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

Nature volume 431, pages 545–549 (2004)Cite this article

Abstract

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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References

  1. Stambuli, J. P. & Hartwig, J. F. Recent advances in the discovery of organometallic catalysts using high-throughput screening assays. Curr. Opin. Chem. Biol. 7, 420–426 (2003)

    Article  CAS  Google Scholar 

  2. Reetz, M. T. Combinatorial and evolution-based methods in the creation of enantioselective catalysts. Angew. Chem. Int. Edn Engl. 40, 284–310 (2001)

    Article  CAS  Google Scholar 

  3. Stambuli, J. P., Stauffer, S. R., Shaughnessy, K. H. & Hartwig, J. F. Screening of homogeneous catalysts by fluorescence resonance energy transfer. Identification of catalysts for room-temperature Heck reactions. J. Am. Chem. Soc. 123, 2677–2678 (2001)

    Article  CAS  Google Scholar 

  4. Taylor, S. J. & Morken, J. P. Thermographic selection of effective catalysts from an encoded polymer-bound library. Science 280, 267–270 (1998)

    Article  ADS  CAS  Google Scholar 

  5. Lober, O., Kawatsura, M. & Hartwig, J. F. Palladium-catalyzed hydroamination of 1,3-dienes: a colorimetric assay and enantioselective additions. J. Am. Chem. Soc. 123, 4366–4367 (2001)

    Article  CAS  Google Scholar 

  6. Evans, C. A. & Miller, S. J. Proton-activated fluorescence as a tool for simultaneous screening of combinatorial chemical reactions. Curr. Opin. Chem. Biol. 6, 333–338 (2002)

    Article  CAS  Google Scholar 

  7. Calderone, C. T., Puckett, J. W., Gartner, Z. J. & Liu, D. R. Directing otherwise incompatible reactions in a single solution by using DNA-templated organic synthesis. Angew. Chem. Int. Edn Engl. 41, 4104–4108 (2002)

    Article  CAS  Google Scholar 

  8. Gartner, Z. J. & Liu, D. R. The generality of DNA-templated synthesis as a basis for evolving non-natural small molecules. J. Am. Chem. Soc. 123, 6961–6963 (2001)

    Article  CAS  Google Scholar 

  9. Gartner, Z. J., Kanan, M. W. & Liu, D. R. Expanding the reaction scope of DNA-templated synthesis. Angew. Chem. Int. Edn Engl. 41, 1796–1800 (2002)

    Article  CAS  Google Scholar 

  10. Rosenbaum, D. M. & Liu, D. R. Efficient and sequence-specific DNA-templated polymerization of peptide nucleic acid aldehydes. J. Am. Chem. Soc. 125, 13924–13925 (2003)

    Article  CAS  Google Scholar 

  11. Li, X. & Liu, D. R. Stereoselectivity in DNA-templated organic synthesis and its origins. J. Am. Chem. Soc. 125, 10188–10189 (2003)

    Article  CAS  Google Scholar 

  12. Wilson, D. S. & Szostak, J. W. In vitro selection of functional nucleic acids. Annu. Rev. Biochem. 68, 611–647 (1999)

    Article  CAS  Google Scholar 

  13. Joyce, G. F. Directed evolution of nucleic acid enzymes. Annu. Rev. Biochem. 73, 791–836 (2004)

    Article  CAS  Google Scholar 

  14. Rostovtsev, V. V., Green, L. G., Fokin, V. V. & Sharpless, K. B. A stepwise huisgen cycloaddition process: copper(I)-catalyzed regioselective ‘ligation’ of azides and terminal alkynes. Angew. Chem. Int. Edn Engl. 41, 2596–2599 (2002)

    Article  CAS  Google Scholar 

  15. Wang, Q. et al. Bioconjugation by copper(I)-catalyzed azide–alkyne [3 + 2] cycloaddition. J. Am. Chem. Soc. 125, 3192–3193 (2003)

    Article  CAS  Google Scholar 

  16. Burrows, C. J. & Muller, J. G. Oxidative nucleobase modifications leading to strand scission. Chem. Rev. 98, 1109–1152 (1998)

    Article  CAS  Google Scholar 

  17. Kramer, M. F. & Coen, D. M. in Current Protocols in Molecular Biology Vol. 2 (eds Ausubel, F. M. et al.) 15.1.1–15.1.3 (Wiley, New York, 2001)

    Google Scholar 

  18. Bailey, P. D., Collier, I. D. & Morgan, K. M. in Comprehensive Organic Functional Group Transformations Vol. 5 (eds Katritzky, A. R., Meth-Cohn, O. & Rees, C. W.) 257–307 (Pergamon, New York, 1995)

    Book  Google Scholar 

  19. Tsuji, J. Palladium Reagents and Catalysts (Wiley, New York, 1995)

    Google Scholar 

  20. Heck, R. F. Palladium-catalyzed vinylation of organic halides. Org. React. 27, 345–390 (1982)

    CAS  Google Scholar 

  21. Li, C.-J. & Chan, T.-H. Organic Reactions in Aqueous Media (Wiley, New York, 1997)

    Google Scholar 

  22. Miyaura, N. & Suzuki, A. Palladium-catalyzed cross-coupling reactions of organoboron compounds. Chem. Rev. 95, 2457–2483 (1995)

    Article  CAS  Google Scholar 

  23. Crabtree, R. H. The Organometallic Chemistry of the Transition Metals (Wiley, New York, 2001)

    Google Scholar 

  24. Smidt, J. et al. Olefinoxydation mit palladiumchlorid-katalysatoren. Angew. Chem. 74, 93–102 (1962)

    Article  CAS  Google Scholar 

  25. Smidt, J. et al. Katalytische umsetzungen von olefinen an platinmetall-verbindungen: das consortium-verfahren zur herstellung von acetaldehyd. Angew. Chem. 71, 176–182 (1959)

    Article  CAS  Google Scholar 

  26. Wadsworth, W. S. J. & Emmons, W. D. Utility of phosphonate carbanions in olefin synthesis. J. Am. Chem. Soc. 83, 1733–1738 (1961)

    Article  CAS  Google Scholar 

  27. Staunton, J. & Weissman, K. J. Polyketide biosynthesis: a millennium review. Nat. Prod. Rep. 18, 380–416 (2001)

    Article  CAS  Google Scholar 

  28. Kohli, R. M., Walsh, C. T. & Burkart, M. D. Biomimetic synthesis and optimization of cyclic peptide antibiotics. Nature 418, 658–661 (2002)

    Article  ADS  CAS  Google Scholar 

  29. Breslow, R. Biomimetic chemistry and artificial enzymes: catalysis by design. Acc. Chem. Res. 28, 146–153 (1995)

    Article  CAS  Google Scholar 

  30. Schultz, P. G. & Lerner, R. A. Completing the circle. Nature 418, 485 (2002)

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

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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  1. Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts, 02138, USA

    Matthew W. Kanan, Mary M. Rozenman, Kaori Sakurai, Thomas M. Snyder & David R. Liu

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  1. Matthew W. Kanan
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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). https://doi.org/10.1038/nature02920

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