The overarching objective of this Research Proposal is to establish dihydrophenazine, phenoxazine and carbazole derivatives as organic photocatalysts (O-PCs) for visible light photoredox catalysis in the formation of challenging covalent bonds vital to synthesis of medicinally relevant molecules. This O-PC platform will expand the synthetic capabilities of chemists for drug development to improve the wellbeing of the society. These O-PCs offer many advantages over commonly used noble-metal based PCs such as Ru(bpy)32+ and fac-Ir(ppy)3: they are generally cheaper, non-air and -moisture sensitive and less toxic in comparison to their noble metal counterparts. Preliminary data suggests that dihydrophenazine, phenoxazine and carbazole O-PCs possess a wide range of excited state reduction potential [E0* = E0(PC?+/3PC*)] and ground state oxidation potential [Eox = E0(PC?+/PC)]. In fact, the classes of dihydrophenazine and phenoxazine O-PCs are more powerful excited state reductants than Ru(bpy)32+ and fac-Ir(ppy)3. Thus, through computationally-guided catalyst design, these O-PCs can be designed to possess desired E0* and Eox, which will be used in various covalent bond coupling methodologies to access a diverse array of medicinally relevant molecules.
Two specific aims have been tailored to achieve this overall goal.
In Aim 1, a combined computational and experimental approach will be capitalized to realize classes of dihydrophenazine, phenoxazine and carbazole O-PC derivatives possessing a broad range of E0* and Eox. These O-PC families will provide organic and medicinal chemists the ability to match the E0* and Eox of the O-PC to the desired substrates in order to mediate selective bond activation and avoid potential side reactions.
In Aim 2, tunable E0* and Eox of dihydrophenazine, phenoxazine and carbazole O-PCs will be exploited to forge challenging C-C, C-O, C-S, and C-N covalent bonds. These coupling reactions will introduce functionalities to medicinally relevant molecules such as pyridines, pyrroles, indoles and benzofurans. Realizing these two aims will convincingly demonstrate the applicability of dihydrophenazine, phenoxazine and carbazole O-PCs, thereby enabling the industrial-scale synthesis of medicinally relevant molecules through visible light photoredox catalysis.

Public Health Relevance

Visible light photoredox catalysis is a powerful synthetic strategy to form challenging covalent bonds and introduce therapeutic functionalities under mild reaction conditions for the synthesis of drug molecules vital to improving human health. In this proposal, I propose the use of organic photocatalysts as cost-effective and versatile catalysts than expensive noble metal-based photocatalysts, enabling the industrial-scale synthesis of medicinally relevant molecules through visible light photoredox catalysis.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Bond, Michelle Rueffer
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Colorado State University-Fort Collins
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Fort Collins
United States
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Lim, Chern-Hooi; Kudisch, Max; Liu, Bin et al. (2018) C-N Cross-Coupling via Photoexcitation of Nickel-Amine Complexes. J Am Chem Soc 140:7667-7673
McCarthy, Blaine G; Pearson, Ryan M; Lim, Chern-Hooi et al. (2018) Structure-Property Relationships for Tailoring Phenoxazines as Reducing Photoredox Catalysts. J Am Chem Soc 140:5088-5101
Liu, Bin; Lim, Chern-Hooi; Miyake, Garret M (2017) Visible-Light-Promoted C-S Cross-Coupling via Intermolecular Charge Transfer. J Am Chem Soc 139:13616-13619
Du, Ya; Pearson, Ryan M; Lim, Chern-Hooi et al. (2017) Strongly Reducing, Visible-Light Organic Photoredox Catalysts as Sustainable Alternatives to Precious Metals. Chemistry 23:10962-10968