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A biomolecule-compatible visible-light-induced azide reduction from a DNA-encoded reaction-discovery system

Nature Chemistry volume 3, pages 146153 (2011) | Download Citation

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Abstract

Using a system that accelerates the serendipitous discovery of new reactions by evaluating hundreds of DNA-encoded substrate combinations in a single experiment, we explored a broad range of reaction conditions for new bond-forming reactions. We discovered reactivity that led to a biomolecule-compatible, Ru(II)-catalysed azide-reduction reaction induced by visible light. In contrast to current azide-reduction methods, this reaction is highly chemoselective and is compatible with alcohols, phenols, acids, alkenes, alkynes, aldehydes, alkyl halides, alkyl mesylates and disulfides. The remarkable functional group compatibility and mild conditions of the reaction enabled the azide reduction of nucleic acid and oligosaccharide substrates, with no detectable occurrence of side reactions. The reaction was also performed in the presence of a protein enzyme without the loss of enzymatic activity, in contrast to two commonly used azide-reduction methods. The visible-light dependence of this reaction provides a means of photouncaging functional groups, such as amines and carboxylates, on biological macromolecules without using ultraviolet irradiation.

  • Compound C7H7N3

    (Azidomethyl)benzene

  • Compound C11H14N4O

    4-Azido-N-butylbenzamide

  • Compound C7H8O

    Anisole

  • Compound C5H8O4

    Dimethyl malonate

  • Compound C12H14O5

    Dimethyl 2-(2-methoxyphenyl)malonate

  • Compound C10H16

    (R)-1-Methyl-4-(prop-1-en-2-yl)cyclohex-1-ene

  • Compound C6H8O4

    2,2-Dimethyl-1,3-dioxane-4,6-dione

  • Compound C13H18O4

    5-Methyl-5-((R)-4-methylcyclohex-3-en-1-yl)-2-oxotetrahydrofuran-3-carboxylic acid

  • Compound C8H7N

    1H-Indole

  • Compound C5H8O3

    Ethyl 2-oxopropanoate

  • Compound C13H15NO3

    Ethyl 2-hydroxy-2-(1H-indol-3-yl)propanoate

  • Compound C21H20N2O2

    Ethyl 2,2-di(1H-indol-3-yl)propanoate

  • Compound C14H11NO2S

    1-(Phenylsulfonyl)-1H-indole

  • Compound C4H6N2

    5-Methyl-1H-imidazole

  • Compound C14H11NO3S

    1-(Phenylsulfonyl)indolin-3-one

  • Compound C7H8O

    Phenylmethanol

  • Compound C7H6O

    Benzaldehyde

  • Compound C30H24N6Ru2+

    Tris(bipyridine)ruthenium(II)

  • Compound C30H24N6Ru+

    Tris(bipyridine)ruthenium(I)

  • Compound C11H16N2O

    4-Amino-N-butylbenzamide

  • Compound C17H15N5O

    N-(2-(1H-Indol-3-yl)ethyl)-4-azidobenzamide

  • Compound C7H5N3O2

    4-Azidobenzoic acid

  • Compound C7H7N3O

    (4-Azidophenyl)methanol

  • Compound C8H9N3O

    2-(4-Azidophenyl)ethanol

  • Compound C15H10N4O

    4-Azido-N-(4-ethynylphenyl)benzamide

  • Compound C11H12N4O

    4-Azido-N-(but-3-en-1-yl)benzamide

  • Compound C6H4ClN3

    1-Azido-4-chlorobenzene

  • Compound C14H11IN4O

    4-Azido-N-(3-iodobenzyl)benzamide

  • Compound C8H8BrN3

    1-Azido-4-(2-bromoethyl)benzene

  • Compound C9H11N3O3S

    4-Azidophenethyl methanesulfonate

  • Compound C7H5N3O

    4-Azidobenzaldehyde

  • Compound C10H10N4

    3-(2-Azidoethyl)-1H-indole

  • Compound C34H36N4O14

    4-Azido-N-(((2R,3S,4S,5R,6S)-3,4-dihydroxy-6-(((S)-5-hydroxy-2-(4-hydroxyphenyl)-4-oxochroman-7-yl)oxy)-5-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)methyl)benzamide

  • Compound C34H38N2O14

    4-Amino-N-(((2R,3S,4S,5R,6S)-3,4-dihydroxy-6-(((S)-5-hydroxy-2-(4-hydroxyphenyl)-4-oxochroman-7-yl)oxy)-5-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)methyl)benzamide

  • Compound C17H17N3O

    N-(2-(1H-Indol-3-yl)ethyl)-4-aminobenzamide

  • Compound C7H7NO2

    4-Aminobenzoic acid

  • Compound C7H9NO

    (4-Aminophenyl)methanol

  • Compound C8H11NO

    2-(4-Aminophenyl)ethanol

  • Compound C15H12N2O

    4-Amino-N-(4-ethynylphenyl)benzamide

  • Compound C11H14N2O

    4-Amino-N-(but-3-en-1-yl)benzamide

  • Compound C6H6ClN

    4-Chloroaniline

  • Compound C14H13IN2O

    4-Amino-N-(3-iodobenzyl)benzamide

  • Compound C8H10BrN

    4-(2-Bromoethyl)aniline

  • Compound C9H13NO3S

    4-Aminophenethyl methanesulfonate

  • Compound C7H7NO

    4-Aminobenzaldehyde

  • Compound C15H20N2O2

    tert-Butyl (2-(1H-indol-3-yl)ethyl)carbamate

  • Compound C27H33NO13

    (S)-7-(((2S,3R,4S,5S,6R)-6-(Aminomethyl)-4,5-dihydroxy-3-(((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-5-hydroxy-2-(4-hydroxyphenyl)chroman-4-one

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Acknowledgements

This work was supported by NIH grant R01GM065865 and the Howard Hughes Medical Institute. We thank Y. Shen and C. Dumelin for MS assistance, and D. Gorin for discussions.

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Affiliations

  1. Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138 USA

    • Yiyun Chen
    • , Adam S. Kamlet
    • , Jonathan B. Steinman
    •  & David R. Liu

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Contributions

Y.C., A.S.K., J.B.S. and D.R.L. designed the research, analysed the data and co-wrote the manuscript, Y.C., A.S.K. and J.B.S. performed the experiments.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to David R. Liu.

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DOI

https://doi.org/10.1038/nchem.932