PROJECT SUMMARY / ABSTRACT 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, carbon– nitrogen, and carbon–oxygen 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 such bonds in the backbone of organic molecules, respectively. 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 products from readily available racemic starting materials. Through the use of transition-metal catalysis, wherein the electrophile is converted into an organic radical, it is possible to begin to address both of the key challenges in nucleophilic substitution reactions of alkyl electrophiles–broader scope and control of enantioselectivity. For example, chiral nickel and copper complexes can catalyze the enantioconvergent coupling of a number of racemic secondary and tertiary alkyl electrophiles with a variety of nucleophiles. To date, only a small fraction of the conceivable permutations of electrophilic and nucleophilic partners for metal-catalyzed substitution reactions of alkyl electrophiles have been explored, and still fewer such processes have been rendered enantioselective. The goal of this research program is to address the many unsolved challenges in this area. 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, including highly hindered substrates, while controlling stereoselectivity at the same time (at up to two stereocenters), including with racemic electrophiles and nucleophiles that lack directing groups. Success in this endeavor will substantially facilitate the synthesis of enantioenriched molecules. Mechanistic studies will be pursued in order to provide insight into the pathways by which the new metal- catalyzed substitution reactions proceed. The mechanistic investigations will facilitate reaction development, as well as enhance the community’s understanding of fundamental chemical reactivity.