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

doi:10.1002/anie.201705855

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

Biology

Research output: Contribution to journal › Article › peer-review

Abstract

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 language	English
Pages (from-to)	12503-12507
Number of pages	5
Journal	Angewandte Chemie - International Edition
Volume	56
Issue number	41
Early online date	27 Sept 2017
DOIs	https://doi.org/10.1002/anie.201705855
Publication status	Published - 2 Oct 2017

Bibliographical note

Keywords

asymmetric catalysis
biocatalysis
chemoenzymatic cascades
norcoclaurine synthase
transaminases

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10.1002/anie.201705855

Erdmann_et_al-2017-Angewandte_Chemie_International_Edition
© 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
Final published version, 881 KBLicence: CC BY-NC

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title = "Enzymatic and Chemoenzymatic Three-Step Cascades for the Synthesis of Stereochemically Complementary Trisubstituted Tetrahydroisoquinolines",

abstract = "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.",

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author = "Vanessa Erdmann and Lichman, {Benjamin R.} and Jianxiong Zhao and Simon, {Robert C.} and Wolfgang Kroutil and Ward, {John M.} and Hailes, {Helen C.} and D{\"o}rte Rother",

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AU - Zhao, Jianxiong

AU - Simon, Robert C.

AU - Kroutil, Wolfgang

AU - Ward, John M.

AU - Hailes, Helen C.

AU - Rother, Dörte

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AB - 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.

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KW - transaminases

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

Abstract

Bibliographical note

Keywords

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Benjamin R. Lichman

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