The Role of Biocatalysis in the Asymmetric Synthesis of Alkaloids - an Update

Overview

Journal RSC Adv

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2022 Apr 28

PMID 35480754

Authors

Emmanuel Cigan

Bettina Eggbauer

Joerg H Schrittwieser

Wolfgang Kroutil

Affiliations

Soon will be listed here.

Abstract

Alkaloids are a group of natural products with interesting pharmacological properties and a long history of medicinal application. Their complex molecular structures have fascinated chemists for decades, and their total synthesis still poses a considerable challenge. In a previous review, we have illustrated how biocatalysis can make valuable contributions to the asymmetric synthesis of alkaloids. The chemo-enzymatic strategies discussed therein have been further explored and improved in recent years, and advances in amine biocatalysis have vastly expanded the opportunities for incorporating enzymes into synthetic routes towards these important natural products. The present review summarises modern developments in chemo-enzymatic alkaloid synthesis since 2013, in which the biocatalytic transformations continue to take an increasingly 'central' role.

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References

Concia A, Gomez L, Parella T, Joglar J, Clapes P . Casuarine stereoisomers from achiral substrates: chemoenzymatic synthesis and inhibitory properties. J Org Chem. 2014; 79(11):5386-9. DOI: 10.1021/jo500991p. View

Fryszkowska A, Devine P . Biocatalysis in drug discovery and development. Curr Opin Chem Biol. 2020; 55:151-160. DOI: 10.1016/j.cbpa.2020.01.012. View

Staben S, Kennedy-Smith J, Huang D, Corkey B, Lalonde R, Toste F . Gold(I)-catalyzed cyclizations of silyl enol ethers: application to the synthesis of (+)-lycopladine A. Angew Chem Int Ed Engl. 2006; 45(36):5991-4. DOI: 10.1002/anie.200602035. View

Ito H, Inoue T, Iguchi K . Toward the synthesis of didemnaketal B: a convergent synthesis of the C9-C28 subunit. Org Lett. 2008; 10(17):3873-6. DOI: 10.1021/ol801395q. View

Mitsukura K, Suzuki M, Tada K, Yoshida T, Nagasawa T . Asymmetric synthesis of chiral cyclic amine from cyclic imine by bacterial whole-cell catalyst of enantioselective imine reductase. Org Biomol Chem. 2010; 8(20):4533-5. DOI: 10.1039/c0ob00353k. View

Prier C, Zhang R, Buller A, Brinkmann-Chen S, Arnold F . Enantioselective, intermolecular benzylic C-H amination catalysed by an engineered iron-haem enzyme. Nat Chem. 2017; 9(7):629-634. PMC: 5555633. DOI: 10.1038/nchem.2783. View

Taher E, Banwell M, Buckler J, Yan Q, Lan P . The Exploitation of Enzymatically-Derived cis-1,2-Dihydrocatechols and Related Compounds in the Synthesis of Biologically Active Natural Products. Chem Rec. 2017; 18(2):239-264. DOI: 10.1002/tcr.201700064. View

Koetter J, Schulz G . Crystal structure of 6-hydroxy-D-nicotine oxidase from Arthrobacter nicotinovorans. J Mol Biol. 2005; 352(2):418-28. DOI: 10.1016/j.jmb.2005.07.041. View

White L, Banwell M . Conversion of the Enzymatically Derived (1S,2S)-3-Bromocyclohexa-3,5-diene-1,2-diol into Enantiomerically Pure Compounds Embodying the Pentacyclic Framework of Vindoline. J Org Chem. 2016; 81(4):1617-26. DOI: 10.1021/acs.joc.5b02788. View

10.

Honig M, Sondermann P, Turner N, Carreira E . Enantioselective Chemo- and Biocatalysis: Partners in Retrosynthesis. Angew Chem Int Ed Engl. 2017; 56(31):8942-8973. DOI: 10.1002/anie.201612462. View

11.

Marco-Contelles J, Carreiras M, Rodriguez C, Villarroya M, Garcia A . Synthesis and pharmacology of galantamine. Chem Rev. 2006; 106(1):116-33. DOI: 10.1021/cr040415t. View

12.

Mordhorst S, Siegrist J, Muller M, Richter M, Andexer J . Catalytic Alkylation Using a Cyclic S-Adenosylmethionine Regeneration System. Angew Chem Int Ed Engl. 2017; 56(14):4037-4041. DOI: 10.1002/anie.201611038. View

13.

Heckmann C, Paradisi F . Looking Back: A Short History of the Discovery of Enzymes and How They Became Powerful Chemical Tools. ChemCatChem. 2020; 12(24):6082-6102. PMC: 7756376. DOI: 10.1002/cctc.202001107. View

14.

White L, Schwartz B, Banwell M, Willis A . A chemoenzymatic total synthesis of (+)-clividine. J Org Chem. 2011; 76(15):6250-7. DOI: 10.1021/jo201005d. View

15.

Palazzotto E, Weber T . Omics and multi-omics approaches to study the biosynthesis of secondary metabolites in microorganisms. Curr Opin Microbiol. 2018; 45:109-116. DOI: 10.1016/j.mib.2018.03.004. View

16.

Endoma-Arias M, Dela Paz H, Hudlicky T . Chemoenzymatic Total Synthesis of (+)-10-Keto-Oxycodone from Phenethyl Acetate. Molecules. 2019; 24(19). PMC: 6804203. DOI: 10.3390/molecules24193477. View

17.

Grogan G, Turner N . InspIRED by Nature: NADPH-Dependent Imine Reductases (IREDs) as Catalysts for the Preparation of Chiral Amines. Chemistry. 2015; 22(6):1900-1907. DOI: 10.1002/chem.201503954. View

18.

Bennett M, Shepherd S, Cronin V, Micklefield J . Recent advances in methyltransferase biocatalysis. Curr Opin Chem Biol. 2017; 37:97-106. DOI: 10.1016/j.cbpa.2017.01.020. View

19.

Firth J, Canipa S, Ferris L, OBrien P . Gram-Scale Synthesis of the (-)-Sparteine Surrogate and (-)-Sparteine. Angew Chem Int Ed Engl. 2017; 57(1):223-226. DOI: 10.1002/anie.201710261. View

20.

Chapman M, Cosgrove S, Turner N, Kapur N, Blacker A . Highly Productive Oxidative Biocatalysis in Continuous Flow by Enhancing the Aqueous Equilibrium Solubility of Oxygen. Angew Chem Int Ed Engl. 2018; 57(33):10535-10539. DOI: 10.1002/anie.201803675. View