New Frontiers in Organocatalysis and Photoredox Catalysis

Abstract

Despite the development of numerous modern synthetic methodologies that have enabled the building of useful bond connections, there remains a need for ever more powerful methods of building molecular complexity. This thesis describes two new synthetic methodologies, one using organocatalysis and the second using photoredox catalysis, that we hope will provide highly useful routes towards the rapid synthesis of important small molecule or biological targets.

An enantioselective method for the conversion of -tosyloxy ketones to -functionalized products through the direct trapping of an electrophilic oxy-allyl cation by a nucleophilic reaction partner is described. Careful design of a C1 symmetric bis-aryl octahydroindolinol organocatalyst both activates the -tosyloxy ketone towards soft enolization/ionization and provides access to an enantiodiscriminant oxy-allyl cation. We demonstrate the successful trapping of this oxy-allyl cation with a range of indole nucleophiles to furnish -arylated products with high enantioselectivities. Moreover, initial reactions with non-indole nucleophiles show promising levels of enantioselectivity, suggesting that accessing this oxy-allyl cation intermediate can become a general platform of asymmetric catalysis. This methodology represents a new area of organocatalysis, termed oxy-allyl cation catalysis, that takes advantage of the highly electrophilic nature of the oxy-allyl cation to provide a complimentary set of -functionalized products to established modes of catalysis such as enamine catalysis.

A photoredox mediated approach towards covalently modifying proteins in a site-selective manner is also described. Taking advantage of the inherently mild conditions photoredox reactions typically take place under, we have developed a photoredox decarboxylative method of alkylating the C-terminal amino acid of proteins under biologically compatible conditions. This demonstrates an important initial step in harnessing the synthetic power of photoredox catalysis to solving challenging problems in chemical biology.