Identification of Novel Structural Motifs for Mining the Conformational Space of Boron- and Peptide-based Molecules

Conformation describes the spatial arrangement of atoms in a molecule. While the binding energy between atoms in a molecule determines its structure, the three-dimensional geometry can have considerable flexibility. This has important ramifications for the way molecules interact with each other. This dissertation describes the conformation-derived properties of novel boron- and peptide-based structures, two emerging modalities in drug discovery and subjects of intense contemporary interest. In Chapter 1, a systematic study of boron’s interactions with a range of protein side-chain residues suggests that boron is a unique electrophile in its chameleonic ability to engage protein targets. These mechanistic and structural insights revealed that boron’s properties are nuanced and arise from its uncommon coordination preferences. In Chapter 2, a general method was developed to connect boron- and nitrogen-containing fragments based on the capacity for boryl aldehydes and acyl boronates to undergo reductive amination with various types of amines. This work highlights the untapped potential of boron-substituted iminium ions and enables access to new classes of stable α- and β-aminoboronic acids. In Chapter 3, we report that the MIDA (N-methyliminodiacetic acid) boryl group can act as a chameleon, displaying high migratory aptitude in its tetracoordinate form in one setting, yet migrate as an electrophile under other conditions. The main finding is that hemilability of the B–N bond plays the key role during migration. Based on the mechanistic results, new reactions were designed for the synthesis of hitherto inaccessible boron-based intermediates and endpoints of synthesis. In Chapter 4, the concept of dominant rotors is applied to explore complex energy landscapes of constrained chains of rotors exemplified by amino acids. The observation of unusual conformations of peptide macrocycles that are close in energy was made possible by operating away from equilibrium. These structural insights suggest the existence of unexplored conformations of ring structures and a path to generate them. In Chapter 5, the Pinc ((N-isocyanimino) triphenylphosphorane)-driven macrocyclization reaction was probed with nucleophilic kinetic traps and unveiled a novel iminophosphorane intermediate. Based on these insights, a new macrocyclization reaction was designed to deliver ring structures of various sizes with a novel bis(heteroaryl) motif.Ph.D