Thesis advisor: Shih-yuan Liu / Thesis advisor: Xiao-Xiang Zhang / The overarching theme of this dissertation is developing 1,2-azaborine motif as a novel arene pharmacophore. The first chapter of this dissertation is about exploring the synthesis and character of a new α-boryl diazo family-diazomethyl-1,2-azaborine and its diverse reaction chemistry. As a remarkable 1,2-azaborine building block, it can undergo a variety of classical diazo reactions including C–H activation, O–H activation, [3+2] cycloaddition, halogenation, and Ru-catalyzed carbonyl olefination. In the second chapter, we take a closer look at the hydrogen bond donor ability of 1,2-azaborines. A congeneric series of 1,2-azaborine ligands were used to probe the strength of hydrogen bonding as a function of the ligand’s steric effects. The results of this study provide fundamental reference data for establishing 1,2-azaborines as potential pharmacophores. Lastly, 1,2-azborine as a new ligand for T4 lysozyme double mutant L99A/M102 was investigated, and a new mode of ligand-protein interaction was discovered and evaluated by X-ray crystallography and ITC. / Thesis (PhD) — Boston College, 2022. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Shih-Yuan Liu / Described herein is the development of a method to directly borylate the C5-position of monocyclic 1,2-azaborines without the use of a metal catalyst, kinetic resolution or directing group. This method tolerates different substitution on the boron as well as at the C3-position of the azaborine. A new BN-isostere of the drug molecule, felbinac, was synthesized to demonstrate the application of this method. / Thesis (MS) — Boston College, 2020. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Kian L. Tan / Thesis advisor: Shih-Yuan Liu / Chapter 1. In the Tan laboratory, we developed synthetic methods to control reaction selectivity (regio-, stereo-, and site-selectivity) using scaffolding catalysis. Our strategy utilizes directing groups that induce intramolecularity through the formation of a labile covalent bond between the substrate and a binding site in a catalytic system. In the first part, we described site-selective functionalization of various carbohydrates and complex polyhydroxylated molecules which contain cis-1,2-diol motif using a chiral organic scaffold. In the second part, meta-selective C–H functionalization of arenes was demonstrated. High meta-selectivity was achieved by the use of a nitrile-based silyl tether which is cleavable and recyclable. Chapter 2. In the Liu laboratory, we focuses on studies of boron-nitrogen containing heterocycles. In this chapter, synthesis of 1,2-azaborines and their binding study with T4 lysozyme mutants were described. Specifically, we directly compared binding of NH-containing 1,2-azaborines and their carbonaceous analogs to probe hydrogen bonding interaction between the NH group of azaborine and a carbonyl oxygen of protein residue. Structural and thermodynamic analysis provided us the first evidence of H-bonding of azaborines with a biological macromolecule. Chapter 3. Described are the synthesis of regioisomers of ethyl-substituted 1,2-azaborines and their binding thermodynamics to T4 lysozyme mutants. To access the azaborine ligands used in the binding study, we developed synthetic methods for regioselective functionalization of six positions of 1,2-azaborines. Isothermal titration calorimetry experiments showed differences in binding free energy for regioisomers to the L99A T4 lysozyme. This result could originate from electronic differences of the isosteric ligands inducing dipole-dipole interaction between ligand and surrounding protein residues or it may be from local dipolar interactions. Chapter 4. A general method for late-stage N-functionalization of 1,2-azaborines is described to afford libraries of BN-containing complex molecules. The chemical transformations include electrophilic substitution reactions, N–C(sp2) bond forming reactions under Buchwald-Hartwig amination conditions, and N–C(sp) bond forming reactions using copper-catalyzed N-alkynylation. As applications in materials science and medicinal chemistry, synthesis of the first parental BN isostere of trans-stilbene and lisdexamfetamine derivative is described utilizing the methodology developed in this work. / Thesis (PhD) — Boston College, 2017. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.