Technology Development: Tailored Nano-Molecular Systems for New Modes of Reactivity

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Despite continual advancements, the synthesis of drug candidates remains a limiting factor in drug discovery. Commercial realities mean that molecules that take too long to access are not made or tested. Photoredox catalysis has quickly made an impact on this problem via late-stage molecule diversification, a promising avenue to increase the chemical space tested with minimal effort. However, the available reactions are limited by the relatively small number of identified catalysts. There is a need for catalysts with new properties that will enable new types of photoredox reactions. Semiconductor quantum dots (QDs) represent a promising class of catalysts that are unlike any currently available. Combining some of the best properties of heterogeneous catalysts with the convenience of homogeneous catalysts, QDs have impressive, easily tuned photophysical properties and a rich surface chemistry. The relative independence of the photophysical properties from the supporting ligands provides a compelling, new opportunities for reaction development. However, the adaptation of QDs to drug discovery has been slowed by the poor overlap between the materials science and organic synthesis. This program’s long-term goals are the development of new types of chemistry enabled by QD surface chemistry. In the proposed R21 grant, a team of materials scientists (Krauss group at the University of Rochester) and synthetic chemists (Weix group at the University of Wisconsin-Madison) will validate the exciting potential of QD photoredox catalysts, develop protocols for their use, and work with chemical suppliers to make these new tools commercially available. Our guiding hypothesis is that the surface chemistry of quantum dots can allow new types of photoredox reactions by accelerating electron transfer and pre-arranging catalysts or substrates. The specific aims of this proposal are to: (1) use supporting and electroactive ligands to fine-tune the properties of QD photoredox catalysts against a suite of known reactions; (2) determine the best approach to attaching small molecule catalysts to the QD surface to enhance multicatalytic reactions; (3) test if Auger recombination can be used to generate strongly reducing states potentially useful in organic synthesis; and (4) validate the use of QD surface chemistry to template macrocyclization reactions. The approach is innovative because QDs are fundamentally different from commonly used photoredox catalysts and will enable reactivity not easily possible with small molecule catalysts. The proposed research is significant because the new tools will be made widely available and can be easily incorporated into established photoredox research programs.