The modern world relies upon chemistry to provide a variety of essential materials. Of particular importanceistheuseofchemicalsynthesistogeneratebiologicallyrelevantcompoundstoprevent,diagnose, and treat disease. It is imperative to render these processes as safe, sustainable, and cost-effective as possibletoensurethelong-termproductivityofthisfield.Twoofthemostcommonlyutilizedtransformationsto this end are oxidation and reduction reactions. Recently, photoredox catalysis has been shown to be a powerful tool to facilitate these reactions. Photoredox catalysis has the benefit of utilizing safe, mild, and sustainable terminal oxidants or reductants in conjunction with a small amount of photosensitive catalyst. Furthermore, iron and copper are earth abundant metals that have been shown to effect a variety of useful oxidationreactions.However,ifironandcopperoxidationreactionscanbecoupledwithphotoredoxcatalysis, stoichiometric metal waste can be circumvented and more sustainable processes will emerge. An important oxidation reaction promoted by copper and iron is the radical enolate coupling with indoles to furnish substituted indoles and the radical enolate coupling with enolates to furnish 1,4-dikeontes. The literature pertaining to copper and iron oxidation is rich, however no catalytic examples exist. Due to the issues associated with stoichiometric use of copper and iron, catalytic asymmetric methodologies with these stoichiometric oxidants are rare. By using an inexpensive terminal oxidant to re-oxidize copper or iron, chiral ligandsmaybeemployedonthemetalcenterstoimpartasymmetryonthebondformation. The Buchwald group has a history of developing catalytic reactions that are useful to the industrial and academic arenas. In order to develop an asymmetric dual catalytic oxidation of enolates to to couple with indoles and enolates we will first explore the racemic reaction with catalytic amounts of copper or iron in the presence of a photocatalyst and stoichiometric terminal oxidant. Once the racemic reaction has been developed and understood, we will explore the use of chiral ligands on copper and iron to generate an asymmetricenolatecouplingreaction.Wewillalsoexploretheimplementationofthischemistryinphoto-flow reactors.Finally,thisreactionwillbeusedasatooleffectsurfacemodificationthroughphoto-patterning. The research proposed herein presents an innovative approach to solving the challenges of catalytic oxidationwithironandcopper.Furthermore,theuseofcatalyticcopperorironwillallowfortheimplementation ofasymmetriccouplingreactionsthroughtheuseofchiralligands.Bycouplingphotoredoxcatalysiswithiron and copper oxidation chemistry, these already useful reactions will become significantly more powerful. Furthermore, the development of catalytic oxidations will allow for the application of these reactions to more diversesystemsforchemicalandmaterialsynthesis.

Public Health Relevance

The discovery and manufacture of biologically relevant compounds that prevent, diagnose and treat disease rely on rational chemical transformations. The proposed research targets asymmetric dual catalytic methodologiestocoupleenolateradicalswithindolesandenolates.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Postdoctoral Individual National Research Service Award (F32)
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Lees, Robert G
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Massachusetts Institute of Technology
Schools of Arts and Sciences
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Dennis, Joseph M; White, Nicholas A; Liu, Richard Y et al. (2018) Breaking the Base Barrier: An Electron-Deficient Palladium Catalyst Enables the Use of a Common Soluble Base in C-N Coupling. J Am Chem Soc 140:4721-4725