Thesis advisor: Amir H. Hoveyda / Chapter 1 Mechanism-Based Enhancement of Scope and Enantioselectivity for Reactions Involving a Copper-Substituted Stereogenic Carbon Center: Organoborons are important building blocks of complex natural products, functional materials, and pharmaceutically relevant compounds due to their prevalent utility in C–C and C–hetero atom bond transformations. Using a readily accessible copper catalyst, we have developed highly site- and enantioselective allylic substitution by way of a threecomponent, single-vessel, and sustainable catalytic protocol. Detailed mechanistic studies revealed valuable insights which led us to develop copper–boron and copper–hydride additions to olefins with broader substrate scope, higher efficiency, and higher enantioselectivity. In addition, the method can be applied to the synthesis of biologically active molecules such as preclamol and heliespirone A and C. Chapter 2 Versatile Homoallylic Boronates by Chemo-, SN2’-, Diastereo- and Enantioselective Catalytic Sequence of Cu–H Addition to Vinyl-B(pin)/Allylic Substitution: To achieve an efficient multicomponent reaction, high chemoselectivity between a starting material and a reagent must be accomplished during the first catalytic transformation to generate an intermediate which then selectively reacts with another substrate to furnish the product in a site-, and/or stereoselective fashion. Development and application of efficient multicomponent reactions involving allylic substitution can provide alternative solutions for difficult synthetic problems in organic chemistry. Our group has developed a sulfonate-containing chiral NHC–Cu catalyzed chemo-, SN2’-, diastereo-, and enantioselective multicomponent reaction through Cu–H addition to readily available vinyl–B(pin) followed by allylic substitution to deliver homoallylic boronates. The derived homoallylic alcohols can be used as building blocks of biologically active molecules. Chapter 3 Enantioenriched Halogen-Substituted Alkenes through NHC–Cu-Catalyzed Borylation/Dehalogenation and Their Applications: Because of their unique properties, mono- and difluoroalkenes have received attention as an important class of compounds as building blocks for fluorine-containing monomers for functional polymers and biologically active molecules in medicine and agriculture. However, reported methods to prepare enantioenriched difluoroalkenes are scarce and often require undesirable amounts of precious transition metals and very high/low temperatures. To solve these challenges, we have developed a highly efficient, regio-, and enantioselective boron allylic substitution to CF3-alkenes and other halogen-substituted olefins by using an abundant copper-based catalyst. / Thesis (PhD) — Boston College, 2017. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: James P. Morken / This dissertation aims to design and develop novel and synthetically useful catalytic enantioselective C-C bond-forming reactions that employ a newly uncovered 3,3'-reductive elimination of bis(allyl)metal species. This elementary transformation allows for new routes for the enantioselective construction of a range of important motifs found in natural products. Enantiomerically enriched Z-allylic alcohols are readily accessed through the Ni-catalyzed allylation of trans,trans-dienals. Importantly, the first example of branch- and enantioselective allyl-allyl cross-coupling is presented as well, suitable for the construction of compounds bearing tertiary and quaternary carbon centers. With the aim to broaden the application of above described transformations, this dissertation also presents the development of highly efficient and convenient methods for the syntheses of substituted and functionalized allylic boronates. / Thesis (PhD) — Boston College, 2012. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

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Thesis advisor: Amir H. Hoveyda / Chapter 1. Part A: N-Heterocyclic Carbenes Catalyzed Enantioselective Boryl Conjugate Additions to α,β-Unsaturated Ketones, Esters, Weinreb Amides and Aldehydes. The first broadly applicable enantioselective boryl conjugate addition reactions to a variety of α,β-unsaturated carbonyls are reported. Transformations are promoted by 5.0 mol % of a chiral Lewis basic N-heterocyclic carbene. The distinctive feature of the reactions in chemoselectivity of the method compared to the Cu-catalyzed variants has been illustrated. Part B: Enantioselective Synthesis of Boron-Substituted Quaternary Carbon Stereogenic Centers through N-Heterocyclic Carbenes Catalyzed Boryl Conjugate Additions to Cyclic and Acyclic Enones The first examples of Lewis base catalyzed enantioselective boryl conjugate additions that afford products containing boron-substituted quaternary carbon stereogenic centers are presented. The carbon–boron bond forming reactions are promoted by 1.0–5.0 mol % of a chiral N–hererocyclic carbene. Cyclic or linear α,β–unsaturated ketones can be used as suitable substrates and the desired products are obtained in 63–95% yield and 91:9 to >99:1 enantiomeric ratio. The utility of the Lewis base-catalyzed approach is demonstrated in the context of an enantioselective formal synthesis of antifungal natural product crassinervic acid. Chapter 2. Enantioselectivity Fluctuations in Phosphine–Cu-Catalyzed Enantioselective Boron-Allyl Addition to Aryl-Substituted Olefins. Catalytic enantioselective multicomponent processes involving B2(pin)2, aryl or heteroaryl monosubstituted olefins, and allylic phosphates or carbonates are disclosed. Transformations promoted by a chiral Cu–phosphine complex afford products that contain a primary C–B(pin) bond and an allyl-substituted tertiary carbon stereogenic center in up to 84% yield and 98:2 enantiomeric ratio. The utility of the approach is showcased in the enantioselective formal synthesis of biologically active heliespirones A and C. Based on mechanistic and computational studies, we show that enantioselectivities variations can depend on electronic and/or steric factors of the alkene substrate and the allyl electrophile as well as their concentration. In most cases, selectivity loss can be minimized and that the resulting insights are also applicable to reactions involving Cu–H species. Chapter 3. Synthesis of Vicinal Diboronate Compounds through Practical Phosphine–Copper Catalyzed Three-Component Processes. The phosphine–Cu-catalyzed multicomponent processes have been developed for a practical and direct synthesis of vicinal diboronate compounds. Reactions of alkenyl–boronates, allylic phosphates, and diboron reagents are promoted by 2.5–10 mol % of a Cy3P–Cu complex affording a wide range of desirable vicinal diboronate products. The ability for easy access to either regioisomers of the products with a C–B(pin) and an adjacent C–B(dan) bond that can be site-selectively functionalized is a noteworthy feature of the method. / Thesis (PhD) — Boston College, 2016. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

" We are investigating resolution of chiral drugs via crystallization on self-assembled monolayers functionalized with achiral and chiral molecules that exhibit varying hydrophobicity/hydrophilicity as a means to bring about enantioseparation. Two goals of this work are to determine (1) whether chiral surfaces can act as templates that bias molecular aggregation at the surface to favor single enantiomers thereby inducing nucleation of conglomerates over racemic crystals, and (2) whether chiral templating can be used to induce selective nucleation of one enantiomer leading to high enantiomeric excess. Racemic compounds being investigated include the antibiotic 3-phenyllactic acid(3PLA) and the muscle-tissue repairing amino acid N-acetylleucine(NAL). Achiral and chiral alkanethiols were self-assembled onto 2D gold substrates by overnight immersion of the gold slides in ethanolic solution of the alkanethiols. The functional groups deposited on the SAM were characterized by grazing incidence IR spectroscopy, contact angle goniometry and ellipsometry. The contact angle and ellipsometry measurements showed that the cysteine SAMs form a bilayer consisting of monolayers of cysteine covalently bonded to gold covered by an overlayer of cysteine. The approach of using chiral templates to induce enantioselective nucleation of racemic drugs on the chiral surface via crystallization was first demonstrated for 3-phenyllactic(3PLA). Homochiral crystals (1), and conglomerates (3) formed from aqueous solution as needles, whereas heterochiral racemic crystals (2) formed from 3:1 hexanes-ethyl acetate as rectangular blocks. A comparison of the thermal stability of the three crystalline forms showed that the crystals of 1 and 3 exhibit greater thermal stability than crystals of 2 such that the racemic form does not appear in the phase diagram. We showed that chiral SAMs of cysteine were able to resolve enantiomers of racemic 3PLA effectively with up to 30% enantiomeric excess in bulk samples of crystals, and that the enantiomer in excess could be controlled based on the choice of D- or L-cysteine as the chiral template. Moreover, crystals of D- or L-3PLA grew oriented with a high degree of selectivity for attachment on the (004) face. We show that the presence of the excess enantiomer (D- or L-3PLA) present in solution acts as an additive to cause a change in the habit of L- or D-3PLA on L- or D-cysteine SAM. We also demonstrated the enantioselective crystallization on chiral SAMs for N-acetylleucine (NAL) which gave a higher enantiomeric enrichment with upto 80% ee. A novel approach of using chiral drugs as templates to amplify the chirality for better self-recognition was designed and SAMs were formed from cysteamine with an overlayer of L-3PLA. As a proof of concept, crystallization of racemic 3PLA on L-3PLA/cysteamine SAMs gave 24% enantiomeric enrichment and our results are comparable to cysteine SAMs. These results confirm our hypothesis that the molecular aggregation on D- and L-cysteine occurs via specific diastereomeric hydrogen-bonding interactions that discriminate between the two enantiomers, thereby promoting enantioselective nucleation and facial selectivity of chiral drugs. "

A highly enantioselective and diastereoselective rhodium-catalysed addition of potassium allyltrifluoroborates to cyclic imines is described within. By utilising rhodium-chiral diene complexes, a wide range of cyclic imines were successfully allylated in high yields and enantioselectivities. Using a variety of more highly substituted allyl reagents, additional stereocentres and further molecular complexity was achieved with good yields, enantioselectivities and diastereoselectivities. Investigations involving isomeric allyl species and deuterated allyl species provided results that gave mechanistic insight, leading to the proposal of a plausible mechanistic pathway and suggested the formation of interconverting allylrhodium intermediates. Furthermore, during these investigations, a highly interesting isomerisation of the allylrhodium intermediate was discovered. Such isomerisation led to the in situ formation of the more complex allylrhodium intermediates which led to complex products upon allylation with cyclic imines that would be difficult to synthesis via other methods. This isomerisation was found to occur for a range of cyclic imines and disubstituted allyltrifluoroborates, proceeding in good yields and diastereomeric ratios. Deuterium studies indicate it is probable that this isomerisation proceeds via a 1,4 rhodium migration and a plausible mechanism is proposed explaining both the connectivity of the products and the relative stereochemistry.

1. ENANTIOSELECTIVE RHODIUM-CATALYSED 1,4-ARYLATION OF ALKENYLAZAARENES An extended study on the enantioselective rhodium-catalysed 1,4-arylation of alkenylazaarenes has been conducted. The 1,4-arylation of various alkenylazaarenes was performed with an extended range of arylboronic acids using a modified catalytic system with a superior chiral diene ligand. The result is the generation of a large number of b-stereocentre-containing azaarene compounds in high enantiopurity. Further studies also enabled the completion of a reactivity index between alkenylazaarenes and more traditional α,β-unsaturated carbonyl compounds and the incorporation of the arylation into arylation-aldol domino processes. 2. ENANTIOSELECTIVE RHODIUM-CATALYSED 1,4-ALKENYLATION OF ALKENYLAZAARENES An extensive study on the enantioselective rhodium-catalysed 1,4-alkenylation of alkenylazaarenes has been performed. Development of the reaction parameters identified novel heterogeneous reaction conditions in pure water with sub-stoichiometric SDS. Subsequent ligand development identified an anilide-based chiral diene that provided the best balance between conversion and enantiopurity. Using the novel conditions, a selection of alkenylazaarenes underwent enantioselective rhodium-catalysed 1,4-alkenylation with two alkenyl MIDA boronates to provide the alkenylation products in good to excellent yields and moderate to excellent enantioselectivities. 3. ENANTIOSELECTIVE COPPER-CATALYSED 1,6-BORATION OF ELECTRON-DEFICIENT DIENES The development of an enantioselective copper-catalysed 1,6-boration of electrondeficient dienes using B2(pin)2 has been achieved. The reactions provide chiral allylboronic esters that, after oxidation, result in secondary allylic alcohols in moderate to high yields with excellent enantioselectivities and 1,6:1,4-regioselectivities. The 1,6-borations proceed efficiently employing catalyst loadings as low as 0.0049 mol% and their scalability has been demonstrated up to 40.4 mmol. The methodology was applied to a concise synthesis of atorvastatin, in which the key 1,6-boration was performed using a catalyst loading of 0.02 mol%.

Organolithiums are key reagents and intermediates in organic synthesis. An exciting and growing field is the use of organolithiums in enantioselective synthesis. The often complex nature of these compounds makes their implementation towards the synthesis of natural products or pharmaceutical targets a challenging yet rewarding endeavour. The ability of organolithiums to form carbon-carbon bonds in a stereoselective and predictable way is vital to their success in organic synthesis.<p> The first chapter in this thesis summarizes the current mechanistic understanding of asymmetric carbon-carbon bond formation adjacent to nitrogen. A brief literature review is presented to illustrate the different ways in which a stereoselective lithiation/substitution reaction at carbon can occur. A review of the application of dipole-stabilized carbanions a to nitrogen used in the stereoselective synthesis of natural products is presented.<p> The second chapter in this thesis describes a study of the use of N-Boc-3-pyrroline, and related compounds, as molecular scaffolds for the stereoselective synthesis of functionalized five-membered ring containing alkaloids. The asymmetric alkylation of N-Boc-3-pyrroline is possible for simple alkyl halides but only modest enantioselectivity can be obtained using chiral lithium amides or s-butyl lithium/(-)-sparteine as bases. More promising was the enantioselective alkylation of a protected 3-pyrroline building block 116. The assignment for the stereochemistry of the alkylated product from 116 and benzaldehyde was achieved by NMR techniques and conformational analysis. The work done on the synthesis of enantiomerically pure castanospermine analogs is also presented.