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Single step syntheses of (1S)-aryl-tetrahydroisoquinolines by norcoclaurine synthases

DOI: 10.1038/s42004-020-00416-8 DOI Help

Authors: Rebecca Roddan (Birkbeck College, London; University College London) , Altin Sula (Birkbeck College, London) , Daniel Méndez-Sánchez (University College London) , Fabiana Subrizi (University College London) , Benjamin R. Lichman (University College London) , Joseph Broomfield (University College London) , Michael Richter (Fraunhofer Institute for Interfacial Engineering and Biotechnology IGB) , Jennifer N. Andexer (University of Freiburg) , John M. Ward (University College London) , Nicholas Keep (Birkbeck College, London) , Helen C. Hailes (University College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Communications Chemistry , VOL 3

State: Published (Approved)
Published: November 2020
Diamond Proposal Number(s): 23583

Open Access Open Access

Abstract: The 1-aryl-tetrahydroisoquinoline (1-aryl-THIQ) moiety is found in many biologically active molecules. Single enantiomer chemical syntheses are challenging and although some biocatalytic routes have been reported, the substrate scope is limited to certain structural motifs. The enzyme norcoclaurine synthase (NCS), involved in plant alkaloid biosynthesis, has been shown to perform stereoselective Pictet–Spengler reactions between dopamine and several carbonyl substrates. Here, benzaldehydes are explored as substrates and found to be accepted by both wild-type and mutant constructs of NCS. In particular, the variant M97V gives a range of (1 S)-aryl-THIQs in high yields (48–99%) and e.e.s (79–95%). A co-crystallised structure of the M97V variant with an active site reaction intermediate analogue is also obtained with the ligand in a pre-cyclisation conformation, consistent with (1 S)-THIQs formation. Selected THIQs are then used with catechol O-methyltransferases with exceptional regioselectivity. This work demonstrates valuable biocatalytic approaches to a range of (1 S)-THIQs.

Journal Keywords: Biocatalysis

Diamond Keywords: Enzymes

Subject Areas: Chemistry, Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography

Added On: 25/11/2020 14:06

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s42004-020-00416-8.pdf

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