Site-Selective Reactions Via Scaffolding Catalysis & Synthesis and Binding Study of 1,2-Azaborines

Abstract

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.