DNA-templated synthesis and DNA-encoded reaction discovery in organic solvents

Molecular evolution has been widely applied in the laboratory to generate novel biological macromolecules. More recently, researchers have sought to apply powerful evolutionary principles to address problems in the chemical sciences including the discovery of functional molecules and new chemical reactions. To date, advances geared at expanding the chemical repertoire of in vitro evolution have been limited to contexts that mimic the biological milieu.; To maximize the chemical impact of applied evolutionary principles, I have developed methods that enable their application in the organic milieu. Here, I describe the development of a Pd(II)-catalyzed alkene-alkyne oxidative coupling reaction discovered with a system reliant on DNA-templated synthesis and in vitro selection. I will describe the utility of the discovered bond-forming reaction as a facile method for macrocycle assembly as well as its transferability to the organic milieu likely required for the solubilization of complex synthetic intermediates. I will further describe the development of methods for DNA-templated synthesis towards selection-based reaction discovery in organic solvents and describe unique aspects of DNA-templated synthesis in solvents including MeCN, DMF, THF and CH2Cl2 as well as the application of these methods to DNA-templated chemistry inaccessible in aqueous systems.; Finally, I will describe the development and application of an approach to reaction discovery that takes advantage of DNA encoding, DNA-programmed assembly of substrate pairs, in vitro selection, and PCR amplification yet does not require reaction conditions that support DNA hybridization. This system allows the simultaneous evaluation of > 200 potential bond-forming combinations of substrates in a single experiment and can be applied in a range of solvent and temperature conditions. In addition to the development and validation of the novel selection-based approach to reaction discovery, I will describe the discovery and development of a simple, mild method for the selective Markovnikov-type hydroarylation of vinyl arenes and tertiary olefins with indoles.