Thesis advisor: James P. Morken / This dissertation will discuss the development of three methodologies that take advantage of the intrinsic reactivity of organoboron “ate” complex to undergo boronate rearrangement. The first chapter will describe a nickel-catalyzed conjunctive cross-coupling reaction between 9-BBN boranes and aryl halides. This process provides secondary organoboranes enantioselectively from readily available alkenyl starting materials. The second chapter will describe the development of conjunctive cross-coupling between 9-BBN boranes and acyl electrophiles. We will highlight its unique value in the syntheses of β-hydroxyl carbonyls and show that this reaction is complementary to the aldol reaction. In the third and last chapter of this manuscript, we report the conjunctive crosscoupling reaction of simple achiral borylenynes towards the enantio- and diastereoselective synthesis of α-borylallenes, which provides α-allenols upon oxidative workup. / Thesis (PhD) — Boston College, 2020. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Jianmin Gao / Besides their broad applications in organic chemistry, boronic acids are also increasingly seen in a variety of biological applications. For instance, they have been used in therapeutic drugs for chemotherapy or probes for the detection of saccharides. One unique feature of boronic acids is that they are capable of forming reversible complexes with sugars or even amino acids. Importantly, they are known to have low inherent toxicity to human. In this work, we have focused on two important reactions involving boronic acids: boronate ester formation, in which boronic acids react with diols and iminoboronate formation in which boronic acids form dative bonds with neighboring amino groups. We have demonstrated the potential of these reactions in bacteria targeting or protein modification. We envisioned that boronic acids could be used as a great warhead to be included in the development of novel antibiotics to counter antibiotic resistance of bacteria, which has emerged to be a serious clinical problem. Different from conventional antibiotics, we decided to utilize reversible covalent chemistries in the design of bacterium binding probes. Inspired by the diol-rich environment on bacterial surface, the first strategy took advantage of the reaction between boronic acid and diols to form boronate esters. We have rationally designed a linear peptide containing five copies of the ‘Wulff-type’ boronic acids or bicyclic amphiphilic peptides with two copies of boronic acids. We examined their capability of binding to E. coli cells or their bactericidal activity against S. aureus. Furthermore, we established a synthetic peptide library (OBTC) incorporating the 2-acetylphenyl boronic acid (2-APBA) warhead to form iminoboronate with the target-lipid II, a precursor for the biosynthesis of peptidoglycan. Although this library failed to generate any potent peptide hits, it provided useful information regarding the development of a synthetic library as well as the screening process. As an extension of the iminoboronate chemistry, thiazolidinoboronate (TzB) attracted our attention for its unique reaction mechanism, superior kinetics and excellent selectivity towards N-terminal cysteine residues. In this work, we have proposed an additional acyl transfer following TzB formation to turn this reaction into an irreversible conjugation. The new reaction inherits the fast kinetics and outstanding selectivity from the TzB chemistry. Excitingly, the product of TzB mediated acyl transfer survived complex conditions such as SDS-PAGE and LC/MS. This reaction was also applied to modify two recombinant proteins with N-terminal cysteine residues or to create a C5C phage library with two distinct modifications. We have further extended the substrate from cysteine to diaminopropionic acid (Dap), serine and tris base. We were delighted to observe imidazolidino boronate (IzB) formation and oxazolidino boronate (OzB) formation, which led to the design of cysteineresponsive probes or peptides that can be spontaneously cyclized in neutral aqueous conditions. / Thesis (PhD) — Boston College, 2020. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Amine-functionalized boronic acids have revolutionized the field of carbohydrate sensing in recent years. Capable of rapidly and reversibly forming cyclic boronate esters with of 1,2- and 1,3-diols, polyols, catechols, and α-hydroxycarboxylic acids, boronic acids have found applications spanning from lipid transport to Hydrogen fuel cells. The majority of the work presented in this dissertation will be aimed at gaining a better understanding of the Boron-Nitrogen interactions in ortho-aminomethyl functionalized boronic acids. Chapter 2 will provide an overview of the mechanistic understanding of boronic acid-diol interactions with a special focus on amine-functionalized boronic acids. Chapters 3 – 5 report the progress made by the Anslyn group to develop a more thorough understanding of Boron-Nitrogen interactions and how they affect boronate ester formation. The first introductory chapter will present a the recent advances that have been made in the development of pattern-based sensor systems. Finally, chapter 6 will present the synthesis of a series of bicycloguanidinium hosts, which will be used in a sensing array for chiral carboxylates. / text

The application of MIDA boronates (MIDA = N-methyliminodiacetic acid) in Suzuki- Miyaura reactions has increased over the last years. This is mainly because in many cases, the replacement of the boronic acid for the respective MIDA boronate has a positive result in the reaction yield. The key feature that makes MIDA boronates efficient coupling partners is that they can undergo a slow hydrolysis reaction under Suzuki-Miyaura conditions, which generates the boronic acid in situ. The control of the hydrolysis rate is crucial to keep a low concentration of the boronic acid to avoid some of the side reactions frequently observed. The kinetics of the hydrolysis reaction from a range of alkyl, aryl, and heteroaryl MIDA boronates have been determined under different reactions conditions. In addition, competition experiments and computational calculations have resulted in the proposal of three distinct mechanisms for the hydrolysis of MIDA boronates: ‘base-promoted’, ‘water-promoted’, and ‘acid-promoted’. The base and acid mediated processes occur at faster rates than the neutral pathway and involves a rate-limiting addition at the MIDA carbonyl carbon by hydroxide or water, respectively. Whilst the 'neutral' hydrolysis requires neither base nor acid and involves ratelimiting B-N bond cleavage by a water cluster. Under certain conditions the neutral mechanism can operate in parallel with the base or with the acid mediated mechanism; relative rates are easily quantified by 18O incorporation in the MIDA, after this is released from the hydrolysis reaction. This insight is expected to assist informed application and optimisation of MIDA boronates in synthesis as well as the design of new MIDA boronate derivatives.

Les hydrogels injectables et auto-réparants suscitent un intérêt particulier dans les domaines de l'ingénierie tissulaire et de la médecine régénératrice. En raison de la nature dynamique de leurs réticulations, ces gels peuvent être pré-formés dans des seringues, extrudés sous cisaillement et s’auto-réparer spontanément après arrêt de la déformation mécanique. Au vu du potentiel que peuvent offrir les polymères fonctionnalisés par des acides boroniques pour la fabrication de gels covalents réversibles, nous avons développé des hydrogels injectables d’acide hyaluronique (HA) réticulés par des liaisons esters boronates pour des applications esthétiques et biomédicales. Pour élaborer de tels gels avec des propriétés optimisées, nous avons exploré l’effet de la nature du dérivé d’acide boronique ainsi que du motif saccharidique greffés sur le HA sur les propriétés rhéologiques dynamiques des gels. Parmi les différents dérivés d'acide boronique, le benzoboroxole (BOR) a été choisi en plus de l'acide phénylboronique (PBA) pour complexer différents motifs saccharidiques greffés sur le HA. Comparé au PBA, le dérivé BOR est, en effet, capable de se complexer de manière plus efficace à pH neutre et avec une plus grande variété de composés saccharidiques, en particulier les glycopyranosides. Cette étude a démontré que les propriétés rhéologiques dynamiques des assemblages de HA formés par complexation des unités de BOR ou PBA avec les différents sucres sont étroitement liées à la dynamique des échanges moléculaires et à la thermodynamique des pontages. En outre, nous avons également établi pour la première fois la possibilité d’obtenir des hydrogels de HA auto-réticulants à pH physiologique via des interactions multivalentes entre les unités de BOR greffées sur le HA et des groupements diols se répétant sur la chaîne polysaccharidique. Outre le BOR, la capacité de son homologue cyclique à six chaînons, la benzoxaborine, et d’un nouveau dérivé original similaire à ce composé a été explorée en tant que nouveaux sites de complexation de saccharides pour la formation de réseaux de HA réversibles. Compte-tenu des propriétés injectables, d'auto-réparation et de réponse à différents stimuli démontrées par ces nouveaux hydrogels de HA, ces biomatériaux apparaissent comme des candidats prometteurs pour de nombreuses applications innovantes dans le domaine biomédical, notamment pour l'ingénierie tissulaire et la thérapie cellulaire. / Injectable and self-healing hydrogels have recently drawn great attention in the fields of tissue engineering and regenerative medicine. Such gels can be pre-formed into syringes, be extruded under shear stress and show rapid recovery when the applied stress is removed due to the dynamic nature of their crosslinks. Given the exciting potential benefit of using boronic acid-containing polymers to construct dynamic covalent hydrogels, we explored this attractive strategy to design injectable boronate-crosslinked hydrogels based on hyaluronic acid (HA) for aesthetic and other biomedical applications. To design hydrogels with optimized properties, we investigated the effect of the nature of the boronic acid moiety as well as the sugar molecule grafted onto the HA backbone on the gel properties. Among arylboronic acid derivatives, benzoboroxole (BOR) was selected in addition to phenylboronic acid (PBA) as the binding site for sugar moieties grafted on HA. This choice was based on the efficient binding capability of BOR at neutral pH compared to PBA, and on its ability to complex glycopyranosides. With this study, we demonstrated that the dynamic rheological properties of the HA networks based on BOR- or PBA-saccharide complexation are closely linked to the molecular exchange dynamics and thermodynamics of the small molecule crosslinkers. Besides, we also established for the first time the feasibility of self-crosslinking HA hydrogels with extremely slow dynamics at physiological pH through multivalent interactions between BOR derivatives grafted on HA and diols from the polysaccharide chains. Finally, in addition to BOR, we demonstrated the unprecedented capacity of its six-membered ring homologue, benzoxaborin, and a new original benzoxaborin-like derivative as new carbohydrate binding sites for the formation of reversible HA networks. Taking into account the injectable, self-healing and stimuli-responsive properties showed by these new HA hydrogels, these biomaterials appear as promising injectable scaffolds for many innovative applications in the biomedical field, including in tissue engineering and cell therapy.

A catalytic (in Brønsted superacid) and a stoichiometric process were developed to synthesise aryl boronic esters with boron cations via electrophilic arene borylation. The treatment of CatBX (Cat = catecholate; X = Cl, Br) with the triethyl salt [Et3Si][closo-CB11H6Br6] in arene solvent gave a transient boron electrophile that reacted as a synthetic equivalent of [CatB]+ in intermolecular electrophilic aromatic borylation at 25 °C. The by-product of the reaction was a strong Brønsted acid that was able to catalyse arene borylation using CatBH at high temperature. This catalytic process furnished aryl boronic esters in high yield with H2 as the only by-product. The use of the robust and weakly coordinating anion [closo-CB11H6Br6]- and the electrophile-resistant catecholborane were crucial for the catalytic process. The reaction mixture of R2BCl (R2 = Cat, Cl4Cat, Cl2), aprotic amine and AlCl3 mainly gave a borenium salt [R2B(amine)][AlCl4] which was in equilibrium with neutral species as revealed by NMR spectroscopy and reactivity studies. This reaction mixture was effective for the regioselective borylation, by electrophilic aromatic substitution, of a range of N-heterocycles, thiophenes and anilines at room temperature. The transterification in situ provided the synthetically useful and more stable pinacol boronate esters in excellent isolated yield. This process displayed remarkable functional-group tolerance for a boron based strong Lewis acid with weak bases (for example -NMe2), ether, and halogen groups all compatible. This process represents a new and inexpensive one-pot direct arene borylation methodology for producing pinacol boronate esters.

Since its discovery in 1912, the Mannich reaction has been widely utilized in organic chemistry to form C-C bonds. Reactivity of an enol with an imine allows for easy formation of a [beta]-aminoketone. Enamines have also been widely utilized as convenient nucleophiles. In our work, unexpected reactivity of the [gamma] position of [beta]-enamidoesters in a Brønsted acid environment and high enantioselectivity of a Mannich reaction were achieved through chiral phosphoramidic acid catalysis. A novel class of chiral phosphoramidic acids was designed, synthesized from the corresponding diamines, with several sulfonyl N-protecting groups, and characterized. Their unique properties arise from their Brønsted acid nature, atropisomerism and ability to form complexes via H-bond. Once prepared, such catalysts were successfully used as organocatalysts for the regio- and enantioselective Mannich reaction of [beta]-enamidoesters and imines. Their activity is described as a method to reverse the regioselectivity of the nucleophile while achieving high enantioselectivities in the formation of chiral benzhydrils. A diverse range of imines has been tested, obtaining yields of up to 93% and enantioselectivities of up to 99:1. A few substituted enamines were also tested to study the influence of substituents on the regioselectivity. A mechanism for this reaction is proposed and kinetic studies confirmed that the reaction is first order in catalyst. The ozonolysis of the product of this Mannich reaction was performed to prove the absolute stereochemistry of the product; and a new efficient methodology for the asymmetric preparation of aminoacid [beta]-phenyl-[beta]-alanine benzyl ester is described. The reduction of the enamide moiety of the Mannich product was attempted via asymmetric hydrogenation and via hydride reduction to diastereomerically obtain 1,3-diamines, which are compounds of major synthetic interest. Unfortunately our attempts in this direction were not successful. Finally, a multicomponent reaction between an aldehyde, a substituted phenol, and a styrylboronate was developed as an alternative method for the preparation of chiral benzhydrils. This process is also organocatalytic and the methodology was optimized in the presence of 3-3'-disubstituted BINOLs. Yields up to 71% and enantioselectivities up to 96:4 were achieved. A mechanism for this organocatalytic reaction is also proposed.

Thesis advisor: James P. Morken / Thesis advisor: Marc L. Snapper / This dissertation will present three projects focusing on the enantioselective synthesis and stereospecific transformation of alkylboronates. The first project describes the development of a nickel-catalyzed enantioselective dicarbofunctionalization of alkenylboronates, which provides a modular route to secondary alkylboronic esters. Intramolecular reaction leads to enantioselective synthesis of exocyclic boronates. The second project depicts a new method for the synthesis of azetidines, pyrrolidines and piperidines via an intramolecular amination of alkylboronic esters. Regioselective amination of vicinal bis(boronates) allows the synthesis of saturated azacycles bearing boronic ester substitutions that can serve as useful synthetic handles. As the transformation is stereospecific, stereodefined cyclic amines can be synthesized from the enantioenriched boronic esters. The method is applied to the synthesis of an intermediate towards a Kras G12C inhibitor. The third project describes the development of a new chiral auxiliary on boron that can be easily synthesized from inexpensive starting materials. The auxiliary is applied to a diastereoselective radical ring-opening/closing [3+2] cycloaddition of cyclopropylanilines with alkenylboron species. / Thesis (PhD) — Boston College, 2022. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

A number of 3,3'-disubstituted binaphthol-modified allylboronates (<strong>2. 42a-m</strong>) were prepared from the reaction between triallylborane and the corresponding 3,3'-disubstituted binaphthols. These chiral allylboronates could allylate carbonyl compounds to produce chiral homoallylic alcohols in high chemical and optical yields. Chiral ligands were readily recycled through simple acid-base extraction. Among all allylboronates tested, 3,3'-(CF₃)₂-BINOL-modified allylboronate (<strong>2. 42b</strong>) is an especially effective reagent that allows for allylborations of both aldehydes and ketones in high enantioselectivities (up to 98% yield and >99% <em>ee</em>). Reagent <strong>2. 42b</strong> represents one of the best allylation reagents for carbonyl compounds developed thus far. <br /><br /> Allylations of cyclic imines using 3,3'-disubstituted binaphthol-modified allylboronates (<strong>2. 42a-j</strong>) were carried out at low temperature. 3,3'-Bis[3,5-(CF₃)₂-C₆H₃]-binaphthol-modified allylboronate (<strong>2. 42j</strong>) gave the best enantioselectivities (91% <em>ee</em> to >99% <em>ee</em>) in the allylation of a variety of cyclic imines. This methodology represents the first successful enantioselective allylboration of cyclic imines. The versatility of the allylation products (chiral a-allyl cyclic amines) was demonstrated through efficient total syntheses of several naturally occurring alkaloids such as coniine, crispine A and corynantheidol. <br /><br /> 3,3'-Disubstituted binaphthol-modified alkynylboronates (<strong>4. 47a-g</strong>) were synthesized according to a reported procedure. It was found that these chiral alkynylboronates add to <em>N</em>-acylaldimines in an enantioselective manner to produce chiral propargylamides in excellent yields and enantioselectivities. Up to >99% <em>ee</em> could be obtained with 3,3'-diphenyl binaphthol-modified alkynylboronates (<strong>4. 47f</strong>). This represents the first direct asymmetric synthesis of chiral propargylamides. Using this methodology, an antitubulin agent (-)-<em>N</em>-acetylcolchinol (AstraZeneca® ZD6126 phenol) was synthesized in 4 steps from commercially available 3-hydroxybenzaldehyde. <br /><br /> During a study of the asymmetric conjugate alkynylation of enones via chiral alkynylboronates, it was found that achiral dialkyl alkynylboronates could add to enones enantioselectively in the presence of catalytic amounts of chiral bidentate ligands (such as 3,3'-disubstituted binaphthols, diisopropyl tartrate and activated chiral amino acids). A catalytic cycle driven by "ligand-exchange" processes was proposed to rationalize this asymmetric induction. This is the first reported example of an asymmetric reaction that is promoted by a catalytic amount of an exchangeable chiral ligand on the boron reagent. More importantly, we have demonstrated a proof of principle that ligand exchange with boronates can be sufficiently fast that catalytic amounts of chiral ligands can be used to effect high levels of stereoselectivity. This catalytic protocol can potentially be applied to other asymmetric reactions providing the following three requirements are met: (1) the starting achiral boronate does not react with the electrophile (no background reaction); (2) the chiral boronate reacts with the electrophile and (3) ligand exchange or transesterification occurs under the reaction conditions. Potential applications of this principle include asymmetric allylboration, hydroboration, aldol reaction and reduction, just to name a few.

A number of 3,3'-disubstituted binaphthol-modified allylboronates (<strong>2. 42a-m</strong>) were prepared from the reaction between triallylborane and the corresponding 3,3'-disubstituted binaphthols. These chiral allylboronates could allylate carbonyl compounds to produce chiral homoallylic alcohols in high chemical and optical yields. Chiral ligands were readily recycled through simple acid-base extraction. Among all allylboronates tested, 3,3'-(CF₃)₂-BINOL-modified allylboronate (<strong>2. 42b</strong>) is an especially effective reagent that allows for allylborations of both aldehydes and ketones in high enantioselectivities (up to 98% yield and >99% <em>ee</em>). Reagent <strong>2. 42b</strong> represents one of the best allylation reagents for carbonyl compounds developed thus far. <br /><br /> Allylations of cyclic imines using 3,3'-disubstituted binaphthol-modified allylboronates (<strong>2. 42a-j</strong>) were carried out at low temperature. 3,3'-Bis[3,5-(CF₃)₂-C₆H₃]-binaphthol-modified allylboronate (<strong>2. 42j</strong>) gave the best enantioselectivities (91% <em>ee</em> to >99% <em>ee</em>) in the allylation of a variety of cyclic imines. This methodology represents the first successful enantioselective allylboration of cyclic imines. The versatility of the allylation products (chiral a-allyl cyclic amines) was demonstrated through efficient total syntheses of several naturally occurring alkaloids such as coniine, crispine A and corynantheidol. <br /><br /> 3,3'-Disubstituted binaphthol-modified alkynylboronates (<strong>4. 47a-g</strong>) were synthesized according to a reported procedure. It was found that these chiral alkynylboronates add to <em>N</em>-acylaldimines in an enantioselective manner to produce chiral propargylamides in excellent yields and enantioselectivities. Up to >99% <em>ee</em> could be obtained with 3,3'-diphenyl binaphthol-modified alkynylboronates (<strong>4. 47f</strong>). This represents the first direct asymmetric synthesis of chiral propargylamides. Using this methodology, an antitubulin agent (-)-<em>N</em>-acetylcolchinol (AstraZeneca® ZD6126 phenol) was synthesized in 4 steps from commercially available 3-hydroxybenzaldehyde. <br /><br /> During a study of the asymmetric conjugate alkynylation of enones via chiral alkynylboronates, it was found that achiral dialkyl alkynylboronates could add to enones enantioselectively in the presence of catalytic amounts of chiral bidentate ligands (such as 3,3'-disubstituted binaphthols, diisopropyl tartrate and activated chiral amino acids). A catalytic cycle driven by "ligand-exchange" processes was proposed to rationalize this asymmetric induction. This is the first reported example of an asymmetric reaction that is promoted by a catalytic amount of an exchangeable chiral ligand on the boron reagent. More importantly, we have demonstrated a proof of principle that ligand exchange with boronates can be sufficiently fast that catalytic amounts of chiral ligands can be used to effect high levels of stereoselectivity. This catalytic protocol can potentially be applied to other asymmetric reactions providing the following three requirements are met: (1) the starting achiral boronate does not react with the electrophile (no background reaction); (2) the chiral boronate reacts with the electrophile and (3) ligand exchange or transesterification occurs under the reaction conditions. Potential applications of this principle include asymmetric allylboration, hydroboration, aldol reaction and reduction, just to name a few.