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In biological systems, most of the active organic molecules are chiral. Some of the main constituents of living organisms are amino acids and sugars. They exist predominantly in only one enantiomerically pure form. For example, our proteins are built-up by L-amino acids and as a consequence they are enatiomerically pure and will interact in different ways with enantiomers of chiral molecules. Indeed, different enantiomers or diastereomers of a molecule could often have a drastically different biological activity. It is of paramount importance in organic synthesis to develop new routes to control and direct the stereochemical outcome of reactions. The aim of this thesis is to investigate new protocols for the synthesis of complex chiral molecules using simple, environmentally friendly proline-based organocatalysts. We have investigated, the aziridination of linear and branched enals, the stereoselective synthesis of β-amino acids with a carbene co-catalyst, the synthesis of pyrazolidines, the combination of heterogeneous transition metal catalysis and amine catalysis to deliver cyclopentenes bearing an all-carbon quaternary stereocenter and a new heterogeneous dual catalyst system for the carbocyclization of enals. The reactions presented in this thesis afforded the corresponding products with high levels of chemo-, diastero- and enantioselectivity. / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 5: Submitted. </p>

The aim of this project was to utilize chiral cation-directed catalysis in the asymmetric synthesis of novel hererocycles. This goal was initially realized by the synthesis of azaindolines in high yields and enantioselectivities (Chapter 2). Extension of this methodology to substrates bearing two stereogenic centres was successful, although control over both diastereoselectivity and enantioselectivity in this process was modest. Finally the synthesis of heterocycles utilizing cation-directed rearrangement processes was examined, with proof of concept obtained for a novel asymmetric cyclization to form xanthenes.

Thesis advisor: James P. Morken / The first highly enantioselective diboration of unfunctionalized terminal alkenes has been developed using a platinum-phosphonite complex. This transformation produces versatile 1,2-bis(boronate)esters that can manipulated chemoselectively to generate a pletheroa of enantioenriched structural motifs. When combined with an appropriate palladium catalyst, the diboration product undergoes an efficient alkyl boron cross-coupling with aryl and vinyl electrophiles producing a wide range of enantioenriched homobenzylic and homoallylic boronates. Alternatively, when the 1,2-bis(boronate)ester diboration product contains an adjacent Z-olefin (derived from diboration of cis-1,3-dienes), allylation to aldehydes can be achieved delivering the syndiastereomer of product exclusively with excellent chirality transfer. Notably, the products obtained from the two described reactions contain an additional boronate moiety, which can be further functionalized through known carbon-boron bond transformations. / Thesis (PhD) — Boston College, 2014. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: James P. Morken / This dissertation describes the development of two enantioselective methods of carbon-carbon bond formation. Chapter one discusses the development of an enantioselective Pd(0)-catalyzed conjugate addition of allylboronic acid pinacol ester to &alpha;,&beta;-unsaturated methylidene ketones. Utilizing the same rationale for regio- and enantiocontrol as in the related enantioselective conjugate allylation of arylidene ketones, this method addresses the gap in technology by expanding the scope of the reaction to include alkyl-substituted enones. Chapter two examines the coupling of allyl electrophiles and allyl metal reagents. With computational insight into the reaction mechanism, a catalyst system was designed to control regioselectivity and enantioselectivity. Isotope labeling studies were carried out to probe the mechanism of the transformation. The reaction also proves to be diastereoselective when a substituted allyl boron reagent is employed. / Thesis (PhD) — Boston College, 2011. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Amir H. Hoveyda / Chapter 1. The development of chiral monodentate N-heterocyclic carbenes (NHCs) is presented. Structurally varied twenty-eight new chiral imidazolinim salts, NHC precursors, were synthesized and characterized. Chapter 2. The first example of Cu-catalyzed enantioselective conjugate additions of alkyl- and arylzinc reagents to unactivated cyclic enones is presented. Transformations are promoted in the presence of 2.5-15 mol % of a readily available chiral NHC-based Cu complex, affording the desired products bearing all-carbon quaternary stereogenic centers in 67-98% yield and in up to 97% ee. Catalytic enantioselective reactions can be carried out on a benchtop, with undistilled solvent and commercially available (not further purified) Cu salts. Chapter 3. A new class of enantioselective conjugate addition (ECA) reactions that involve aryl- or alkenylsilylfluoride reagents and are catalyzed by chiral non-C2-symmetric Cu-based NHC complexes are presented. Transformations have been designed based on the principle that a catalytically active chiral NHC-Cu-aryl or NHC-Cu-alkenyl complex can be accessed from reaction of a Cu-halide precursor with in situ-generated aryl- or alkenyl-tetrafluorosilicate. Reactions proceed in the presence of 1.5 equivalents of the aryl- or alkenylsilane reagents and 1.5 equivalents of tris(dimethylamino)sulfonium difluorotrimethylsilicate. Desired products are isolated in 63-97% yield and 73.5:26.5-98.5:1.5 enantiomeric ratio (47%-97% ee). Chapter 4. An efficient Cu-catalyzed protocol for enantioselective addition of a dimethylphenylsilanyl group to a wide range of cyclic and acyclic unsaturated ketones, esters, acrylonitriles and dienones is presented. Reactions are performed in the presence of 1-5 mol % of commercially available and inexpensive CuCl, a readily accessible monodentate imidazolinium salt as well as commercially available (dimethylphenylsilyl)pinacolatoboron. Cu-catalyzed 1,4- and 1,6-conjugate additions afford the enantiomerically enriched silanes in 72%-98% yield and 90:10->99:1 enantiomeric ratio (er) with up to >25:1 of Z:E selectivity. Chapter 5. A Cu-catalyzed method for enantioselective boronate conjugate additions to trisubstituted alkenes of acyclic a,b-unsaturated carboxylic esters, ketones, and thioesters is presented. All transformations are promoted by 5 mol % of a chiral monodentate NHC-Cu complex, derived from a readily available C1-symmetric imidazolinium salt, and in the presence of commercially available bis(pinacolato)diboron. Reactions are efficient (typically, 60% to >98% yield after purification) and deliver the desired boryl carbonyls in up to >98:2 enantiomer ratio (er). In addition, metal-free, nucleophilic activation of a B-B bond has been exploited in the development of a highly efficient method for conjugate additions of commercially available bis(pinacolato)diboron to cyclic or acyclic a,b-unsaturated carbonyls. Reactions are readily catalyzed by 2.5-10 mol % of a simple NHC. A variety of cyclic and acyclic unsaturated ketones and esters can serve as substrates. Transformations deliver boryl carbonyls bearing tertiary as well as quaternary B-substituted carbons in up to >98% yield. / Thesis (PhD) — Boston College, 2010. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: James P. Morken / (+)-Discodermolide is a marine natural product and is one of the most potent microtubule stabilizers in human cell lines. Because of its unique linear structure and important properties, a number of total syntheses of (+)-discodermolide and its derivatives have been reported. Herein, an efficient, highly convergent, and stereocontrolled total synthesis is presented (Chapter 2). The synthesis relied on the development of three catalytic and stereoselective processes: platinum-catalyzed asymmetric diene diboration, nickel-catalyzed diastereoselective hydroboration of chiral dienes (Chapter 1), and nickel-catalyzed borylative diene-aldehyde coupling (see Chapter 4). Combination of these reactions allows preparation of the target in a short sequence. Moreover, the development of rhodium-catalyzed asymmetric hydroformylation (Chapter 3) makes this approach the first Roche ester free (+)-discodermolide synthesis. / Thesis (PhD) — Boston College, 2014. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

This thesis describes the discovery of catalytic reactions that create carbon-carbon bonds stereoselectively between substrates bearing an alkene and organoboronic acids reagents. Chiral rhodium(I) catalysts were found to react with various meso-symmetrical substrates, thereby resulting in enantioselective desymmetrization reactions. The methodologies presented herein allow the rapid synthesis of several chiral functionalized molecules; including branched homoallylic alcohols, cyclopentenyl hydrazines, and ketohydrazines. The thesis is divided according to three main transformations: asymmetric allylic substitution of allylic carbonates, asymmetric ring-opening of [2.2.1]-diazabicyles, and carbonylation of alkenes or alkynes. Chapter 2 details the investigations of a ligand-controlled catalytic process to prepare either trans-2-arylcyclopent-3-enols (up to 94% ee), or trans-4-arylcyclopent-2-enols (up to 99% ee) as the major products starting from cyclic meso allylic dicarbonates. This rhodium-catalyzed methodology was extended to include linear allylic dicarbonates, thereby yielding chiral 2-arylbut-3-enols with up to 95% ee. An enantioselective desymmetrization of strained alkenes by ring-opening of meso bicyclic hydrazines is described in Chapter 3. The reaction allows one to prepare trans-2-arylcyclopent-3-enyl hydrazides with up to 99% ee. In addition, an enantioselective hydroarylation process was identified to yield 5-aryl-2,3-diazabicyclo[2.2.1]heptanes. Mechanistic investigations showed that the reaction proceeds via an unusual C-H activation/1,4-migration of the rhodium catalyst. Finally, Chapter 4 outlines the development of a mild catalytic acylation of pi systems. This mode of reactivity was optimized to promote the desymmetrization of [2.2.1]-diazabicycles via a formal allylic substitution with acyl anions as nucleophiles. The method yields densely functionalized trans-2-ketocyclopent-3-enyl hydrazides. In addition, preliminary studies demonstrate that the rhodium(I)-catalyzed acyl anion addition is also possible with other pi electrophiles. For example, with alkyne, it provided a synthesis of cyclopentenones that complements the Pauson-Khand reaction. Overall, the catalytic transformations reported herein give access to seven classes of products stereoselectively; starting from simple reagents.

This thesis describes the discovery of catalytic reactions that create carbon-carbon bonds stereoselectively between substrates bearing an alkene and organoboronic acids reagents. Chiral rhodium(I) catalysts were found to react with various meso-symmetrical substrates, thereby resulting in enantioselective desymmetrization reactions. The methodologies presented herein allow the rapid synthesis of several chiral functionalized molecules; including branched homoallylic alcohols, cyclopentenyl hydrazines, and ketohydrazines. The thesis is divided according to three main transformations: asymmetric allylic substitution of allylic carbonates, asymmetric ring-opening of [2.2.1]-diazabicyles, and carbonylation of alkenes or alkynes. Chapter 2 details the investigations of a ligand-controlled catalytic process to prepare either trans-2-arylcyclopent-3-enols (up to 94% ee), or trans-4-arylcyclopent-2-enols (up to 99% ee) as the major products starting from cyclic meso allylic dicarbonates. This rhodium-catalyzed methodology was extended to include linear allylic dicarbonates, thereby yielding chiral 2-arylbut-3-enols with up to 95% ee. An enantioselective desymmetrization of strained alkenes by ring-opening of meso bicyclic hydrazines is described in Chapter 3. The reaction allows one to prepare trans-2-arylcyclopent-3-enyl hydrazides with up to 99% ee. In addition, an enantioselective hydroarylation process was identified to yield 5-aryl-2,3-diazabicyclo[2.2.1]heptanes. Mechanistic investigations showed that the reaction proceeds via an unusual C-H activation/1,4-migration of the rhodium catalyst. Finally, Chapter 4 outlines the development of a mild catalytic acylation of pi systems. This mode of reactivity was optimized to promote the desymmetrization of [2.2.1]-diazabicycles via a formal allylic substitution with acyl anions as nucleophiles. The method yields densely functionalized trans-2-ketocyclopent-3-enyl hydrazides. In addition, preliminary studies demonstrate that the rhodium(I)-catalyzed acyl anion addition is also possible with other pi electrophiles. For example, with alkyne, it provided a synthesis of cyclopentenones that complements the Pauson-Khand reaction. Overall, the catalytic transformations reported herein give access to seven classes of products stereoselectively; starting from simple reagents.

La preparación de nuevos ligandos quirales P-OP (fosfina-fosfinitos y fosfina-fosfitos), fácilmente preparados con una estrategia sintética en dos etapas desde una aproximación covalente, es descrita en la presente Tesis Doctoral. El mejor catalizador de la serie ha demostrado tener propiedades catalíticas excelentes en la hidrogenación asimétrica catalizada por rodio de una amplia variedad de olefinas funcionalizadas. El resultado excelente y el diseño modular de los ligandos sintetizados hacen éstos muy atractivos para futuras aplicaciones.La presente Tesis Doctoral describe también la preparación de nuevos ligandos quirales que pueden comportarse como catalizadores supramoleculares inspirados en el mecanismo de regulación alostérica de los enzimas. / A library of enantiomerically pure P-OP ligands (phosphine-phoshinites and phosphine-phosphites) straightforwardly available in two synthetic steps from enantiopure Sharpless epoxy ethers is reported in the present PhD. Thesis. The "lead" catalyst of the series has proven to have outstanding catalytic properties in the rhodium-catalysed asymmetric hydrogenation of a wide variety of functionalised alkenes. Their excellent performance and modular design makes them attractive for future applications.This PhD. Thesis also reports the development of a practical route to chiral diphosphine ligands with supramolecular motifs, with potential for allosteric modulation, which we prepared for future catalytic studies.