A Dual Catalytic Strategy for Enantioselective Pyridinium Photochemistry

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Project Summary/Abstract Control over the enantioselectivity of photochemical processes has remained an open problem despite the inherent promise of light-driven methodologies to deliver a broad range of medicinally-relevant scaffolds. Indeed, absorption of a photon energetically enables substantial increases in molecular complexity (commensurate with modern pharmaceuticals) without the generation of any additional waste. The key challenge, to reign in the substantial energetic input and direct it towards selective formation of a single enantiomer, has been met with limited success by the synthetic community. Triumph in this arena would represent a major step forward for our collective ability to synthesize biologically important compounds, enabling the next generation of life-saving pharmaceuticals and diagnostic probes to be developed, while cutting costs and reducing waste for existing manufacturing processes. This proposal outlines a novel strategy to circumvent the central challenges in this sphere by employing a combination of hydrogen-bond donor and primary amine organocatalysts to selectively activate substrates for photochemical transformation. This dual catalytic reactivity manifold has been fabulously successful in the past for the generation, stabilization, and enantiofacial control of myriad cationic intermediates, and extension into photochemical reaction space will further the synthetic potential of the strategy immensely. The research plan outlines a specific line of attack for identifying an appropriate catalyst system to enable enantioselective pyridinium photochemistry, accessing densely functionalized aminocyclopentenone motifs which are in turn poised for synthetic elaboration to a wide variety of bioactive molecules. The key strategic underpinning is the ability to induce a bathochromic shift in the absorption spectrum of the substrate upon complexation with the catalyst pair via both covalent and non-covalent interactions. Advances in LED technology in recent years put this specific scientific advance within tangible grasp, and the implementation of the catalytic strategy outlined herein is poised to deliver on the promise of enantioselective photochemistry. Moreover, enantioinduction will in turn allow for mechanistic information to be gleaned. By extracting precise structure-activity relationships, a glimpse behind the rate-limiting photoexcitation step can be obtained. Overall, the proposed research will enable facile access to complex medicinally relevant compounds in a methodologically novel and efficient fashion while substantially increasing scientific knowledge.