Thesis advisor: James Morken / This dissertation details two different alkene difunctionalization strategies that are utilized in the synthesis of three types of organoboron species in racemic and enantioenriched fashion. Chapter one will introduce the carbohydrate and DBU co-catalyzed transition-metal-free enantioselective diboration reactions of unactivated alkenes. Mechanistic insights guided reaction condition design will be discussed. In chapter two, a nickel-catalyzed conjunctive cross-coupling of 9-BBN borane and carboxylic acid derivatives is presented. Its development and detailed mechanistic studies, along with the efforts in asymmetric induction will be covered. Finally, the first enantio- and diastereoselective synthesis of 1,2-anti-silylboronates enabled by palladium-catalyzed conjunctive cross-coupling will be described. The optimization of chemo-, enantio- and diastereoselectivity in the reactions and their following transformations (e.g. oxidation and amination) is demonstrated. / Thesis (PhD) — Boston College, 2020. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

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 Morken / Boronates are extremely useful in synthesis due to the ability of carbon-boron bonds to be transformed into carbon-oxygen, carbon-nitrogen, or carbon-carbon bonds stereospecifically. This makes the stereoselective construction of carbon-boron bonds especially useful. The development of transition-metal catalyzed diboration of alkenes gave synthetic organic chemists a way to quickly make not one, but two carbon-boron bonds in a stereoselective fashion. However, there are many drawbacks to transition-metal catalysis, such as high cost of catalysts and chiral ligands, and air and moisture sensitivity of catalysts. These issues, in addition to difficulties in removing trace amounts of metal contaminants from reaction products have prevented transition-metal-catalysis from being used on the industrial scale. Discussed in this thesis are two different methods for stereoselective, transition-metal-free diboration of alkenes developed by the Morken group. Also discussed is the pioneering work in the area of transition-metal-free diboration done by the Fernández group, which inspired these methodologies. / Thesis (BS) — Boston College, 2016. / Submitted to: Boston College. College of Arts and Sciences. / Discipline: Departmental Honors. / Discipline: Chemistry.

Thesis advisor: James P. Morken / This dissertation describes the first enantioselective 1,2-diboration of cis-substituted 1,3-dienes. In the presence of a platinum catalyst and TADDOL-derived phosphonite ligands, both 4,4-disubstituted and mono-cis-substituted 1,3-dienes undergo regioselective 1,2-diboration to afford the corresponding 1,2-diols upon oxidation in up to 98:2 er and high yield. By achieving enantioselective 1,2-diboration of 1,3-dienes, a new synthetic route to α-chiral (Z)-allylboronate reagents has been developed. In the presence of an aldehyde, these allyl bis(boronate) esters undergo highly diastereoselective allylboration reaction to afford enantioenriched 1,5-homoallylic alcohols bearing all-carbon quaternary centers or syn-propionate motifs. In the presence of 1,4-dicarbonyl compounds, the (Z)-allylboronates undergo a double allylation reaction to afford cyclohexanols with four contiguous stereocenters in good yield and moderate to excellent diastereoselectivity. The tandem diboration/double allylation has been applied to the total synthesis of pumilaside B aglyon, and the partial synthesis 1β-hydroxy arbusculin A and bromophycolide F. / Thesis (PhD) — Boston College, 2013. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: James P. Morken / Platinum-catalyzed enantioselective diboration of various hydrocarbon starting materials to form stereodefined carbon-boron bonds is reported. The asymmetric Pt-catalyzed 1,4-diboration of <italic>trans</italic>-1,3-dienes provided 1,4-bis(boronate)esters in up to 98:2 er, representing the first enantioselective diene diboration. The enantioselective 1,2-diboration of <italic>cis</italic>-1,3-dienes and 4,4-disubstituted dienes afforded 1,2-bis(boronate)esters in up to 98:2 er. The intermediate allylboronates were utilized in aldehyde allylations to furnish polypropionate-like compounds and stereodefined carbon quaternary centers. The development of a Pt-catalyzed enantioselective diboration of terminal olefins is disclosed, giving the corresponding 1,2-diols in up to 97:3 er. Further optimization and expansion of the scope of this method is also discussed. / Thesis (PhD) — Boston College, 2011. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Els compostos organoborats són intermedis de reacció molt valuosos en síntesi orgànica, degut a que l'enllaç carboni-bor pot ser derivatitzat de múltiples maneres. La diboració catalitzada d'alquins i alquens ha estat ampliament estudiada en els darrers quinze anys, essent la diboració catalitzada d'alquins un procés en el que s'han obtingut elevats rendiments i activitats. No obstant això, en la diboració catalitzada d'alquens la presència de la reacció secundaria de b-eliminació de H sempre s'ha presentat com un seriós inconvenient, impedint un bon compromís entre activitat catalítica i quimioselectivitat. En el primer capítol de la present tesi es recull l'evolució a través de la bibliografia de les reaccions de diboració d'alquens i alquins, els diferents metalls i lligands utilitzats en la reacció catalítica de diboració i els estudis mecanístics que s'han realitzat fins a data d'avui. Tanmateix, s'han posat de manifest les diferents derivatitzacions que s'han dut a terme a partir d'intermitjos organoborats. També es descriu breument la tècnica de les microones. Com a punt final del capítol, s'introdueixen els objectius de la tesi, incloent-hi el desenvolupament de nous sistemes catalítics que millorin l'activitat, quimioselectivitat i enantioselectivitat dels catalitzadors reportats prèviament en la reacció de diboració catalítica, l'estudi del mecanisme de la reacció de diboració d'alquens catalitzada per rodi, i la busqueda de nous mètodes de fluorofuncionalització d'esters vinic(bisboronics). En el segon capítol es descriu l'activitat, quimioselectivitat i enantioselectivitat de diferents precursors catalítics en la diboració catalitzada d'alquens i alquins. En el primer apartat es porta a terme un estudi en profunditat de la diboració d'alquens catalitzada per compostos de Rh(I), observant-se que en aquest cas els efectes estèrics en el diborà tenen un efecte dramàtic en la quimioselectivitat de la reacció. També s'observa que el lligand que ofereix una major quimioselectivitat es el DPPM (bis(difenilfosfino)metà), mostrant una influència del bite angle del lligand, mentre que el lligand QUINAP (1-(2-difenilfosfino-1-naftil)isoquinolina) és el que ofereix una major enantioselectivitat. En els següents apartats es descriu la utilització de diferents complexos d’or, argent, coure i platí modificats amb lligands carbens, els quals augmenten la quimioselectivitat de la reacció, reduïnt la producció de subproductes de b-eliminació de H. Malgrat que s’han utilitzat diferents carbens quirals, només en un cas s’ha aconseguit induir asimetria, utilitzant un complex de Cu(I) modificat amb un lligand carbé quiral, però comprometent la quimioselectivitat. També es descriu l’aplicació de carbens de platí i coure a la diboració catalitzada d’alquins, obtenint-se bons resultats d’activitat i quimioselectivitat. La utilització d’unes noves condicions de reacció, en les que es requereix un excés de diborà (2 eq.) i l’addició d’una base (NaOAc), fa que precursors catalítics en principi inactius, com complexos d’Au(I) modificats amb lligands difosfina tipus BINAP (2,2'-bis(difenilfosfino)-1,1'-binaftil), donin bons resultats d’activitat i quimioselectivitat, encara que malauradament no indueixen asimetria. Per últim, es descriu l’aplicació de les tècniques de microones com a mitjà d’acceleració en la diboració d’alquins catalitzada per Pt(0), disminuint-se espectacularment els temps de reacció. En el tercer capítol de la tesi es porta a terme un estudi mecanístic de la reacció de diboració d’alquens catalitzada per Rh(I)-QUINAP. En primer lloc es porta a terme un estudi de RMN (Ressonància Magnètica Nuclear) per a detectar les possibles espècies metàl·liques implicades. A partir d’aquí, es realitza un estudi computacional DFT (Density Functional Theory) del mecanisme de reacció, observant-se que després de l’addició oxidant es produeix la inserció de l’alqué en un enllaç Rh-B, seguida d’un reordenament per a ocupar la posició vacant creada, finalitzant amb la eliminació reductora del producte, essent el camí més favorable aquell en el qual l’alquè queda coordinat trans al nitrogen del lligand QUINAP. L’estudi de la reacció secundària de b-eliminació de H demostra que la utilització de BINAP com a lligand l’afavoreix, en comparació amb la utilització del lligand QUINAP. En el quart capítol es descriu la flurofuncionalització d’ésters vinil (bisborònics), la qual dóna lloc a la formació de cetones a,a-difluorades a través d’un procés de fluoració electròfila. Primer de tot, es fa una petita introducció als processos de fluoració electròfila, amb especial interès en la fluoració electròfila de compostos organosilats, els quals estan força relacionats amb els compostos organoborats. La reacció es duu a terme a partir dels alquins, a través d’un procés tandem de diboració catalítica/fluoració electròfila. Només els esters vinil(bisborònics) derivats del bis(pinacolato)diborà són susceptibles d’ésser derivatitzats d’aquesta manera. Els alquins interns són més actius que els alquins terminals. També es descriu la síntesi d’a,a-difluoroimines directament a partir d’alquins mitjançant un procés tandem de diboració catalítica/fluoració electròfila/iminació, l’eficiència del qual depen de les propietats electròniques del sustrat. Per últim, en el capítol 5 es descriu la fluoració electròfila asimètrica d’a- nitroésters, la qual es porta a terme mitjançant la utilització d’auxiliars quirals derivats d’alcaloids de cincona, obtenint-se excessos enantiomèrics de fins a un 40%. / Organoboron compounds are very useful intermediates in organicsynthesis, because the carbon-boron bond can be cleaved in a variety of ways leading to the formation of useful functional groups. The catalyzed diboration ofalkenes and alkynes has been widely studied in the last 15 years, obtaining high yields and activities in the alkyne catalyzed diboration reaction. However, when alkenes are used as substrates in the catalyzed diboration reaction, the problem of b-hydride elimination could arise, preventing a good agreement between catalytic activity and chemoselectivity. In the first chapter of this thesys an overview of the precedents of the diboration reactions of alkenes and alkynes is presented, including the different metals and ligands used in this reactions and the mechanistic studies published to date. Moreover, there has been collected the different derivatizations of organoboron intermediates carried out. The microwave technique is also described briefly. Finally, the scope of this thesys is explained, including the development of new catalytic systems which improve the activity, chemoselectivity and enantioselectivity of the catalytic systems previously reported, the study of the mechanism of the rhodium catalyzed alkene diboration reaction, and the search of new routes for the fluorofunctionalization of organoboron compounds. In the second chapter, the activity, chemoselectivity and enantioselectivity of different catalytic precursors in the alkene and alkyne catalytic diboration reaction is described. In the first part, a deep study on the rhodium catalyzed alkene diboration reaction is carried out, finding in this case that the steric effects on the diborating reagent have a dramatic effect on the chemoselectivity of the reaction. It is also observed that the DPPM (bis(diphenylphosphino)methane) is the ligand which provide a better chemoselectivity, showing an important bite angle influence on the ligand, while QUINAP (1-(2-diphenilphosphino-1-naphthyl)isoquinoline) is the ligand which offers a higher enantioselectivity. In the next parts it is described the utilization of different gold, silver, copper and platinum complexes as catalyst precursors, which improve the chemoselectivity of the reaction, reducing the b-hydride elimination side reaction. Despite several chiral carbene modified complexes have been used, only in one case some enantioselectivity was induced, using a carbene modified copper complex, but reducing chemoselectivity. It is also described the application of arbene modified copper and platinum complexes as catalyst precursors in the alkyne diboration reaction, obtaining good results in activity and chemoselectivity. The utilization of new reaction conditions, in which an excess of the diborating reagent (2 eq.) and the addition of a base (NaOAc) is required, improve the activity of catalytic systems like BINAP 2,2’-bis(difenilfosfino)-1,1’-binaphthyl) modified gold complexes, whose activity was very low under the typical conditions; unfortunately, no enantioselectivity was obtained in this case. Finally, it is described the application of microwave techniques to the platinum catalyzed alkyne diboration reaction, in order to reduce the reaction times.In the third chapter, an in-depth study of the mechanism of the Rh(I)-catalyzed alkene diboration reaction is described. First of all, an NMR (Nuclear Magnetic Ressonance) study was carried out in order to identify plausible intermediates. Next, a DFT (Density Functional Theory) study of the reaction mechanism was carried out, finding that after the oxidative addition of the diborane, an insertion of the alkene into a Rh-B bond is produced, followed by an internal rearrangement in order to ocupy the vacant position created, and,finally, reductive elimination of the product is produced, being the most favourable path that in which the alkene is placed trans to the nitrogen of the QUINAP ligand. The study of the b-hydride elimination side reaction shows that the utilization of BINAP as ligand favours it, with respect to the utilization of QUINAP. In the fourth chapter, the fluorofunctionalization of cis-1,2-bis(boryl)alkenes is described, leading to the formation of a,a-difluorinated ketones through an eletrophilic fluorination process. First of all, a little introduction to the electrophilic fluorination processes is made, with special interest to the electrophilic fluorination of organosilanes, which are quite similar to the organoboron compounds. The reaction is carried out starting from alkynes, through a tandem catalytic diboration/electrophilic fluorination process process. Only the cis-1,2-bis(boryl)alkenes derived from bis(pinacolato)diboron are susceptible to the fluorination process. Internal alkynes are more reactive than terminal ones. It is also described the synthesis of a,a-difluoroimines directly from alkynes through a tandem catalytic diboration/electrophilic fluorination/imination process, the efficiency of which depends on the electronic properties of the substrate.Finally, in the fifth chapter, the asymmetric electrophilic fluorination of a-nitro esters is described. This process was carried out using cinchona derivatives chiral auxiliaries, obtaining enantiomeric excesses up to 40%.

Thesis advisor: James P. Morken / This dissertation describes three methods towards the stereoselective synthesis of organoboronates, and their application towards pharmacological targets of interest. The first chapter describes the use of alkyl migrating groups and alkyl electrophiles in the synthesis of secondary boronic esters through a highly selective nickel-catalyzed three component conjunctive cross-coupling reaction. Products from this conjunctive cross-coupling reaction are then converted to two alkaloids through boron amination and annulation processes. The second chapter describes the platinum-catalyzed diastereoselective diboration of carbocyclic, heterocyclic, and bicyclic alkenes. This reaction proceeded under air and both a homogeneous and heterogeneous catalyst was employed. Application of this reaction towards synthesis of the nucleoside analog Aristeromycin is also described. The final chapter details the development of an inexpensive and easily synthesized chiral diazaborinine that provides stereoinduction across a wide range of concerted and stepwise cycloaddition processes, affording heterocyclic-boron containing products in high yield and selectivity. Transformations of resulting organoboronates are also described. / Thesis (PhD) — Boston College, 2022. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Organoboron compounds have shown a wide variety of applications in both organic synthesis and the pharmaceutical field in the past decades. Transition metal-catalyzed boration of unsaturated compounds has been studied extensively as an efficient method to install C-B bonds. Most of the previous examples employed symmetrical diboron reagents such as B₂(pin)₂ (pin = pinacolate) and B₂(cat)₂ (cat = catecholate). There are, however, limited examples of boration using unsymmetrical diboron reagents. This dissertation discloses two transition metal-catalyzed borations of unsaturated compounds with unsymmetrical diboron compounds. A Cu-catalyzed β-boration of electrophilic allenoates with a novel sp²-sp³ hybridized diboron reagent (PDIPA) is described. This unsymmetrical diboron reagent is preactivated and allows the boration to go smoothly under mild reaction conditions. The reaction provides β-borylated β,γ- unsaturated esters with exclusive (Z)-double bond geometry. These borylated products are useful intermediates for subsequent Suzuki-Miyaura cross-coupling reaction. In order to install two C-B bonds in one reaction, a Pt-catalyzed diboration of allenes with a differentially protected diboron reagent (PDAN) is presented. This unsymmetrical diboron reagent is prepared from the sp²-sp³ hybridized diboron compound, and it reacts with a series of 1,1- disubstituted allenes chemo- and regioselectively. Steric control ensures that both boryl moieties add to the terminal double bond, and the pinacol boronate preferentially attaches to the sp-hybridized carbon. The bis-boronyl products can be further converted to other functional groups as well as cross-coupling reactions. A collaborative project with Department of Physics and Department of Chemical Engineering is also discussed. In this project, a series of 𝑜-nitrobenzyl ligands containing a disulfide group as the anchor to gold surfaces are synthesized. The 𝑜-nitrobenzyl group uncages an amine upon photoexcitation. Attempts to make a water soluble analog failed, however, the mixture of methanol and water as the solvent was sufficient to attach them on gold surfaces. / Ph. D.

Our research seeks new methods for functionalizing organic small molecules using organoboronic derivatives as a versatile handle for late-stage manipulations. Metal-catalyzed formation of new carbon-boron bonds and their subsequent transformations are highlighted. Among the myriad of unsaturated substrates for conducting borylation reactions, allenes have received minimal attention. These substrates are uniquely advantageous given that diboration results in the formation of both allylic and vinylic boronates. Orthogonal reactivity of the sp2 and the sp3 C-B bonds can allow for chemoselective transformations. However, oxidation of the carbon-boron bond is one example in which the conditions are unselective. To address this shortcoming, a platinum catalyst was developed for the diboration of 1,1-diaryl allenes with a differentially protected diboron reagent, pinB-Bdan. The reaction proceeds regioselectively in high yields to furnish olefins bearing a vinylic Bpin and an allylic Bdan moiety. The subsequent chemoselective transformation of each boron center was demonstrated. Methods for preparing 1,8-diaminonaphthalene protected vinylboronates conjugated to carbonyl groups are severely limited. A simple and efficient protocol was developed for carrying out an environmentally friendly copper(II)-catalyzed beta-borylation of alkynoates and alkynamides in water and open-to-air. Following the discriminative activation of the more Lewis acidic pinacol protected boron center in pinB-Bdan, a regio-, stereo- and chemoselective beta-borylation of acetylenic substrates delivers (Z)-beta-boryl enoates and primary, secondary, and tertiary enamides under very mild conditions. As an inexpensive and earth abundant metal, catalysts based on copper are highly desirable. An international collaborative project to develop a copper-catalyzed cross-coupling reaction of beta-boryl carbonyl compounds was explored. Preliminary results found these substrates to be either unstable towards or unreactive under the reactions conditions screened. / Ph. D. / The very basis of everything in existence is the atom. The idiosyncratic arrangements and interactions of atoms confer distinctive physical properties which give rise to the biological processes of organic lifeforms or the diverse characteristics of inorganic substances, like salts and minerals. In organic chemistry, the carbon-based backbone of the compound is decorated with socalled functional groups, which govern the physical or biological properties of the molecule. Building the unique structural arrangement of functional groups within a pharmaceutical, for example, requires multi-step reaction sequences and purifications to deliver the desired product. Thus, their assembly must be extremely selective and highly efficient to yield the final compound in useable amounts. The overarching goal of our work is to develop such methods for building complex small molecules from very simple starting materials. The carbon—boron bond is a particularly versatile tool in synthetic chemistry because it offers direct access to a myriad of different functional groups. We utilize the unique properties of boron, a tunable semi-metallic element, in the formation and transformation of carbon—boron bonds with divergent reactivity. Catalysis offers a modern approach to enhance the selectivity and sustainability of preparative organic chemistry. Energy input is needed to make and break chemical bonds. Conducting the reaction at an elevated temperature, for example, is a conventional way to provide the energy necessary for molecules to come together. Conversely, metal catalysts can be cleverly designed to lower the potential energy barrier, which gives rise to new pathways for carrying out chemical transformations. Moreover, incredibly small amounts of the metal is sufficient because a catalyst propagates the process in a cyclic and repetitive fashion. In this work, metal catalysts were optimized to form carbon—boron bonds from diboron reageants containing two different boron centers. Taking advantage of the orthogonal reactivity of each boron allowed for the selective installation of functional groups in subsequent transformation reactions.

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.