Thesis advisor: James P. Morken / Detailed within this dissertation are three new reactions involving allylboron reagents. Chapter 1 describes the development of Pd-catalyzed allyl-allyl cross-coupling for the preparation of enantioenriched all-carbon quaternary stereogenic centers. This methodology represents a novel approach to a significant challenge for synthetic chemists. Subsequently, an allyl-allyl cross-coupling is described which generates functionally differentiated 1,5-dienes. Such structures allow for several chemoselective manipulations, which add a significant practical note to this cross-coupling methodology. Chapter 2 details the development of the allylboration of nitrosobenzene with (Z)-crotylboronate derivatives, which results in the formation of branched allylic alcohols. This methodology provides a regioselective complement to standard boron oxidation conditions. / Thesis (PhD) — Boston College, 2012. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Amir H. Hoveyda / Homoallylic alcohols and amines are commonly used building blocks for synthesis of biologically active molecules, yet a survey of the methods for their synthesis reveals a plague of limitations. Notably, the use of toxic reagents (Cr-, Mn-, and Sn-containing), precious metal catalysts (Ir- and In-based), non-ambient reaction temperatures (–78 to 140 °C), and extended reaction times (up to 240 hours), limit application on larger scale. The protection/deprotection sequences required to install directing/activating groups for reaction efficiency and enantioselectivity not only add synthetic steps but the conditions required for removal of such entities are not amenable to more complex and sensitive molecules. The development of catalytic enantioselective methods for addition of allyl moieties to readily available substrates including halomethyl ketones, trifluoromethyl-substituted ketimines, and nitriles have been developed. In the first two cases, an aminophenol-based boryl catalyst is utilized for enantioselective additions of allyl moieties through transition states controlled by either electrostatic attraction between a C–X bond and the catalyst’s ammonium moiety or minimization of steric and dipolar repulsion. In the latter, multicomponent additions to nitriles have been developed for synthesis of cyclic amines. In all cases, application is demonstrated through synthesis of otherwise difficult-to-access derivatives or biologically active molecules. / Thesis (PhD) — Boston College, 2020. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Amir H. Hoveyda / A previously developed catalytic system which can catalyze a variety of efficient and enantioselective allyl additions has been expanded to include regio-, diastereo-, Z-, and enantioselective crotyl addition reactions. As discussed in Chapter 1, we were able to carry out efficient crotyl additions to N-phosphinoyl imines by discovering a sufficiently Lewis acidic co-catalyst, zinc(II) methoxide. This finding enabled us to vastly improve reaction efficiency, in addition to enabling a 1,3-borotropic shift during the course of the reaction, turning a previously α selective transformation into a γ-selective one. These findings allowed us to develop a catalytic, enantioselective crotyl addition to N-phosphinoyl imines utilizing the commercially available Z-crotyl–B(pin). When the reaction conditions elucidated for crotyl additions to imines were utilized on a more electrophilic substrate, such as trifluoromethyl ketones, an entirely different finding was observed (Chapter 2). We found that if direct addition is more facile than 1,3-borotropic shift the transformation will again be α-selective, furnishing a linear product, rather than the typically observed, branched crotyl addition product. This finding allowed us to establish the first broadly applicable, efficient, regio-, Z-, and enantioselective crotyl addition to trifluoromethyl ketones. We then highlighted the utility of these products by using this method in tandem with Z-selective olefin metathesis, affording complex, enantioenriched, trifluoromethyl-containing homoallylic alcohols. During the course of these studies, and through density functional theory computations, we learned that Z- and E-crotyl–B(pin) react through distinct transition states to form the same Z-olefin-containing product with varying levels of enantioselectivity. These findings led us to the results reported in Chapter 3, the first examples of enantioselective aminophenol-promoted allyl additions to aldehydes. We were able to utilize Z-CF3-allyl–B(pin) and Z-Cl-allyl–B(pin) (both accessed through catalytic olefin metathesis) in Z- and enantioselective additions to aldehydes, affording products which cannot be accessed readily through previously reported methods. We quickly realized the potential of Z-chloro-substituted homoallylic alcohols for the synthesis of Z-homoallylic alcohols, to demonstrate this potential, we carried out the total synthesis of mycothiazole, which we accomplished in seven steps from commercially available materials and 17% overall yield, a marked improvement over the previous synthetic strategy. / Thesis (PhD) — Boston College, 2018. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: James P. Morken / Described herein are methods for asymmetric allylation. Chapter 1 describes the scope of the Pd-catalyzed asymmetric diboration of prochiral allenes. The products of this process possess both a chiral allylboronate functional group and a vinylboronate moiety. The allylboronate functionality can subsequently be used for imine allylation, without isolation of the diboron intermediate, resulting in the formation of atypical allylation products through a tandem, one-pot sequence. Furthermore, enantioselection in the catalytic diboration and chirality transfer in the subsequent imine allylation are high; thus, non-racemic, protected homoallylic amines, and other derivatives, are produced in high enantiomeric excess. Chapter 2 describes the discovery and development of a transition-metal-catalyzed asymmetric conjugate allylation of allylboronate ester nucleophiles to activated enones. The scope, utility, and mechanistic aspects of this new reaction are discussed. / Thesis (PhD) — Boston College, 2008. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Amir H. Hoveyda / A general method for the catalytic enantioselective addition of silylallenes to phosphinoyl aldimines has been developed. Reactions are promoted in the presence of 5.0 mol% of an N–heterocyclic carbene–copper complex and a silyl-protected propargyl boron reagent. The reaction is efficient, requiring only 10 minutes, highly group selective, enantioselective and products can be further functionalized. Utility is highlighted in the total synthesis of marine alkaloid (S)-(–)-cyclooroidin using our product as a key intermediate in the total synthesis. The catalytic enantioselective addition of a 1,3-butadiene has been developed using a homoallenylboron reagent. These transformations are promoted by a C1-symmetric N–heterocyclic carbene–copper complex within 4 hours. Products can be obtained with gamma selectivity to afford the diene containing product. Efforts have been expanded towards the application of our product as a key intermediate towards the total synthesis of (+)-homochelidonine. Key transformations include a highly selective 1,2-protoboration of the 1,3-diene product followed by a Pd-catalyzed intramolecular sp2-sp3 Suzuki cross coupling. The development of a general catalytic enantioselective method for the propargyl addition to trifluoroketones has been studied. Reactions are complete within 15 minutes, broadly applied to alkyl-, alkenyl, alkynyl, aryl, and heteroaryl-substituted trifluoroketones, highly enantioselective and group selective. Key findings include use of an aminophenol containing an electron-withdrawing to improve reactivity and enantioselectivities. The method can be carried out on gram scale and has been applied to a substrate which can be elaborated towards glucocorticoid agonist BI 653048. / Thesis (PhD) — Boston College, 2017. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Amir H. Hoveyda / Chapter One Development of Simple Organic Molecules as Catalysts for Enantioselective Allyl Additions to N-Phosphinoylaldimines and Isatins A new catalytic protocol for the enantioselective addition of organoborates to imines and carbonyls is described. This novel method, which does not require transition metals utilizes a modular and easily accessed aminophenol to dictate the stereochemistry of the products. Allyl-additions to N-phosphinoylaldimines and isatins, as well as allenyl-additions to isatins are studied and literature relevant to these transformations is discussed. Additionally, two separate methods for obtaining "crotyl-type" addition products to aldimines; one requiring α-chiral allylboronates and the other requiring a zinc-alkoxide, are discussed. Studies to elucidate the mechanism of this catalytic protocol are also contained in this chapter. Chapter Two Enantioselective Additions to Fluorinated Ketones: A Platform for Studying the Interaction Between Organofluorine and a Small Molecule Utilizing the new protocol discussed in Chapter One, allyl- and allenyl-groups are added enantioselectively to ketones containing a fluorinated substituent. Myriad tertiary alcohols are synthesized, demonstrating the value of this method. This study also allows for examining how organofluorine containing compounds bind to other organic molecules, which is a current topic of intense interest in the field of medicinal chemistry. Mechanistic studies support the idea that, in many cases, the fluorine of the substrate is electrostatically attracted to the ammonium-ion in the catalyst. Chapter Three Enantioselective Additions of Organoboronates to Ketones and Alphaketoesters Promoted by an Aminophenol Containing Catalyst Modification of the aminophenol disclosed in Chapter One allows for increased enantioselectivity for the allyl-addition to both simple ketones (such as acetophenone) and alphaketoesters. For simple ketones, a critical component of the optimal catalyst is replacing the tert-butyl group ortho to the phenol with the sterically large triphenylsilyl group. For alphaketoesters, this tert-butyl group was replaced with the sterically smaller metyl group. Rationale for why these contradictory changes in the catalyst structure lead to higher enantioselectivity for reactions with these two classes of ketones is discussed. Chapter Four Ag-Catalyzed Enantioselective Vinylogous Mannich Reactions of γ-Substituted Siloxyfurans with Aldimines A previously disclosed Ag-catalyzed enantioselective vinylogous Mannich reaction (EVM) with α-, β-, and unsubstituted siloxyfurans is extended to include γ-substituted siloxyfurans. This method, which generates a tertiary stereogenic center concurrent with an adjacent to a quaternary stereogenic center, requires a rarely used 2-thiomethylaniline N-protecting group for the aldimines. / Thesis (PhD) — Boston College, 2014. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Methylene-butyrolactones are readily accessed by two methodologies based on a particular ene reaction. Both methodologies have been applied to the synthesis of the northern fragment of Polycavernoside. A reverse Julia reaction was used as the key step of a new methodology towards triene frameworks ; a mechanistic study revealed the unexpected role of triflic acid in the field of metal triflates catalysed acylation of alcohols, and a new tandem Brook rearrangement-allylation sequence was developed in the viewpoint of an improved total synthesis of Polycavernoside A.

Methylene-butyrolactones are readily accessed by two methodologies based on a particular ene reaction. Both methodologies have been applied to the synthesis of the northern fragment of Polycavernoside. A reverse Julia reaction was used as the key step of a new methodology towards triene frameworks ; a mechanistic study revealed the unexpected role of triflic acid in the field of metal triflates catalysed acylation of alcohols, and a new tandem Brook rearrangement-allylation sequence was developed in the viewpoint of an improved total synthesis of Polycavernoside A.

The efficient construction of complex organic molecules mandates that an assortment of methods for forming C-C bonds be available to the practicing synthetic chemist. The addition of carbon based nucleophiles to carbonyl compounds represents a broad class of reactions used to achieve this goal. Traditional methodology requires the use of stoichiometrically preformed organometallic reagents as nucleophiles in this type of reaction. However, due to the moisture sensitivity, excessive preactivation and inevitable generation of stoichiometric waste required for the use of these reagents, alternative methods have become a focus of the synthetic organic community. The research presented in this dissertation describes a new class of C-C bond forming reactions enabled through catalytic transfer hydrogenation. Here, the development and implementation of efficient green methods for carbonyl addition employing π-unsaturates as surrogates to preformed organometallic reagents is described. Additionally, this research describes the first systematic studies toward using alcohols as electrophiles in carbonyl allylation, propargylation and vinylation reactions. / text

D.Sc. (Chemistry) / The aim of this study was to develop new methodology for the transformation of unsaturated carbohydrates utilising organometallic compounds. The first half of the study was directed toward developing a general synthesis of complex allyltins and in determining their application to carbon-carbon bond formation. It was decided to utilise carbohydrate substrates in this regard to develop a novel method of producing glycosides...