The palladium-catalysed asymmetric allylic alkylation is a mild and versatile bond forming reaction between a nucleophile and allylic electrophile. The wide scope of nucleophiles used, and the high regio- and stereoselectivity obtainable renders this transformation an important technique in enantioselective synthesis. The mechanism is known to go via a key palladium π-allyl intermediate, followed by nucleophilic addition occurring at the terminal allylic carbon. Both the formation of the palladium π-allyl, and the nucleophilic addition to generate the alkylated product and palladium(0) proceed with high levels of inversion of stereochemistry, and both provide an opportunity for the induction of stereochemistry. However in the case of ligand controlled nucleophilic addition memory effects have been observed. The epimerisation of the palladium π-allyl before nucleophilic attack is key to achieving high levels of selectivity when racemic starting materials and chiral ligands are employed. Previous work in the Lloyd-Jones group has determined that prolonging the lifetime of the palladium π-allyl species, either by the use of weakly coordinating counter ions or slow addition of the nucleophile reduces this memory effect, however increasing the rate of epimerisation would have a result in a similar effect. One of the mechanisms resulting in the epimerisation of the palladium π-allyl species is mediated by palladium(0), however the details of the mechanism are not well understood. We describe the synthesis of a diastereotopic palladium cyclohexenyl ester and labelled the complex with 108palladium and d3 at the cyclohexenyl ester. Using simultaneous 31P NMR and mass spectrometry, we have acquired strong evidence against mechanisms involving a single electron transfer, as proposed by Stille, of formation of a dinuclear palladium(I) species followed by an inversion event, and we have gained evidence supporting the direct nucleophilic addition of the palladium(0), resulting in inversion of stereochemistry. The differences in rates of nucleophilic attack involving monodentate and bidentate phosphine ligands on both the palladium I-cyclohexenyl ester have also been explored. Throughout the mechanistic investigation, it was noted that the 31P NMR spectroscopy experiment used gave non-quantitative results, and in fact the differences in quantification of the species varied with the spectrometer used. We also describe our investigations into where these differences arise from and an optimum set of parameters for quantitative 31P NMR spectroscopy. The conclusions are also applicable to other heternuclear NMR spectroscopic experiments.

Verdazyl radicals started receiving attention as substrates for organic synthesis only a few years ago. Since then, the chemistry of verdazyl radicals has advanced at a very fast rate. There are now a number of generations of novel molecular scaffolds derived from verdazyl radicals. Traditionally, verdazyl radicals have been synthesized from mono-substituted alkyl hydrazine and phosgene, which are extremely dangerous to handle. Alkyl hydrazines are restricted from being imported into certain countries, including Canada. A completely new alkyl hydrazine- and phosgene-free synthesis is reported in this thesis. The new synthesis, relative to previously reported syntheses of verdazyl radicals, is safer, more economical and provides the ability to derivatize verdazyl radicals to a larger extent. In addition, enantioselective 1,3-dipolar cycloaddition reactions with various metal- or organo-catalysts are reported. The project is still in progress with the highest e.e. of > 90%.

Verdazyl radicals started receiving attention as substrates for organic synthesis only a few years ago. Since then, the chemistry of verdazyl radicals has advanced at a very fast rate. There are now a number of generations of novel molecular scaffolds derived from verdazyl radicals. Traditionally, verdazyl radicals have been synthesized from mono-substituted alkyl hydrazine and phosgene, which are extremely dangerous to handle. Alkyl hydrazines are restricted from being imported into certain countries, including Canada. A completely new alkyl hydrazine- and phosgene-free synthesis is reported in this thesis. The new synthesis, relative to previously reported syntheses of verdazyl radicals, is safer, more economical and provides the ability to derivatize verdazyl radicals to a larger extent. In addition, enantioselective 1,3-dipolar cycloaddition reactions with various metal- or organo-catalysts are reported. The project is still in progress with the highest e.e. of > 90%.

Nous avons développé de nouveaux accès pour la construction de molécules comportant les motifs Csp3-CF3 et Csp3-SCF3. Deux réactions de transfert d'hydrure sur des composés trifluorométhylés par catalyse avec des métaux de transition ont été réalisées : 1) l'isomérisation catalytique d'alcools allyliques trifluorométhylés par des complexes de fer (II); 2) le transfert d'hydrogéne énantiosélectif de céto-imines trifluorométhylées par des complexes chiraux de ruthénium en utilisant l'isopropanol comme source d'hydrure pour obtenir des amines trifluorométhylées optiquement actives avec de hauts rendements et de hautes énantiosélectivités. La trifluorométhylthiolation allylique nucléophile de dérivés de Morita-Baylis-Hillman a été étudiée. L'accès régio- et stéréosélectif aux produits SCF3 thermodynamiques a été réalisé par la combinaison de S8/CF3SiMe3/KF/DMF avec de bons rendements. Le produit cinétique a été obtenu en utilisant le réactif de Zard. / We have developed new accesses for the construction of molecules featuring Csp3-CF3 and Csp3-SCF3 motifs. Two atom-economical hydride transfer reactions of trifluoromethylated compounds by transition-metal catalysis were realized: 1) the isomerization of trifluoromethylated allylic alcohols by iron (II) complexes; 2) the enantioselective transfer hydrogenation of trifluoromethylated ketimines by a chiral complex of ruthenium and isopropanol as hydride source for the preparation of optically pure trifluoromethylated amines in high yields and high enantioselectivities. The nucleophilic allylic trifluoromethylthiolation of Morita-Baylis-Hillman derivatives was investigated. The regio- and stereoselective access to thermodynamic trifluoromethylthiolated products has been achieved by combination of S8/KFfMe3SiCF3/DMF in good yields. The kinetic trifluoromethylthiolated products were obtained by using Zard's trifluoromethylthiolating reagent.

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.

Thesis advisor: X. Peter Zhang / Highly strained three membered heterocycles are a common motif in many biologically relevant molecules and represent a versatile building block for organic synthesis. Of special interest for asymmetric synthesis is the construction of enantioenriched aziridines and epoxides, which are often used as chiral synthons to introduce heteroatoms in a stereoselective fashion. Among different elegant strategies, the direct aziridination and epoxidation of the ubiquitous alkene functionality represents one of the most powerful methods to access these motifs. Given the synthetic importance of the enantioenriched smallest aza- and oxaheterocycles, the focus of this dissertation is centered on the design and use of chiral cobalt porphyrins as catalysts to develop new methodologies for the asymmetric radical aziridination and epoxidation of alkenes.In the first part of this dissertation, we focused on using carbonyl azides as nitrogen source for the enantioselective radical aziridination of alkenes. Despite its high functionality and versatility for further derivatization, carbonyl azides have never been reported as nitrogen source for intermolecular asymmetric alkene aziridination. In the second part of this dissertation, we focused on opening up a new area of research, which involves the generation and characterization of the unprecedented cobalt porphyrin-supported oxygen-centered radical species. Finally, we demonstrated the synthetic utility of these new radical species by developing a new system for the asymmetric epoxidation of alkenes through the design and development of a novel family of catalyst named “JesuPhyrin”. / Thesis (PhD) — Boston College, 2021. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: James P. Morken / Thesis advisor: Marc L. Snapper / This dissertation will present three projects focusing on the enantioselective synthesis and stereospecific transformation of alkylboronates. The first project describes the development of a nickel-catalyzed enantioselective dicarbofunctionalization of alkenylboronates, which provides a modular route to secondary alkylboronic esters. Intramolecular reaction leads to enantioselective synthesis of exocyclic boronates. The second project depicts a new method for the synthesis of azetidines, pyrrolidines and piperidines via an intramolecular amination of alkylboronic esters. Regioselective amination of vicinal bis(boronates) allows the synthesis of saturated azacycles bearing boronic ester substitutions that can serve as useful synthetic handles. As the transformation is stereospecific, stereodefined cyclic amines can be synthesized from the enantioenriched boronic esters. The method is applied to the synthesis of an intermediate towards a Kras G12C inhibitor. The third project describes the development of a new chiral auxiliary on boron that can be easily synthesized from inexpensive starting materials. The auxiliary is applied to a diastereoselective radical ring-opening/closing [3+2] cycloaddition of cyclopropylanilines with alkenylboron species. / Thesis (PhD) — Boston College, 2022. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: James P. Morken / This dissertation will present four main projects focused on stereoselective construction of borylated compounds as well as their applications in asymmetric syntheses. The first two projects describe the development of a catalytic conjunctive cross-coupling reaction. By merging three simple starting materials, an organolithium reagent, an organoboronate, and an organic electrophile, a synthetically valuable secondary boronate is furnished by the conjunctive cross-coupling in an efficient and enantioselective fashion. Next, this strategy is expanded to synthesize severely hindered tertiary boronates, a synthetic challenging but powerful building block to access a variety of quaternary stereocenters. The third project presents a platinum-catalyzed enantioselective diboration of alkenyl boronates to furnish a broad range of 1,1,2-tris(boronates) products. A deborylative alkylation of the 1,1,2-tris(boronates) leads to a variety of internal vicinal bis(boronates) with high diastereoselectivity. In the final chapter, a general and practical synthesis of alkenyl boronates via the boron-Wittig reaction is disclosed. Utilizing readily accessible geminal bis(boronates) and aldehydes, a broad range of disubstituted and trisubstituted alkenyl boronates are afforded with good yield and stereoselectivity. / Thesis (PhD) — Boston College, 2017. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

The research presented herein is concerned with the exploration of the rhodium catalysed addition of organoboron reagents. Chapter 1 firstly introduces the area of organoboron reagents, focussing on the applications of potassium alkenyl trifluoroborate reagents. Secondly, an extensive discussion of the rhodium catalysed conjugate addition of organboron reagents demonstrates its utility as a key coupling step in recent syntheses. Chapter 2 describes synthetic methods towards alkenylboron reagents and describes the synthesis of functionalised and enantiopure alkenyl trifluoroborate salts. Chapter 3 discusses the rhodium catalysed addition of potassium alkenyl trifluoroborate salts to α,β-unsaturated compounds. A gas chromatography study addresses issues concerning protodeboronation and highlights the potential for olefin transposition. A new rhodium catalysed olefin transposition reaction has been thoroughly investigated and applied using the synthesised potassium alkenyl trifluoroborate salts. Chapter 4 describes the synthesis of biologically relevant, enantiopure dihydropyranones for use as acceptors in the rhodium catalysed conjugate addition reaction. The hetero-Diels-Alder reaction is employed to synthesise the dihydropyranones. Rhodium catalysed conjugate addition of arylboronic acids and potassium alkenyl trifluoroborates is utilised to concisely assemble late stage intermediates of natural products including diospongin B. Chapter 5 describes the synthesis and characterisation of the compounds discussed in chapters 2, 3 and 4.

Thesis advisor: Marc M. Snapper / Thesis advisor: James J. Morken / This dissertation will present three main projects focusing on the catalytic enantioselective synthesis and stereospecific functionalization of tertiary alkylboronates. In the first project, acyl chlorides were incorporated as a new class of electrophile in conjunctive cross-coupling, from which, a variety of tertiary β-boryl amides were successfully synthesized with high enantioselectivity. The utility of the tertiary alkylboronates products was also demonstrated through several orthogonal functionalizations of the boronic ester group and amide groups. The project culminated in the enantioselective total synthesis of natural product (+)-adalinine that leveraged this newly developed methodology. In the second project, a conjunctive cross-coupling enabled ring closure was developed to synthesize tertiary alkylboronates residing on carbocyclic and heterocyclic scaffolds. A Phosphinooxazoline (Phox) ligand was identified as a non-expensive ligand that catalyzed the conjunctive cyclization reaction with high enantioselectivity. A Series of synthetically challenging enantimerically enriched spirocyclic and aryl bicyclic tertiary alkylboronates were efficiently generated using this method, and several cyclopentyl boronic esters with two continuous stereogenic centers were synthesized with high diastereoselectivity. In the third project, a Rh-catalyzed diboration reaction was successfully employed to diborate monosubstituted cyclobutenes with excellent enantioselectivity. The less sterically hindered secondary boronic ester units in the diboron products can be regioselectively functionalized using the newly developed tert-butyllithium activation-transmetallation strategy. As a result, a variety of stereochemically defined β-substituted cyclobutyl tertiary boronic esters were synthesized with high efficiency. / Thesis (PhD) — Boston College, 2024. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.