Novel Transformations and Strategies in Enantioselective Catalysis Enabled by Non-Covalent Transition State Stabilization

Abstract

Dissertation Advisor: Professor Eric N. Jacobsen Daniel Aaron Strassfeld

Novel Transformations and Strategies in Enantioselective Catalysis Enabled by Non-Covalent Transition State Stabilization Abstract In Chapter 1, we report the development of enantioselective, hydrogen-bond-donor catalyzed tail-to-head cyclizations. Mechanistic investigations revealed that the reactions proceed through concerted transition states, which we propose are critical for allowing the challenging ionization of primary allylic chlorides, facilitating carbocyclization over byproduct formation, and enabling catalyst control over enantioselectivity. In preliminary studies, we have demonstrated that this same strategy can promote low yielding but highly enantioselective tail-to-head polycyclizations. Chapter 2 details the development and synthetic applications of a highly enantioselective desymmetrization of achiral oxetanes through hydrogen-bond-donor catalyzed bromide delivery. This transformation provides access to a broad range of silyl-protected 1,3-bromohydrins, which are valuable chiral building blocks. The synthetic utility of this methodology is demonstrated in a 3-step, gram-scale synthesis of the antitubercular drug pretomanid. Chapter 3 presents the discovery that the enantioselective oxetane opening reaction occurs via simultaneous Brønsted and Lewis acid mechanisms. The recognition of the Brønsted acid pathway led to the development of a scalable protocol for the reaction through the controlled addition of water. Moreover, this study provides insight into the concept of privileged chiral scaffolds. The optimal catalyst is uniquely capable of inducing high levels of enantioselectivity through both pathways, which we propose is due to its possession of multiple, co-localized functional groups capable of recognizing the positive charge that is common to both reaction mechanisms. In Chapter 4, we present studies on cooperative catalysis between achiral and chiral hydrogen-bond-donor catalysts in enantioselective oxetane openings and asymmetric tail-to-head cyclizations. The addition of an achiral hydrogen-bond donor led to significantly enhanced reaction rates in the former transformation and improved product distributions in the latter. Contrary to naïve expectations, the presence of an achiral hydrogen-bond donor did not decrease the enantiomeric excess of the products, instead, increasing the enantioselectivity of the reactions in many cases. We propose that this is due to the ability of the chiral catalysts to selectively stabilize the enantiodetermining transition states through non-covalent interactions. This ensures that the chiral hydrogen-bond donor is the most active catalyst for the enantiodetermining step, allowing it to outcompete the achiral catalyst in a phenomenon akin to ligand-accelerated catalysis.