Reaction discovery enabled by DNA-templated synthesis and in vitro selection

• Published in: Nature Vol. 431; no. 7008; pp. 545 - 549
• Main Authors: Liu, David R, Kanan, Matthew W, Rozenman, Mary M, Sakurai, Kaori, Snyder, Thomas M
• Format: Journal Article
• Language: English
• Published: LONDON Springer Nature 30.09.2004; Nature Publishing; Nature Publishing Group
• Subjects: Alkenes - chemistry; Alkynes - chemistry; Base Pairing; Biochemistry; Biological and medical sciences; Carbon - chemistry; Catalysis; Chemical reactions; Cyclization; Deoxyribonucleic acid; DNA; DNA - chemical synthesis; DNA - chemistry; DNA Replication; Fundamental and applied biological sciences. Psychology; General aspects; Molecular and cellular biology; Molecular Structure; Multidisciplinary Sciences; Oligonucleotide Array Sequence Analysis; Palladium - chemistry; Polymerase Chain Reaction; Science & Technology; Science & Technology - Other Topics; Substrate Specificity; Templates, Genetic; ORGANIC-SYNTHESIS; CYCLOADDITION; EVOLUTION; FLUORESCENCE; ENZYMES; COMBINATORIAL; CATALYSTS
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature02920

Current approaches to reaction discovery focus on one particular transformation. Typically, researchers choose substrates based on their predicted ability to serve as precursors for the target structure, then evaluate reaction conditions for their ability to effect product formation. This approach is ideal for addressing specific reactivity problems, but its focused nature might leave many areas of chemical reactivity unexplored. Here we report a reaction discovery approach that uses DNA-templated organic synthesis and in vitro selection to simultaneously evaluate many combinations of different substrates for bond-forming reactions in a single solution. Watson-Crick base pairing controls the effective molarities of substrates tethered to DNA strands; bond-forming substrate combinations are then revealed using in vitro selection for bond formation, PCR amplification and DNA microarray analysis. Using this approach, we discovered an efficient and mild carbon-carbon bond-forming reaction that generates an enone from an alkyne and alkene using an inorganic palladium catalyst. Although this approach is restricted to conditions and catalysts that are at least partially compatible with DNA, we expect that its versatility and efficiency will enable the discovery of additional reactions between a wide range of substrates.