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Thesis advisor: James P. Morken / 1,1-Bis(boronic) esters have attracted significant attention these days due to their unique reactivity. In this thesis, I will show that readily available reagents can undergo deborylative alkylation to deliver synthetically useful primary, secondary and tertiary boronic esters. 1,1-Diboryl alkanes can also engage in base-promoted deborylative cyclization to afford diversified cyclopentane rings with boron motifs attached. This transformation is very appealing because of the prevalence of five-membered rings in natural products. Lastly, it will be showed that geminal bis(boronic) esters can act as an important cornerstone in constructing relatively complicated structures such as natural product Arenolide. / Thesis (PhD) — Boston College, 2018. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Since its discovery in 1979, the Suzuki-Miyaura (SM) reaction has become one of the most widely utilised tools for carbon-carbon bond formation. The palladium catalysed coupling of an organoboron and organohalide compounds proceeds through a three-stage mechanism of oxidative addition, transmetalation and reductive elimination. The transmetalation of boronic acids to a palladium(II) complex has been widely studied. However, very little is known about the transmetalation of boronic esters, which are commonly used as an alternative to unstable boronic acids. Whether these species undergo direct transmetalation or prior hydrolysis to the boronic acid under SM conditions remains unknown. This research aimed to elucidate the mechanism of this cross-coupling process. Initial results under typical SM conditions created a biphasic reaction, promoted by the inorganic base and solvent composition, and showed that the boronic esters and corresponding boronic acid couple at the same absolute rate. This is thought to be a consequence of the formation of a biphasic mixture, rendering phase transfer the turnover-limiting step. The conditions were thus adapted to maintain a monophasic system using an organic soluble base, 2-tert-butyl-1,1,3,3-tetramethylguanidine, enabling the focus to be transmetalation as the turnover-limiting step. These new conditions show a significant difference in both reaction rate and induction period when using a boronic ester compared to the corresponding boronic acid. The use of guanidine was also shown to have an interesting effect on the boronic acid/ester species by 19F and 11B NMR. Further studies found the use of guanidine to create a boronate species, with this species being an aryl trihydroxyboronate or the hydroxyl"ate"-complex of the boronic ester, depending on the presence of diol in the system. Formation of a boronate species was found to be crucial for efficient cross-coupling. When testing weaker bases, unable to form a boronate species, poor SM cross-coupling conversion was found using the newly developed phosphine-free guanidine conditions, showing the importance of the boronate species under these conditions. The results suggest that depending on the strength of base used, the pathway of transmetalation pathway can be switched, between the boronate pathway and the oxo-palladium pathway, under the specific conditions developed.

The Suzuki-Miyaura Cross-Coupling of aryl halides and aryl boronic esters has become one of the most important and oft used C-C bond forming reactions in industry and academia alike. Recently, substantial effort has been invested in expanding this reaction to include alkyl boronic esters as coupling partners, though until recently, success has been limited to primary alkyl boronic esters. Secondary alkyl boronic esters, with the inherent possibility of being chiral, have proven to be more difficult to couple. As a means of expanding our program on the enantio- and regioselective hydroboration of styrene derivatives, we sought to develop conditions that could couple benzylic (secondary) boronic esters. Not only was the coupling to aryl iodides achieved in moderate to good yield with a commercially available (and relatively cheap) catalyst system and phosphine, but the coupling reaction proceeds with almost complete retention of the stereochemistry installed during the hydroboration reaction. Interestingly, these conditions leave primary (linear) alkyl boronic esters completely untouched. Further examination of the chemoselectivity of the reaction revealed that, despite being unable to cross-couple strictly aliphatic secondary boronic esters, our silver-mediated protocol was able to effectively cross-couple chiral allylic boronic esters in high yield and good regioselectivity. The asymmetric syntheses of novel secondary boronic esters have also been developed to overcome the substrate limitations of the hydroboration reaction. Together with our effective cross coupling strategy, these novel chiral boronic esters have led to the synthesis of exciting new classes of molecules, most notably, the asymmetric triarylmethanes. Finally, the stability of mesoporous silica supports used in Pd catalysis was assessed. Though silica supports effectively reduce Pd-contamination in reaction mixtures to sub-ppm levels, their long-term reusability is hindered by material degradation caused by harsh reaction conditions. It was found that aqueous base, required for the Suzuki-Miyaura reaction, is responsible for silica degradation and the collapse of mesostructure. Interestingly, it was determined that the reaction itself had a protective effect on the material, with the boric acid side-product mitigating the deleterious effect of the base. / Thesis (Ph.D, Chemistry) -- Queen's University, 2011-09-19 14:53:49.444

Neste trabalho, avaliou-se o potencial do uso de oxidantes quirais em oxidações enantiosseletivas de compostos orgânicos de boro. É de conhecimento geral que compostos orgânicos de boro, especialmente ésteres e ácidos borônicos são facilmente oxidados por hidroperóxidos em meio básico. No entanto, são escassos na literatura exemplos destas reações de modo enantiosseletivo. A fim de realizar as reações mencionadas, sintetizou-se os hidroperóxidos quirais TADOOH ({(4R,5R)-5-[(hidroperoxidifenil)metil]-2,2-dimetil-1,3-dioxolan-4il}difenilmetanol) e o hidroperóxido quiral derivado de carboidrato, 2,3-dideoxi1-O-oxidanil-4,6-di-O-pivaloil-α-D-eritro-hex-2-enopiranose (di-O-PivOOH). Estes compostos apresentaram resultados interessantes na literatura em oxidações enantiosseletiva de sulfetos orgânicos, em epoxidações de alcenos e em oxidações de Baeyer-Villiger. Inicialmente o potencial oxidativo de ambos hidroperóxidos, bem como a seletividade destes, foi avaliado frente a diversos ésteres borônicos, sendo que somente o TADOOH apresentou resultados promissores. (Ver esquema no PDF) Observou-se uma melhor seletividade do TADOOH frente a ésteres borônicos que possuíam grupos carbonílicos em sua estrutura. Ao submeter o β-boronil-éster, 3-fenil-3-(4,4,5,5-tetrametil-1,3,2-dioxaborolan-2-il)propanoato de etila, à oxidação com o TADOOH em THF utilizando NaOH como base, a -30°C por 1 hora, obteve-se o respectivo álcool com 40% de e.e. Cálculos de DFT para o estado de transição na oxidação dos ésteres borônicos com o TADOOH foram realizados em colaboração com o grupo do Prof. Dr. Ataualpa Albert Carmo Braga. Estes cálculos demonstraram que o estado de transição é estabilizado por uma ligação de hidrogênio não clássica entre o oxigênio da carbonila e umas das ligações C-H dos grupos fenila do TADOOH. Além dos estudos relatados, a reconhecida metodologia de Sharpless na epoxidação assimétrica de alcoóis alílicos foi adaptada para a oxidação enantiosseletiva de ésteres borônicos. Ao trocar o ligante derivado de éster tártarico, normalmente utilizado nas epoxidações de Sharpless, por (-)-efedrina observou-se uma moderada seletividade deste sistema frente ao pinacol l-fenietilboronato. Investigações mais detalhadas demonstraram que a presença do Ti(IV) não era necessária, sendo que a (-)efedrina era a responsável pela ativação e indução quiral nesta reação. / In this work, it was investigated the potential use of chiral oxidants in organic boron compound oxidation. It is known in the literature, that organic boron compounds can be easily oxidized by hydroperoxides. However, an enantioselective approach in literature is scarce. In order to perform these reactions, hydroperoxide TADOOH ({(4R,5R)-5[(hydroperoxydiphenyl)methyl]-2,2-dimethyl-l,3-dioxolan-4-yl}diphenylmethanol) and carbohydrate derived hydroperoxide, 2,3-dideoxy-1-O-oxidanyl-4,6-di-O-pivaloyl-α-D-erythro-hex-2-enopyranose (di-O-PivOOH), have been synthesized. These compounds showed interesting results in several enantioselective oxidations, as like, organic sulfides oxidation, alkenes epoxidation and Baeyer-Villiger oxidations. The oxidative potential of both hydroperoxides, as well as their selectivity, were evaluated against several boronic esters. Only TADOOH has shown promissing results for further studies. (See Scheme on PDF). Boronic esters containing a carbonyl moiety showed better selectivities with TADOOH, for example, the reaction of β-boronyl-ester, ethyl 3-phenyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)propanoate, gave the correponding alcohol with 40% e.e. DFT calculations for the transition state in the oxidation of the boronic esters with TADOOH were carried out in collaboration with the group of Prof. Dr. Ataualpa Albert Carmo Braga. These calculations have shown that the transition state is stabilized by a non-classical hydrogen bond between the carbonyl oxygen and one of the C-H bonds of the TADOOH phenyl groups. In addition to the studies, the well-known Sharpless protocol for asymmetric epoxidation of allylic alcohols was adapted in the enantioselective oxidation of boronic esters. By replacing the tartaric ester-derived, commonly used in the Sharpless experiments, for (-)-ephedrine moderate selectivity was observed with pinacol 1-phenylethyl boronate. Further investigations showed that the presence of Ti (IV) was not necessary, and (-)-ephedrine was responsible for the activation and chiral induction in this reaction.

In recent years, photoredox catalysis emerged as a privileged tool for small molecules activation via single-electron transfer mechanisms. Despite their ubiquity as reagents in organic synthesis, the use of boronic acid derivatives to generate carbon-centred radicals remains elusive. This dissertation explores the utilisation of photoredox catalysis to generate carbon radicals from boronic acid derivatives and subsequently engage them in C–C cross-coupling reactions. In the first chapter, an introduction to photoredox catalysis and organoboron reagents is provided, as well as a discussion on the key mechanistic aspects of photoredox catalysed C–C cross-coupling reactions. The second chapter presents our initial coupling strategy and how it evolved in understanding that pinacol boronic ester species can be used as a source of carbon radicals via single-electron oxidation from a photoredox catalyst. Coordination of the boronic esters with Lewis basic species was identified as a fundamental activating interaction. The synthetic utility of this discovery was highlighted by performing a wide range of photoredox catalysed arylations of pinacol boronic esters. The third chapter builds on our mechanistic understanding to identify a set of Lewis base catalysts that conveniently activates boronic esters and acids towards single-electron oxidation. The usefulness of this improved set of conditions was demonstrated by alkylating a wide range of boronic acid derivatives. The fourth chapter describes the application of this methodology in synthesising four active pharmaceutical ingredients from the GABA family. An emphasis was made on developing an efficient flow process and “transition metal free” conditions to survey the attractiveness of the method for the pharmaceutical industry. Finally, the fifth chapter describes the experimental procedures relevant to the results described in chapters 2 to 4.

Neste trabalho, avaliou-se o potencial do uso de oxidantes quirais em oxidações enantiosseletivas de compostos orgânicos de boro. É de conhecimento geral que compostos orgânicos de boro, especialmente ésteres e ácidos borônicos são facilmente oxidados por hidroperóxidos em meio básico. No entanto, são escassos na literatura exemplos destas reações de modo enantiosseletivo. A fim de realizar as reações mencionadas, sintetizou-se os hidroperóxidos quirais TADOOH ({(4R,5R)-5-[(hidroperoxidifenil)metil]-2,2-dimetil-1,3-dioxolan-4il}difenilmetanol) e o hidroperóxido quiral derivado de carboidrato, 2,3-dideoxi1-O-oxidanil-4,6-di-O-pivaloil-α-D-eritro-hex-2-enopiranose (di-O-PivOOH). Estes compostos apresentaram resultados interessantes na literatura em oxidações enantiosseletiva de sulfetos orgânicos, em epoxidações de alcenos e em oxidações de Baeyer-Villiger. Inicialmente o potencial oxidativo de ambos hidroperóxidos, bem como a seletividade destes, foi avaliado frente a diversos ésteres borônicos, sendo que somente o TADOOH apresentou resultados promissores. (Ver esquema no PDF) Observou-se uma melhor seletividade do TADOOH frente a ésteres borônicos que possuíam grupos carbonílicos em sua estrutura. Ao submeter o β-boronil-éster, 3-fenil-3-(4,4,5,5-tetrametil-1,3,2-dioxaborolan-2-il)propanoato de etila, à oxidação com o TADOOH em THF utilizando NaOH como base, a -30°C por 1 hora, obteve-se o respectivo álcool com 40% de e.e. Cálculos de DFT para o estado de transição na oxidação dos ésteres borônicos com o TADOOH foram realizados em colaboração com o grupo do Prof. Dr. Ataualpa Albert Carmo Braga. Estes cálculos demonstraram que o estado de transição é estabilizado por uma ligação de hidrogênio não clássica entre o oxigênio da carbonila e umas das ligações C-H dos grupos fenila do TADOOH. Além dos estudos relatados, a reconhecida metodologia de Sharpless na epoxidação assimétrica de alcoóis alílicos foi adaptada para a oxidação enantiosseletiva de ésteres borônicos. Ao trocar o ligante derivado de éster tártarico, normalmente utilizado nas epoxidações de Sharpless, por (-)-efedrina observou-se uma moderada seletividade deste sistema frente ao pinacol l-fenietilboronato. Investigações mais detalhadas demonstraram que a presença do Ti(IV) não era necessária, sendo que a (-)efedrina era a responsável pela ativação e indução quiral nesta reação. / In this work, it was investigated the potential use of chiral oxidants in organic boron compound oxidation. It is known in the literature, that organic boron compounds can be easily oxidized by hydroperoxides. However, an enantioselective approach in literature is scarce. In order to perform these reactions, hydroperoxide TADOOH ({(4R,5R)-5[(hydroperoxydiphenyl)methyl]-2,2-dimethyl-l,3-dioxolan-4-yl}diphenylmethanol) and carbohydrate derived hydroperoxide, 2,3-dideoxy-1-O-oxidanyl-4,6-di-O-pivaloyl-α-D-erythro-hex-2-enopyranose (di-O-PivOOH), have been synthesized. These compounds showed interesting results in several enantioselective oxidations, as like, organic sulfides oxidation, alkenes epoxidation and Baeyer-Villiger oxidations. The oxidative potential of both hydroperoxides, as well as their selectivity, were evaluated against several boronic esters. Only TADOOH has shown promissing results for further studies. (See Scheme on PDF). Boronic esters containing a carbonyl moiety showed better selectivities with TADOOH, for example, the reaction of β-boronyl-ester, ethyl 3-phenyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)propanoate, gave the correponding alcohol with 40% e.e. DFT calculations for the transition state in the oxidation of the boronic esters with TADOOH were carried out in collaboration with the group of Prof. Dr. Ataualpa Albert Carmo Braga. These calculations have shown that the transition state is stabilized by a non-classical hydrogen bond between the carbonyl oxygen and one of the C-H bonds of the TADOOH phenyl groups. In addition to the studies, the well-known Sharpless protocol for asymmetric epoxidation of allylic alcohols was adapted in the enantioselective oxidation of boronic esters. By replacing the tartaric ester-derived, commonly used in the Sharpless experiments, for (-)-ephedrine moderate selectivity was observed with pinacol 1-phenylethyl boronate. Further investigations showed that the presence of Ti (IV) was not necessary, and (-)-ephedrine was responsible for the activation and chiral induction in this reaction.

Thesis advisor: Jeffery A. Byers / This dissertation will discuss the development of Suzuki-Miyaura cross-coupling reactions catalyzed by iron-based complexes with an emphasis on addressing limitations to their practical application in industrial contexts. Chapter 1 will provide an overview of the development of the palladium-catalyzed Suzuki-Miyaura cross-coupling reaction and key factors which have enabled its prevalent use in various industries, with a comparison to how those factors have limited similar development of iron-catalyzed analogues. Chapter 2 will discuss the initial discovery and subsequent development of a series of iron-based precatalysts for the cross-coupling reaction of unactivated aryl boronic esters and alkyl halides. Chapter 3 will discuss the development and validation of a bench-stable iron(III)-based complex capable of catalyzing the Suzuki-Miyaura cross-coupling reaction between unactivated aryl boronic esters and alkyl halides. To conclude, Chapter 4 will discuss the ability of iron-based complexes to participate in the Suzuki-Miyaura cross-coupling reaction with alkyl tosylate electrophiles and its implications for harnessing the ability of iron catalysis to operate under different mechanistic manifolds. / Thesis (PhD) — Boston College, 2021. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Marc M. Snapper / Thesis advisor: James J. Morken / This dissertation will present three main projects focusing on the catalytic enantioselective synthesis and stereospecific functionalization of tertiary alkylboronates. In the first project, acyl chlorides were incorporated as a new class of electrophile in conjunctive cross-coupling, from which, a variety of tertiary β-boryl amides were successfully synthesized with high enantioselectivity. The utility of the tertiary alkylboronates products was also demonstrated through several orthogonal functionalizations of the boronic ester group and amide groups. The project culminated in the enantioselective total synthesis of natural product (+)-adalinine that leveraged this newly developed methodology. In the second project, a conjunctive cross-coupling enabled ring closure was developed to synthesize tertiary alkylboronates residing on carbocyclic and heterocyclic scaffolds. A Phosphinooxazoline (Phox) ligand was identified as a non-expensive ligand that catalyzed the conjunctive cyclization reaction with high enantioselectivity. A Series of synthetically challenging enantimerically enriched spirocyclic and aryl bicyclic tertiary alkylboronates were efficiently generated using this method, and several cyclopentyl boronic esters with two continuous stereogenic centers were synthesized with high diastereoselectivity. In the third project, a Rh-catalyzed diboration reaction was successfully employed to diborate monosubstituted cyclobutenes with excellent enantioselectivity. The less sterically hindered secondary boronic ester units in the diboron products can be regioselectively functionalized using the newly developed tert-butyllithium activation-transmetallation strategy. As a result, a variety of stereochemically defined β-substituted cyclobutyl tertiary boronic esters were synthesized with high efficiency. / Thesis (PhD) — Boston College, 2024. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.