New photocatalytic methods for the synthesis of complex heterocyclic scaffolds and base metal-catalysed cross-coupling
Lead Research Organisation:
University of Oxford
Abstract
This project falls within the EPSRC Synthetic Organic Chemistry research area.
Since its rise to prominence roughly a decade ago, photoredox catalysis has rapidly evolved into a powerful tool in synthetic organic chemistry, with applications in fields as diverse as radiolabelling, polymer manufacture, and the total synthesis of natural products. In addition to providing a milder alternative to traditional photochemical methods, the unique modes of reactivity offered by visible light photocatalysts are fundamentally changing the ways in which organic chemists approach the design of new reactions and the disconnection of target molecules. In this respect, the vast untapped potential of visible light photocatalysis in organic synthesis represents an important avenue of research, especially considering the growing need for 'greener' chemistry to ensure the long-term sustainability of large-scale chemical manufacture. In this project, we aim to exploit several underexplored reactivity platforms in visible light photocatalysis to enable the development of new, broadly applicable synthetic methods of interest to the pharmaceutical, agrochemical and fine chemical industries.
In the first instance, we aim to develop novel photocatalytic cascade processes capable of providing access to previously uncharted 3-D chemical space. The rapid generation of molecular complexity in this manner is particularly relevant to small-molecule drug design, where clinical candidates containing a high fraction of sp3-hybridized atoms are more likely to succeed than the 'flat', sp2-rich scaffolds that presently dominate commercial fragment libraries. We envisage that the use of recalcitrant substrates such as aryl iodides in such transformations will be facilitated by the recent advent of strongly reducing organic dye photocatalysts, which present significant cost advantages over their precious metal-based counterparts. Moreover, our strategy for engaging unactivated organyl halides in a redox-neutral photocatalytic cycle will overcome the current limitations of state-of-the-art transformations involving these readily available compounds, which are typically net-reductive.
We also seek to identify new visible light-induced C-C and C-heteroatom bond-forming reactions catalysed by copper and other readily available transition metals. Transition metal catalysis is a well-established strategy for a wide range of cross-coupling reactions; however, this mode of activation typically relies on costly and unsustainable catalysts. Mild and stereoselective methods for industrially relevant coupling reactions that avoid high temperatures and precious metals such as palladium are therefore urgently needed to improve the cost and energy efficiency of large-scale chemical processes. We seek to address this problem by developing new photochemical methods catalysed by inexpensive base metal catalysts, such as copper, for the coupling of diverse reaction partners; in principle, these reactions could operate under metallaphotoredox catalysis (the fusion of photoredox and transition metal catalysis) or via the direct excitation of a photoresponsive transition metal complex, which is relatively unexplored.
Since its rise to prominence roughly a decade ago, photoredox catalysis has rapidly evolved into a powerful tool in synthetic organic chemistry, with applications in fields as diverse as radiolabelling, polymer manufacture, and the total synthesis of natural products. In addition to providing a milder alternative to traditional photochemical methods, the unique modes of reactivity offered by visible light photocatalysts are fundamentally changing the ways in which organic chemists approach the design of new reactions and the disconnection of target molecules. In this respect, the vast untapped potential of visible light photocatalysis in organic synthesis represents an important avenue of research, especially considering the growing need for 'greener' chemistry to ensure the long-term sustainability of large-scale chemical manufacture. In this project, we aim to exploit several underexplored reactivity platforms in visible light photocatalysis to enable the development of new, broadly applicable synthetic methods of interest to the pharmaceutical, agrochemical and fine chemical industries.
In the first instance, we aim to develop novel photocatalytic cascade processes capable of providing access to previously uncharted 3-D chemical space. The rapid generation of molecular complexity in this manner is particularly relevant to small-molecule drug design, where clinical candidates containing a high fraction of sp3-hybridized atoms are more likely to succeed than the 'flat', sp2-rich scaffolds that presently dominate commercial fragment libraries. We envisage that the use of recalcitrant substrates such as aryl iodides in such transformations will be facilitated by the recent advent of strongly reducing organic dye photocatalysts, which present significant cost advantages over their precious metal-based counterparts. Moreover, our strategy for engaging unactivated organyl halides in a redox-neutral photocatalytic cycle will overcome the current limitations of state-of-the-art transformations involving these readily available compounds, which are typically net-reductive.
We also seek to identify new visible light-induced C-C and C-heteroatom bond-forming reactions catalysed by copper and other readily available transition metals. Transition metal catalysis is a well-established strategy for a wide range of cross-coupling reactions; however, this mode of activation typically relies on costly and unsustainable catalysts. Mild and stereoselective methods for industrially relevant coupling reactions that avoid high temperatures and precious metals such as palladium are therefore urgently needed to improve the cost and energy efficiency of large-scale chemical processes. We seek to address this problem by developing new photochemical methods catalysed by inexpensive base metal catalysts, such as copper, for the coupling of diverse reaction partners; in principle, these reactions could operate under metallaphotoredox catalysis (the fusion of photoredox and transition metal catalysis) or via the direct excitation of a photoresponsive transition metal complex, which is relatively unexplored.