyBOX cooperative catalyst system for the enantioselective conversion of a-amino C-H bonds through the generation of an iminium by (F5C6)3B-catalyzed hydride abstraction process (Chapter 2). We then envisioned that in situ generated iminium ions could be further deprotonated to furnish an enamine intermediate, which may react with electrophilic species for a-amino C-H functionalization. The design and development of such a catalyst system were discussed in Chapter 3. Finally, we disclose enantioselective Cu–BOX-catalyzed hetero Diels-Alder reactions of enol ethers generated through Ph3C+-mediated oxidation of alkyl ethers. (Chapter 4). / Thesis (PhD) — Boston College, 2022. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Masayuki Wasa / This dissertation describes the development of cooperative catalyst systems for the functionalization of monocarbonyl compounds and stereoselective transformations of alpha-C–H bonds of N-alkylamines, inspired by the concepts of frustrated Lewis pairs (FLPs). Prior to this dissertation research, practical and broadly applicable C–C and C–heteroatom bond forming reactions involving the FLP complexes that provide synthetically desirable products with high enantioselectivity remained to be developed. Chapter 1 of this dissertation describes the recent advances in the transformations involving FLPs and B(C₆F₅)₃-catalyzed reactions. Inspired by the unique capability of FLP catalysts to activate otherwise unreactive molecules, and circumvent undesirable acid–base complexation, we have developed potent cooperative acid/base catalysts for C–C bond forming reactions of various monocarbonyl compounds and an appropriate electrophile, which will be discussed in Chapter 2. Another reactivity of FLPs to be explored has to do with the catalytic and enantioselective reactions of N-alkylamines, where two Lewis acid catalysts with potentially overlapping functions, work cooperatively to activate alpha-amino C–H bonds and promote the enantioselective C–C bond forming reaction between N-alkylamines and a nucleophilic species. In Chapter 3, B(C₆F₅)₃-catalyzed union of N-alkylamines and silicon enolates followed by the enantioselective B(C₆F₅)₃/Mg–PyBOX-catalyzed alpha-alkylation of N-alkylamines and alpha,beta-unsaturated compounds to form beta-amino carbonyl compounds will be described. In Chapter 4, B(C₆F₅)₃/Cu–PyBOX-catalyzed alpha-C–H alkynylation of N-alkylamines and the applications in late-stage functionalization and stereoselective synthesis will be discussed. / Thesis (PhD) — Boston College, 2020. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

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La fonctionnalisation tardive de molécules (Late stage functionalization – LSF) offre l’opportunité d’explorer l’espace chimique plus efficacement, en particulier en considérant les liaisons C-H aromatiques comme des points potentiels de diversification pour générer de nouveaux analogues directement en une seule étape au lieu de faire une synthèse totale dite de novo. La fonctionnalisation directe de composés élaborés peut en particulier se faire en utilisant la technologie superacide comme démontré par les nombreux travaux du professeur Jacquesy. L’un des meilleurs exemples de cette stratégie est certainement la transformation directe de la vinorelbine (Navelbine®) par fluoration en conditions superacides pour conduire à son analogue difluoré (Vinflunine), commercialisé par les laboratoires Pierre Fabre comme agent anticancéreux Javlor®. C’est dans ce contexte que ce travail de thèse a porté sur le développement de nouvelles méthodes de fonctionnalisation directe de composés aromatiques azotés.Il s’agissait effectivement de développer de nouveaux outils de synthèse en conditions superacides afin :1. d’hydroxyler directement des composés aromatiques par voie électrophile;2. d’halogéner des composés aromatiques azotés allant d’anilines simples à des composés élaborés naturels ou de synthèse;3. d’appliquer ces méthodes à la synthèse de molécules marquées par des isotopes stables. / Late-stage functionalization can now be considered as a synthetic tool of choice to create molecular diversity, especially in a medicinal chemistry context. For example, aromatic C-H bonds can be regarded as functional groups and points of potential diversification to generate new analogs of a lead structure without resorting to de novo synthesis.The direct functionalization of elaborated compounds can also be done using superacid chemistry as demonstrated by the previous work of professor Jacquesy. One of the best examples of this strategy is certainly the direct transformation of vinorelbine (Navelbine®) by fluorination in superacid conditions to lead to its difluorinated analogue (Vinflunine), marketed by Pierre Fabre laboratories as an anticancer agent Javlor®.In this context, these studies focused on the development of new methods for the direct functionalization of aromatic nitrogen containing compounds.In particular, this work aimed at developing new synthetic tools in superacid for:1. the direct hydroxylation of aromatic compounds;2. the halogenation of aromatic nitrogen compounds from simple anilines to naturally occurring or synthetic compounds;3. the synthesis of labelled compounds with stable isotopes.