Executive Summary : | Transition metal-catalyzed insertion of carbenes into X-H (X=C, N, O, S, Si, B, etc.) bonds presents one of the most direct ways of constructing C-X bonds. To date, several precious metals such as Rh, Pd, Ir, Ru, Au, Ag, etc., have been used to affect these complex transformations. Recent efforts are now focused on developing Fe based cheap and less toxic catalysts. However, owing to the rather limited mechanistic insights, the development of asymmetric variants has considerably lagged, thereby implying a pressing need for a clear mechanistic understanding. For reactions proceeding via an initial nucleophilic attack, the presence of metal-free species such as enol/ylid makes it extremely difficult to attain high levels of selectivity with chiral metal complexes. Once the metal dissociates, resulting in a free enol/ylid, the high selectivity seems counterintuitive. However, Notable exceptions where high selectivities have been obtained are the Pd and Rh catalyzed indole alkylation, Fe(spirobox) catalyzed O-H insertion, and N-H insertion. Previous mechanistic studies have suggested an enol pathway for Rh catalyzed reactions. Thus the origin of selectivity remains a conundrum. Other than these reactions, most other X-H insertions such as indole alkylation, N-H insertion, S-H insertion catalyzed by Fe have yielded only low-modest ees (enantiomeric excess). The objective of the current proposal is to delineate the mechanisms of X-H insertion reactions (X=O, S, N, C) that proceed in a stepwise manner using DFT (density functional theory) methods. The focus will be on reactions catalyzed by chiral metal complexes. For instance, the indole functionalization with Rh and Pd yields ee greater than 99%, but with Fe only 75% has been attainable. Even though the overall TOFs are comparable, the differences in ee suggest significant mechanistic variations in the catalytic cycle. We also plan to study other insertion reactions catalyzed by Fe complexes and decipher the stereoinduction model. The final objective is to propose new ligands based on our stereochemical model. In addition, we would also like to investigate similar reactions catalyzed by engineered myoglobin and cytochrome P450s. Even with enzymes, the selectivity remains low. Based on our model, we would also like to propose mutations in the active site of these enzymes that can enhance the ee. Our mechanistic insights would also be beneficial to develop multicomponent reactions where the metal-carbenoid reacts with other electrophiles. |