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Single step syntheses of (1S)-aryl-tetrahydroisoquinolines by norcoclaurine synthases
DOI:
10.1038/s42004-020-00416-8
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

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
Documents:
s42004-020-00416-8.pdf
Discipline Tags:
Health & Wellbeing
Biochemistry
Catalysis
Chemistry
Structural biology
Organic Chemistry
Drug Discovery
Life Sciences & Biotech
Technical Tags: