Browse by author
Lookup NU author(s): Monse Manzo Ruiz, Professor Paul RaceORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2025 The Royal Society of Chemistry. The tetrodecamycins are tetracyclic natural products that exhibit potent antimicrobial activity against a multitude of drug-resistant pathogens. These compounds are structurally distinguished by the presence of a tetronate ring and trans-decalin with six contiguous asymmetric centres united by a seven-membered oxygen heterocycle. Herein we describe the first total synthesis of the antibiotic (−)-13-deoxytetrodecamycin. Our strategy is predicated on an enantioselective [4 + 2]-cycloaddition catalysed by the FAD-dependent Diels-Alderase TedJ, forming the trans-decalin with concomitant creation of two rings and four contiguous stereocenters with exquisite selectivity under mild conditions. In complementary studies, in vitro enzyme assays, X-ray crystallography and computational modelling are used to provide molecular insights into the TedJ catalysed reaction. These studies illustrate the power of adopting a chemoenzymatic approach for the enantioselective synthesis of a target compound which would be difficult to achieve using non-biological methods and provide a practical demonstration of the use of Diels-Alder biocatalysts in total synthesis. This approach has potentially widespread value in the global challenge of discovery and development of new antibiotics.
Author(s): Russell SJ, Back CR, Perry C, Cheung KA, Maschio L, Charlton SN, Lees NR, Manzo-Ruiz M, Hayes MA, van der Kamp MW, Race PR, Willis CL
Publication type: Article
Publication status: Published
Journal: Chemical Science
Year: 2025
Volume: 16
Issue: 36
Pages: 16993-16999
Print publication date: 28/09/2025
Online publication date: 26/08/2025
Acceptance date: 17/08/2025
Date deposited: 30/09/2025
ISSN (print): 2041-6520
ISSN (electronic): 2041-6539
Publisher: Royal Society of Chemistry
URL: https://doi.org/10.1039/d5sc05480j
DOI: 10.1039/d5sc05480j
Data Access Statement: The data supporting this article have been reported as part of the SI. Supplementary information is available and includes experimental procedures, analytical and spectral data, NMR spectra, computational methods, protein expression, purification, crystallisation and X-ray. See DOI: https://doi.org/10.1039/d5sc05480j.
Altmetrics provided by Altmetric
