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Lichman BR, Zhao J, Hailes HC, et al. Enzyme catalysed Pictet-Spengler formation of chiral 1,1'-disubstituted- and spiro-tetrahydroisoquinolines. Nat Commun. 2017;8:14883doi: 10.1038/ncomms14883.
Lichman, B. R., Zhao, J., Hailes, H. C., & Ward, J. M. (2017). Enzyme catalysed Pictet-Spengler formation of chiral 1,1'-disubstituted- and spiro-tetrahydroisoquinolines. Nature communications, 814883. https://doi.org/10.1038/ncomms14883
Lichman, Benjamin R, et al. "Enzyme catalysed Pictet-Spengler formation of chiral 1,1'-disubstituted- and spiro-tetrahydroisoquinolines." Nature communications vol. 8 (2017): 14883. doi: https://doi.org/10.1038/ncomms14883
Lichman BR, Zhao J, Hailes HC, Ward JM. Enzyme catalysed Pictet-Spengler formation of chiral 1,1'-disubstituted- and spiro-tetrahydroisoquinolines. Nat Commun. 2017 Apr 03;8:14883. doi: 10.1038/ncomms14883. PMID: 28368003; PMCID: PMC5382262.
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Nat Commun. 2017 Apr 03;8:14883. doi: 10.1038/ncomms14883.

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

Nature communications

Benjamin R Lichman, Jianxiong Zhao, Helen C Hailes, John M Ward

Affiliations

  1. Department of Biochemical Engineering, University College London, Gower Street, London WC1E 6BT, UK.
  2. Department of Chemistry, University College London, Christopher Ingold Building, 20 Gordon Street, London, WC1H 0AJ, UK.

PMID: 28368003 PMCID: PMC5382262 DOI: 10.1038/ncomms14883

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.

References

  1. J Biol Chem. 2007 Mar 2;282(9):6274-82 - PubMed
  2. Nat Prod Rep. 2016 Mar;33(3):491-522 - PubMed
  3. Protein Expr Purif. 2007 Dec;56(2):197-204 - PubMed
  4. Plant Cell. 2010 Oct;22(10):3489-503 - PubMed
  5. Tetrahedron Lett. 2010 Aug 18;51(33):4400-4402 - PubMed
  6. J Am Chem Soc. 2012 Jan 25;134(3):1498-500 - PubMed
  7. Proc Natl Acad Sci U S A. 2015 Mar 17;112(11):3205-10 - PubMed
  8. J Org Chem. 2010 Dec 17;75(24):8542-9 - PubMed
  9. Angew Chem Int Ed Engl. 2013 Sep 16;52(38):9980-4 - PubMed
  10. Sci Rep. 2016 Dec 19;6:39256 - PubMed
  11. Nat Chem Biol. 2015 Jul;11(7):465-71 - PubMed
  12. Angew Chem Int Ed Engl. 2011 Sep 5;50(37):8538-64 - PubMed
  13. Science. 2015 Sep 4;349(6252):1095-100 - PubMed
  14. Chem Biol. 2015 Jul 23;22(7):898-906 - PubMed
  15. Tetrahedron Lett. 2012 Feb 29;53(9):1071-1074 - PubMed
  16. Chem Pharm Bull (Tokyo). 2002 Feb;50(2):253-7 - PubMed
  17. Plant J. 2004 Oct;40(2):302-13 - PubMed
  18. J Comput Chem. 2010 Jan 30;31(2):455-61 - PubMed
  19. J Am Chem Soc. 2008 Jan 16;130(2):710-23 - PubMed
  20. Nat Chem Biol. 2010 Jun;6(6):408-10 - PubMed
  21. J Biol Chem. 2009 Jan 9;284(2):897-904 - PubMed
  22. Biosci Biotechnol Biochem. 2014;78(4):701-7 - PubMed
  23. FEBS J. 2015 Mar;282(6):1137-51 - PubMed
  24. Phytochemistry. 1999 Oct;52(3):373-82 - PubMed
  25. Plant Physiol Biochem. 2008 Mar;46(3):340-55 - PubMed
  26. Proc Natl Acad Sci U S A. 2008 May 27;105(21):7393-8 - PubMed
  27. Chem Commun (Camb). 2011 Mar 21;47(11):3242-4 - PubMed
  28. Expert Opin Drug Discov. 2016 Sep;11(9):831-4 - PubMed
  29. Nat Commun. 2011;2:326 - PubMed

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