Lichman, BR;
Zhao, J;
Hailes, HC;
Ward, JM;
(2017)
Enzyme catalysed Pictet-Spengler formation of chiral 1,1 '-disubstituted- and spiro-tetrahydroisoquinolines.
Nature Communications
, 8
, Article 14883. 10.1038/ncomms14883.
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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.
| Type: | Article |
|---|---|
| Title: | Enzyme catalysed Pictet-Spengler formation of chiral 1,1 '-disubstituted- and spiro-tetrahydroisoquinolines |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/ncomms14883 |
| Publisher version: | http://dx.doi.org/10.1038/ncomms14883 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| Keywords: | Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, Norcoclaurine Synthase, Strictosidine Synthase, Alkaloid Biosynthesis, Asymmetric-Synthesis, Erythrina Alkaloids, Yeast, 1,2,3,4-Tetrahydroisoquinolines, Spirobenzylisoquinoline, Mechanism, Skeleton |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Biochemical Engineering UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/1549498 |
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