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Enzyme catalysed Pictet-Spengler formation of chiral 1,1’-disubstituted- and spiro-tetrahydroisoquinolines

Author

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  • Benjamin R. Lichman

    (University College London
    Present address: John Innes Centre, Norwich Research Park, Norwich NR4 7UH, UK)

  • Jianxiong Zhao

    (University College London)

  • Helen C. Hailes

    (University College London)

  • John M. Ward

    (University College London)

Abstract

The Pictet–Spengler reaction (PSR) involves the condensation and ring closure between a β-arylethylamine and a carbonyl compound. The combination of dopamine and ketones in a PSR leads to the formation of 1,1′-disubstituted tetrahydroisoquinolines (THIQs), structures that are challenging to synthesize and yet are present in a number of bioactive natural products and synthetic pharmaceuticals. Here we have discovered that norcoclaurine synthase from Thalictrum flavum (TfNCS) can catalyse the PSR between dopamine and unactivated ketones, thus facilitating the facile biocatalytic generation of 1,1′-disubstituted THIQs. Variants of TfNCS showing improved conversions have been identified and used to synthesize novel chiral 1,1′-disubstituted and spiro-THIQs. Enzyme catalysed PSRs with unactivated ketones are unprecedented, and, furthermore, there are no equivalent stereoselective chemical methods for these transformations. This discovery advances the utility of enzymes for the generation of diverse THIQs in vitro and in vivo.

Suggested Citation

  • Benjamin R. Lichman & Jianxiong Zhao & Helen C. Hailes & John M. Ward, 2017. "Enzyme catalysed Pictet-Spengler formation of chiral 1,1’-disubstituted- and spiro-tetrahydroisoquinolines," Nature Communications, Nature, vol. 8(1), pages 1-9, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14883
    DOI: 10.1038/ncomms14883
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