Reactivity of Targeted Covalent Inhibitor Fragments and Transition Metal-Catalyzed Alkene Functionalization Reactions

Density functional theory (DFT) is a convenient and robust tool that has been widely applied to explore reaction mechanisms, thermodynamics, and kinetics of various organic reactions, many of which are catalyzed by transition metal complexes. The insights gained through DFT calculations provide chemists with critical information for the development of new organic reactions to achieve novel synthetic transformations. This thesis describes the applications of DFT calculations to study thio-Michael addition, Cu-catalyzed alkene hydroboration, and Pd-catalyzed alkene functionalization reactions. Kinase activity can be modulated reversibly or irreversibly by reactions of the targeted covalent inhibitors with the nucleophilic residues in protein active sites. Thiol reactivity studies were performed to support α-methylene–γ-lactams as a tunable surrogate for the highly reactive α-methylene–γ-lactones. A series of N-substituted α-methylene–γ-lactams with different electronic properties were synthesized and the reactivity of the α-methylene towards glutathione was determined via mass spectrometry. DFT calculations were performed to identify a robust method for the accurate prediction of the reactivity difference between covalent modifier fragments. These studies revealed that the M06-2X functional with SMD solvation model and methyl thiolate as a model nucleophile reliably predicts the relative reactivities of the α-methylene–γ-lactams, and quasiharmonic approximations improve the agreement between the experiment and computation. In the following chapter, DFT calculations were applied to study the Cu-catalyzed hydroboration of benzylidenecyclobutanes and benzylidenecyclopropanes that tolerates a wide variety of heterocycles prevalent in clinical and preclinical drug development, giving access to valuable synthetic intermediates. Computational studies provided insight into how the rigidity and steric environment of the bisphosphine ligands influence the relative activation energies of β-carbon elimination versus protodecupration from the benzylcopper intermediate. Energy decomposition analysis calculations revealed that electron-deficient P-aryl groups on the bisphosphine ligands enhance the T-shaped π/π interactions with the substrate and stabilize the migratory insertion transition state. Lastly, two Pd-catalyzed, transient directing group-mediated alkene functionalization reactions, an enantioselective Heck hydroarylation and a Pd-catalyzed C–H activation that achieves atropoisomeric synthesis of 1,3-dienes are presented. The reaction mechanisms, rate- and selectivity-determining steps, and origins of enantioinduction and atroposelectivity were studied using DFT calculations