The objective of this research program is to address a longstanding carbon-carbon bond formation problem using a novel, synergistic catalysis mode. C-H activation is a leading area of modern chemical research with extraordinary promise. Successful functionalization of unreactive carbons in a selective manner could fundamentally impact retrosynthetic analysis of natural product and drug targets, enabling drastically simplified syntheses. Herein we present a novel construction of a ubiquitous moiety in Nature - the aliphatic-aryl C-C bond. Our approach harnesses a radical coupling strategy recently discovered by the merger of two distinct catalysis modes which act in concert to achieve selective C-H bond arylation. Previously, this bond formation could only be accomplished with transition-metal catalysis with the requirement of two stoichiometric prefunctionalized reagents and careful reaction conditions. In our analysis, this venerable strategy could be improved significantly with the elimination of both toxic metal byproducts and activated substrates. Additionally, an improved protocol under ambient conditions would largely benefit the practitioner. Central to this new mode of activation is an organocatalyzed hydrogen atom abstraction triggered by photoredox catalysis, which results in the catalytic activation of each reaction partner. Upon their formation, the two components engage in radical-radical coupling to provide the desired product from simple, commercial materials under mild reaction conditions. We will begin with the benzylic substrate class and electron-deficient arenes. The diaryl methane products obtained are prevalent in drug molecule scaffolds and natural products. This technology would enable facile syntheses as well as open access to analogues in an effort to improve bioactivity and/or selectivity of medicinal agents. After optimization of the initial protocol, we propose expansion of this reaction manifold to the allylic substrate class - a prevalent organic building block. We also disclose a desymmetrization strategy for asymmetric induction using symmetrical or meso substrates, further increasing reaction utility. With the goal of ease of operation in mind, these reactions will be performed under ambient atmosphere and temperature. The two catalyst classes (photoredox and thiol organocatalyst) are commercially available and will be used out of the bottle. Additionally, reaction substrates and coupling partners require no synthesis or preactivation, are widely available, and will be used as received.

Public Health Relevance

The proposed research program will address a longstanding challenge in organic synthesis - organocatalytic C-H bond activation. This new reaction will connect a typically unreactive carbon of a common building block with a second, useful reaction partner to give a value-added product. The two components we couple are found in nearly every pharmaceutical compound and will lead to significantly shorter and efficient syntheses with less toxic byproducts.

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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Lees, Robert G
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Princeton University
Schools of Arts and Sciences
United States
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Capacci, Andrew G; Malinowski, Justin T; McAlpine, Neil J et al. (2017) Direct, enantioselective ?-alkylation of aldehydes using simple olefins. Nat Chem 9:1073-1077