Keynote, Zero Hunger (SDG 2), Good Health & Well-being (SDG 3)
The sustainable biocatalytic synthesis of alkaloids
Helen C. Hailes * Department of Chemistry, University College London, 20 Gordon St, London, WC1H 0AJ, UK. E-mail: h.c.hailes@ucl.ac.uk We are interested in using biocatalytic strategies for the preparation of single isomer compounds and valuable synthons. To achieve this, enzymes are required that can be used in single-step transformations and multi-step enzymatic or chemoenzymatic cascades. In this presentation, firstly some our recent work on single-step biocatalytic reactions will be described to biologically relevant compounds. The tetrahydroisoquinoline ring system is present in a large variety of structurally diverse natural products exhibiting a wide range of biological activities. This has encouraged the development of strategies, particularly aimed at the enantioselective synthesis of non-natural tetrahydroisoquinoline alkaloids. Routes to mimic the biosynthetic pathways to such alkaloids, by building biocatalytic cascade reactions in vitro, represents a successful approach and offers better stereoselectivities than traditional synthetic methods. Here, the use of enzymes including tyrosinases, a tyrosine decarboxylase and transaminase, norcoclaurine synthases and methyl transferases will be described, to generate novel alkaloids in high yields and optical purities. Key words: Sustainable synthesis, biocatalysis, alkaloids, bioactives, norcoclaurine synthase References 1. B. R. Lichman, J. Zhao, H. C. Hailes, J. M. Ward, ‘Enzyme catalyzed Pictet-Spengler formation of chiral 1,1’-disubstituted- and spiro-tetrahydroisoquinolines’, Nat. Commun. 2017 , 8, 14883. 2. J. Zhao, B. R. Lichman, J. M. Ward, H. C. Hailes, ‘One-Pot Chemoenzymatic Synthesis of Trolline and Tetrahydroisoquinoline Analogues’, Chem. Commun. 2018 , 54, 1323. 3. R. Roddan, G. Gygli, A. Sula, D. Méndez-Sánchez, J. Pleiss, J. M. Ward, N. H. Keep, H. C. Hailes, ‘Acceptance and Kinetic Resolution of Alpha-Methyl-Substituted Aldehydes by Norcoclaurine Synthases’, ACS Catal. 2019 , 9, 9640. 4. Y. Wang, N. Tappertzhofen, D. Méndez-Sánchez, M. Bawn, B. Lyu, J. M. Ward, H. C. Hailes, ‘Design and use of de novo cascades for new benzylisoquinoline alkaloid biosynthesis’, Angew. Chem. Int. Ed. 2019 , 58, 10120. 5. R. Roddan, F. Subrizi, J. Broomfield, J. M. Ward, N. H. Keep, H. C. Hailes, ‘Chemoenzymatic cascades towards methylated tetrahydroprotoberberine and protoberberine alkaloids’, Org. Lett. 2021 , 23, 6342. 6. F. Subrizi, Y. Wang, B. Thair, D. Méndez-Sánchez, R. Roddan, M. Cárdenas-Fernández, J. Siegrist, M. Richter, J. N. Andexer, J. M. Ward, H. C. Hailes, ‘Multienzyme one-pot cascades incorporating methyltransferases for the strategic diversification of tetrahydroisoquinoline alkaloids’, Angew. Chem. Int. Ed. , 2021 , 60, 18673. 7. Y. Wang, F. Subrizi, E. M. Carter, T. D. Sheppard, J. M. Ward, H. C. Hailes, ‘Enzymatic synthesis of benzylisoquinoline alkaloids using a parallel cascade strategy and tyrosinase variants’, Nature Commun. 2022 , 13, 5436. 8. M. T. Salinger, J. M. Ward, T. S. Moody, J. W. E. Jeffries, H. C. Hailes, ‘Bioalkylation Strategies to Synthesize Allylated Tetrahydroisoquinolines by Using Norcoclaurine Synthase and O-Methyltransferases’, ChemCatChem , 2024 , 16, e202401668.
© The Author(s), 2025
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