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In order to provide scalable, efficient and selective routes towards pharmaceutically relevant compounds, we have focused on improving the economical viability and practicality of strained-silane Lewis acid activation. Towards these goals, the Leighton group has developed a new mode of anion catalysis to activate silane Lewis acids. Weakly coordinating anions have been used to access hyper-coordinate silicon species with unprecedented levels of reactivity, which have facilitated previously unattainable complex fragment couplings. A highly enantioselective and efficient method for anion catalyzed nucleophilic addition to aldehydes has enabled the synthesis of rationally designed, structurally simplified D-ring modified analogs of spongistatin 1. The completion of a step-economical route towards extremely potent, linker-handle equipped spongistatin 1 analogs and their application to targeted drug delivery will be discussed.

Thesis advisor: Marc L. Snapper / Chapter 1. Review of concept and methodology development for asymmetric allylation of carbonyls and imines. Chapter 2. Description of the catalytic asymmetric addition of allyltrichlorosilane to aldehydes catalyzed by a proline-based N-oxide catalyst. Chapter 3. Introduction of the first catalytic asymmetric silylation of alcohols for desymmetrization of meso-diols. Chapter 4. Presentation of asymmetric silylation for synthesis of chiral syn-1,2-diols by kinetic resolution or divergent reaction on a racemic mixture. / Thesis (PhD) — Boston College, 2008. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

This thesis outlines work carried out over the past three years concerning the development of an experimentally simple, sustainable catalytic method for the functionalisation of pyridines by means of a zinc nitrate based Lewis acid. It encompasses reaction discovery and optimisation, determination of the scope of the method through nucleophile and substrate screens as well as investigations into the mechanism by which the reaction takes place. Chapter 1 gives a general overview of the industrial relevance of pyridine functionalisation as well as the synthetic methods for the synthesis of ring functionalised pyridines, covering traditional stoichiometric aromatic substitution methods, transition metal catalysed cyclisations, standard catalytic methods for the functionalisation of pyridines: Buchwald-Hartwig and Ulmann reactions, as well as a précis of some recent transition metal catalysed methods for C-H functionalisation of pyridines. It also reviews classical and transition metal catalysed methods for conjugate addition and Diels–Alder reactions of vinylpyridines. Chapter 2 involves reaction discovery for the use of Lewis acids for the activation of pyridines towards nucleophilic aromatic substitutions, reaction optimisations, kinetic investigations and an examination of the scope in substrates and incoming groups. Chapter 3 investigates the use of Lewis acids for the activation of vinylpyridines toward conjugate addition, reaction optimisations, investigations into scope of incoming groups and subsequent optimisation studies for each. The method is also extended to Diels–Alder cyclisations, for which the reaction is also optimised.

Après avoir pu développer une nouvelle méthode de déracémisation de biphényles iodés permettant, pour la première fois, d’influencer la diastéréosélectivité de la réaction de piégeage du réactif d’Andersen par dédoublement cinétique, nous avons obtenu de nombreuses informations et développé des méthodes permettant de lever différents verrous synthétiques pour accéder à des paires de Lewis frustrées basées sur le squelette biphénylique et portant simultanément ou non un groupement acide de Lewis et une base de Lewis. Par la fonctionnalisation de ces biphényles, nous avons pu accéder à de nouvelles biphénylphosphines énantiopures pouvant jouer le rôle de base de Lewis dans le domaine des paires de Lewis frustrées (FLP) mais aussi d'organocatalyseur nucléophile ou de ligand pour la catalyse organométallique. Différentes méthodes ont ensuite été (re)développées, pour accéder à des acides de Lewis : d'une part la synthèse de boranes par fonctionnalisation de sels d'organotrifluoroborate de potassium comme précurseurs polyvalents d’acides de Lewis chiraux et énantiopurs et d'autre part l’utilisation de silanes électrophiles. L’ensemble des informations et méthodes découlant de ce travail pourront être appliquées à la synthèse de molécules ambiphiles, nouvelles paires de Lewis atropo-frustrées. / After having developed a new method of deracemization of iodinated biphenyls allowing us, for the first time, to influence the diastereoselectivity of the trapping by the Andersen reagent, we have turned our attention to the use of this molecular scaffold in the design of new frustrated Lewis pairs bearing either a Lewis acidic group, a Lewis basic group or simultaneously both groups. We first accessed a new series of enantiopure biphenylphosphines that can find applications as Lewis base (including the field of frustrated Lewis pairs), as nucleophilic organocatalyst or as ligand in organometallic catalysis. Then, various methods were (re)developed to access chiral biphenyl-based Lewis acids: firstly, the functionalization of biphenyltrifluoroborate salts as chiral and enantiopure borane precursors and secondly the use of electrophilic silanes. The whole information and methodologies developed herein may be applied to the synthesis of new ambiphilic compounds as new atropo-frustrated Lewis pairs.

This dissertation presents new approaches towards the asymmetric allylation of the imino and formyl functionalities by using strained silanes as Lewis acids. Here in the Laboratory of Professor James L. Leighton, chiral homoallylic alcohols and amines are considered privileged products given their important role as building blocks in natural product synthesis. The new approaches reported herein are focused on expanding the scope of imine allylation reactions and gaining full synthetic utility of the corresponding homoallylic amine products by means of economic and user-friendly protocols. In addition, the discovery of a novel catalytic and mild approach to the asymmetric allylation of aldehydes will be the focus of discussion at the end of this works. Chapter 1 will give a brief introduction about general concepts in asymmetric allylation of aldehydes and imines as well as in applications of strained silane Lewis acids in these reactions. Chapter 2 will discuss the development of a novel asymmetric allylation method for N-heteroaryl hydrazones and the N-heteroaryl cleavage from the product to unmask the corresponding free amines. Chapter 3 will carry on these studies into different imine activating groups in search for a more general and user-friendly approach towards both allylation and cleavage protocols. Finally, Chapter 3 will discuss the development of a new methodology in which chiral bismuth (III) complexes can catalyze the asymmetric allylation of aldehydes with achiral strained allylsilanes.

Stoichiometric and catalytic small molecule activation reactions are vital for the synthesis of new materials. The activation of phosphorus-hydrogen or phosphorus-phosphorus bonds allows for the facile synthesis of new phosphorus-containing molecules for a wide variety of applications.1 An investigation of the P-H dehydrocoupling reaction was undertaken utilizing two rhodium(I) based catalysts. Over the course of this investigation it was found that the Rh(I) systems were also active catalysts for the reverse reaction: phosphorus-phosphorus bond hydrogenation (and hydrosilylation). This reaction was exploited for the synthesis of novel phosphines from P-P bound species. Molecules with P-P bonds were reacted in a stoichiometric fashion with the catalyst precursor, producing a variety of novel species with interesting bonding features which shed some light on the reaction mechanism. Following the discovery in 2006 that a linked phosphine-borane system could reversibly activate hydrogen2 a tremendous effort has been put forth to understand and expand this unprecedented reactivity.3,4 This new archetype for metal-free small molecule activation, containing a bulky Lewis acid and Lewis base which are unable to bond directly due to steric repulsion, has been termed a “frustrated Lewis pair” (FLP).3,4 The FLP concept is expanded to include bulky P-P bound species, pyridines and P-O bound Lewis bases as partners for B(C6F5)3. In some cases small molecule activation produced ion pairs or zwitterions related to those found for reactions with tertiary phosphines,3,4 but in others novel reaction pathways were discovered including phosphorus-phosphorus bond cleavage, catalytic hydrogenations and the formation of novel intramolecular FLPs. An unexpected situation was observed for the pair of 2,6-lutidine with B(C6F5)3, where adduct formation was observed along with free Lewis acid and base, but H2 activation by the FLP proceeded smoothly. Covalently bound phosphinoboranes of the general formula R2PB(C6F5)2 are synthesized. While systems with small R groups dimerized, monomers existed for cases with bulkier R groups. These monomers were found to exhibit extraordinarily short phosphorus-boron bonds yet were still capable of H2 activation analogous to bimolecular phosphine-borane systems. These systems also showed unique reactivity with Lewis acids and Lewis bases. This work further demonstrates the broad and general utility of the FLP concept in the synthesis of new materials and in catalytic transformations.