Enzymatic and Chemoenzymatic Three-Step Cascades for the Synthesis of Stereochemically Complementary Trisubstituted Tetrahydroisoquinolines

Vanessa Erdmann, Benjamin R. Lichman, Jianxiong Zhao, Robert C. Simon, Wolfgang Kroutil, John M. Ward, Helen C. Hailes, Dörte Rother*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Chemoenzymatic and enzymatic cascade reactions enable the synthesis of complex stereocomplementary 1,3,4-trisubstituted tetrahydroisoquinolines (THIQs) with three chiral centers in a step-efficient and selective manner without intermediate purification. The cascade employs inexpensive substrates (3-hydroxybenzaldehyde and pyruvate), and involves a carboligation step, a subsequent transamination, and finally a Pictet–Spengler reaction with a carbonyl cosubstrate. Appropriate selection of the carboligase and transaminase enzymes enabled the biocatalytic formation of (1R,2S)-metaraminol. Subsequent cyclization catalyzed either enzymatically by a norcoclaurine synthase or chemically by phosphate resulted in opposite stereoselectivities in the products at the C1 position, thus providing access to both orientations of the THIQ C1 substituent. This highlights the importance of selecting from both chemo- and biocatalysts for optimal results.

Original languageEnglish
Pages (from-to)12503-12507
Number of pages5
JournalAngewandte Chemie - International Edition
Issue number41
Early online date27 Sept 2017
Publication statusPublished - 2 Oct 2017

Bibliographical note

© 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.


  • asymmetric catalysis
  • biocatalysis
  • chemoenzymatic cascades
  • norcoclaurine synthase
  • transaminases

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