Thesis advisor: James P. Morken / This dissertation will discuss in depth four main projects pertaining to the synthesis and utility of organoboronates for the construction of enantioenriched small molecules. First, reaction optimization and substrate scope expansion of the platinum-catalyzed enantioselective diboration of alkenes are reported. Based on extensive experimental and computational mechanistic analysis, a preliminary stereochemical model is also proposed. A practical boron-Wittig reaction is presented in which synthetically challenging di- and trisubstituted vinyl boronates can be accessed in a highly stereoselective fashion from readily available starting materials. The enantioselective diboration of cis- and trans-vinyl boronates furnished novel 1,1,2-tris(boronate) esters in up to 95:5 er. The intermediate tris(boronate) esters were employed successfully in deborylative alkylations to furnish enantioenriched internal vicinal bis(boronates) in excellent diasteoselectivity. In the final chapter, an enantioselective palladium-catalyzed intramolecular Suzuki-Miyaura coupling between allyl boronates and aryl electrophiles is disclosed. The newly developed transformation provides enantioenriched 5, 6, and 7-membered carbocycles in up to 93:7 er. / Thesis (PhD) — Boston College, 2015. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

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Phytosterols are major components of food and are structurally related to cholesterol, but differ from it by virtue of a carbon substituent at the C-24 position and in some cases, a double bond between C-22 and C-23 (Figure i). Furthermore, phytosterols are shown to have protective actions against colon, breast, and prostate cancer1; further investigation is required as their mode of action is unknown. Thus, reported herein is the design and synthetic implementation required to construct these naturally occurring compounds. Figure i : Cholesterol Construction towards a double bond flanked by two asymmetric carbon atoms, observed in the phytosterol side chain, will be synthesised using an asymmetric Horner-Wittig (H-W) reaction, involving a chiral α-substituted aldehyde and a chiral β-substituted phosphine oxide. In addition to the synthesis, the stereochemical outcomes of these H-W reactions were probed. The results demonstrated, that by varying the steric bulk, electronic nature, and aromatic properties of the groups β to the phosphorus and α to the aldehyde can control the cis/trans selectivity in alkene formation. Finally, to display the utility of this methodology, the phytosterol compounds will be synthesised and tested in MD-MBA-231 cancer cell lines, allowing further investigation into the phytosterol mechanism of action.

Phytosterols are major components of food and are structurally related to cholesterol, but differ from it by virtue of a carbon substituent at the C-24 position and in some cases, a double bond between C-22 and C-23 (Figure i). Furthermore, phytosterols are shown to have protective actions against colon, breast, and prostate cancer1; further investigation is required as their mode of action is unknown. Thus, reported herein is the design and synthetic implementation required to construct these naturally occurring compounds. Figure i : Cholesterol Construction towards a double bond flanked by two asymmetric carbon atoms, observed in the phytosterol side chain, will be synthesised using an asymmetric Horner-Wittig (H-W) reaction, involving a chiral α-substituted aldehyde and a chiral β-substituted phosphine oxide. In addition to the synthesis, the stereochemical outcomes of these H-W reactions were probed. The results demonstrated, that by varying the steric bulk, electronic nature, and aromatic properties of the groups β to the phosphorus and α to the aldehyde can control the cis/trans selectivity in alkene formation. Finally, to display the utility of this methodology, the phytosterol compounds will be synthesised and tested in MD-MBA-231 cancer cell lines, allowing further investigation into the phytosterol mechanism of action.

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.

This thesis presents the synthesis of porphyrin arrays for light-harvesting applications using Wittig chemistry, which allows the construction of covalently bound systems that are conjugated, stable and easy to characterize. This was achieved using a dendrimer strategy utilizing tetraarylporphyrins as building blocks, monofunctionalized with either aldehyde or phosphonium salt groups at the β-pyrrolic position, and benzenes, polyfunctionalized with either aldehyde or phosphonium salt groups; stepwise control of the addition of each porphyrin moiety was thus obtained. In this way, different porphyrins in different metallated states were arranged in a determinate geometrical relationship, which is of great importance in the investigations on electron/energy transfers. Arrays containing up to five metalloporphyrin units (two kinds of porphyrins coordinating two different metals) were synthesized and characterized. The unexpected chromatography behaviour and 1H-NMR spectra of a Zn porphyrin functionalized with a 1,3-bis(methyl(diethylphosphonate) benzene were the reason for an investigation, which uncovered, mainly with the use of NMR spectrometry, the first case of intramolecular coordination between the Zn centre and a phosphonate group of the same porphyrin. The dynamic nature of this coordination was characterized and chemical-physical parameters for Zn porphyrin/phosphonate binding were determined. In order to establish the photophysical properties of our conjugated arrays, we synthesized a series of dyads containing Zn and free-base tetraphenylporphyrins (TPPs) connected through variable length phenylenevinylene-type bridges; along with this series, the preparation of the Zn and free-base homometallic homologue dyads and two series of monomers carrying the conjugated linker were realized. Collaboration with IFOS-CNR in Bologna, Italy was established in order to investigate the intramolecular photophysics of those systems, which involve efficient intramolecular energy transfer from the Zn to the free-base porphyrin. Finally, dyads composed of Fe(III) and Zn porphyrin were prepared as part of a project in collaboration with the University of Pennsylvania for the investigation of new artificial photosynthetic systems. Two series of dimers were prepared in order to obtain incorporation in both the classes of hydrophobic and hydrophilic proteins. TPPs were used for the making of the hydrophobic dyads while hydrophilicity was achieved by employing tetraester porphyrin derivatives, which can be quantitatively hydrolyzed to afford the correspondent water soluble acids. A new monosubstituted porphyrin was also synthesized and incorporated in the arrays to minimize steric hindrance inside the protein binding sites.

Thesis (Ph.D.)--Hong Kong University of Science and Technology, 2004. / Includes bibliographical references (leaves 206-216). Also available in electronic version. Access restricted to campus users.

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Chapter One presents an overview of phosphorus reagents for the carbon homologations of aldehydes and ketones leading to functionalized carbonyl derivatives. Select examples are provided to exemplify the utility of carbon homologation methodology in synthesis and asymmetric organocatalysis and in the total synthesis of natural products. The directing effect of acetals on regioselective ylide formation is explored in Chapter Two. Evidence is presented for ylide formation through a complex induced proximity effect with lithium bases under coordinating conditions. Moreover, four-carbon donors represent a limit for useful directed ylide formation with trialkylphosphine-derived Wittig salts in carbonyl homologation reactions. A facile approach to the synthesis of methyl vinyl ketones (MVKs), using acetonyl tripropylphosphoranes under mild conditions, is reported in Chapter Three. A library of diversely functionalized MVKs was synthesized as a demonstration of the scope and generality of the methodology. The application of MVKs as substrates for organocatalysis and as building blocks for useful polyketide intermediates is briefly highlighted. In Chapter Four, the two-carbon homologation methodology that was presented in the previous chapter is applied to the synthesis of the polyketide olivetol and a series of O-methyl derivatives. Cyclic diketone intermediates were aromatized with catalytic iodine and DMSO as a terminal oxidant. Modification of the solvent system allowed for the selective synthesis of mono- or dimethyl ethers of methyl olivetolate. The selectivity of this aromatization is further explored in the final chapter with more complex substrates. Chapter Five focuses on the synthesis of the meroterpene phytocannabinoids found in Cannabis sativa. A synthetic strategy involving the sequential condensation/[3+3]-annulation of citral with cyclic 1,3-diketones synthesized in the previous chapter. This afforded non-aromatic meroterpenes that were subjected to acid-mediated thermal rearrangement and catalytic oxidative aromatization. Evidence for chemoselectivity of the aromatization methodology was demonstrated and a synthesis of methyl cannabinolate is presented. / Thesis / Doctor of Philosophy (PhD) / Methodologies for the extension of aldehydes to functionalized olefins and their application to the synthesis of cannabinolic acid methyl ester are presented.

La synthèse stéréosélective d'une nouvelle classe d'amino acides boronatés est réalisée par réaction de Wittig, puis borylation catalysée par un complexe d'iridium. Des amino esters portant un noyau aromatique en position δ de la chaîne latérale, sont tout d'abord préparés par réaction de Wittig d'un sel de phosphonium dérivé d'amino acide avec l'aldéhyde aromatique correspondant, puis estérification et hydrogénation. La borylation de ces amino esters avec le bis(pinacolato)diborane (B2Pin2) en présence d'un complexe d'iridium comme catalyseur, conduit aux dérivés correspondants boronatés avec des rendements atteignant 74% . Enfin, des dérivés iodés ou trifluoroboratés sont facilement obtenus à partir des amino acides boronatés, par réaction avec Nal ou avec KHF2. L'hydrolyse des trifluoroborates d'amino acides en solution tampon a été étudiée par RMN 19F. Dans le cas des amino esters difluorophényle et thiophényle, ces composés montrent une très bonne stabilité à l'hydrolyse. D'un autre côté, la synthèse stéréosélective d'amino acides silylés est également obtenue par réaction de Wittig du sel de phosphonium dérivé d'amino acide avec le 4-di-t-butylsilanobenzaldéhyde. L'amino acide silylé a été utilisé pour la préparation d'un dipeptide avec un rendement de 80%, puis son dérivé fluorosilane sans racémisation, par réaction avec KF. Le dipeptide fluorosilylé obtenu montre une excellente stabilité à l'hydrolyse après 10 jours. Finalement, la méthode de synthèse mise au point, se révèle très efficace pour la préparation d'amino acides boronatés et silylés, et pour leur application au marquage par l'iode ou les fluorures / The stereoselective synthesis of new boronato amino acid derivatives, using Wittig and C-H iridium-catalyzed borylation as key step reactions, is described. Firstly, the synthesis of amino ester precursors bearing an aromatic moiety in -position of the lateral chain, was achieved by Wittig reaction of a phosphonium salt derived from amino acid with the corresponding aromatic aldehyde, then esterification and hydrogenation. The reaction of the amino esters with the bis(pinacolato)diborane reagent (B2Pin2) in presence of an iridium complex as catalyst, leads to the corresponding boronato derivatives in yields up to 74 %. Finally, the iodo- or trifluoroborato derivatives were easily prepared from the boronato amino acid by reaction either with NaI or with KHF2. The hydrolysis of the trifluoroborato amino acid derivatives was studied in buffer solution using 19F NMR monitoring. In the case of the difluorophenyl and thiophenyl amino esters, the corresponding trifluoroborates derivatives show good to excellent stability toward hydrolysis. In addition, the stereoselective synthesis of silano amino acid has been developped by Wittig reaction of the phosphonium salt derived from amino acid with the 4-di-t-butylsilanobenzaldehyde. The silano amino acid was used to prepare a dipeptide with 80% yield, and the corresponding fluorosilane derivative without racemization, by reaction with KF. The hydrolysis of the fluorosilylated dipeptide in aqueous media shows an excellent stability, up to 10 days. Finally, this stereoselective synthesis of hetero substituted amino acids, offers a promising tool for the application of the boronated and silyled derivatives to the fluoride labeling