The discovery of powerful new methods for the synthesis of organic compounds can be enabling for biomedical research, e.g., by providing more ready access to known families of target molecules or access for the first time to new classes of molecules. Catalytic and enantioselective methods for carbon?carbon formation are of particular interest, due to issues including sustainability, the potentially divergent bioactivity of the two enantiomers of a compound, and the predominance of carbon?carbon bonds in the backbone of organic molecules. The substitution reaction of an alkyl electrophile by a nucleophile is a particularly straightforward approach to the assembly of organic molecules. Classical pathways for substitution, such as the SN1 and the SN2 reactions, are limited in scope with respect to both the electrophile and the nucleophile. Furthermore, these pathways almost never provide access to highly enantioenriched product from readily available racemic starting materials. It has recently been established that, by achieving substitution reactions via a transition-metal-catalyzed pathway wherein an organic radical serves as a key intermediate, it is possible to begin to address both of the key challenges?broader scope and control of enantioselectivity. For example, chiral nickel complexes can catalyze the coupling of a variety of racemic secondary alkyl electrophiles with an array of nucleophiles with good enantioselectivity. To date, only a small fraction of the conceivable permutations of electrophilic and nucleophilic partners for substitution reactions of alkyl electrophiles have been explored, and still fewer such processes have been rendered enantioselective. The goal of this proposal is to address this unsolved challenge. Efforts will focus on the development of mild and versatile methods to couple families of electrophiles and nucleophiles that have not previously been shown to be suitable reaction partners in aliphatic substitution reactions, while controlling stereoselectivity at the same time (at up to two stereocenters). Success in this endeavor will substantially facilitate the synthesis of enantioenriched molecules that have application across a broad spectrum of biomedical research. Mechanistic studies will be pursued in order to provide insight into the pathways by which the new metal- catalyzed enantioconvergent substitution reactions proceed. The mechanistic investigations will facilitate reaction development, as well as enhance the community?s understanding of fundamental chemical reactivity.

Public Health Relevance

/ RELEVANCE The development of efficient new reactions for organic synthesis can have an impact on the wide array of scientific disciplines (including biology, biological chemistry, pharmaceutical chemistry, bioinorganic chemistry, bioorganic chemistry, and organic chemistry) that utilize organic compounds. Because the two enantiomers (mirror-image isomers) of a molecule often have different biological activity, due to the 'handedness' of the molecules of life (e.g., peptides, DNA, RNA, and carbohydrates), there is a need to efficiently generate compounds in enantiomerically pure form. The development of powerful new catalytic enantioselective reactions for the synthesis of organic compounds is therefore an important objective for the biomedical community.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Brown, Patrick
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California Institute of Technology
Schools of Arts and Sciences
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