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


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 conditions1,2,3,4,5,6 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 synthesis7,8,9,10 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.

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Figure 1: Key elements of a new approach to reaction discovery.
Figure 2: Results from reaction discovery selections and analysis.
Figure 3: Characterization in a DNA-templated format of array positives resulting from exposure to 500 µM Na2PdCl4 at 37 °C for 1 h, or at 25 °C for 20 min.
Figure 4: Characterization of a new alkyne–alkene macrocyclization reaction in a non-DNA-templated format.


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We thank P. Kehayova for the initial analysis of early reaction discovery selections, and C. Bailey (Bauer Center for Genomics Research) for assistance with DNA microarray preparation and analysis. We thank DNA Software for assistance with screening coding and annealing sequences. This work was supported by the National Institutes of Health, the Office of Naval Research, and the Arnold and Mabel Beckman Foundation. M.W.K. and T.M.S. are NSF Graduate Research Fellows. M.M.R. is an NDSEG Graduate Research Fellow. K.S. is a Helen Hay Whitney Postdoctoral Research Fellow.

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Correspondence to David R. Liu.

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D.R.L. owns shares of Ensemble Discovery, a new (and non-public) company that has licenced DNA-templated synthesis technologies from Harvard University.

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Kanan, M., Rozenman, M., Sakurai, K. et al. Reaction discovery enabled by DNA-templated synthesis and in vitro selection. Nature 431, 545–549 (2004).

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