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Mimicking oxidative radical cyclizations of lignan biosynthesis using redox-neutral photocatalysis

Nature Chemistry volume 13, pages 24–32 (2021)Cite this article

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Abstract

Oxidative cyclizations create many unique chemical structures that are characteristic of biologically active natural products. Many of these reactions are catalysed by ‘non-canonical’ or ‘thwarted’ iron oxygenases and appear to involve long-lived radicals. Mimicking these biosynthetic transformations with chemical equivalents has been a long-standing goal of synthetic chemists but the fleeting nature of radicals, particularly under oxidizing conditions, makes this challenging. Here we use redox-neutral photocatalysis to generate radicals that are likely to be involved in the biosynthesis of lignan natural products. We present the total syntheses of highly oxidized dibenzocyclooctadienes, which feature densely fused, polycyclic frameworks that originate from a common radical progenitor. We show that multiple factors control the fate of the proposed biosynthetic radicals, as they select between 5- or 11-membered ring cyclizations and a number of different terminating events. Our syntheses create new opportunities to explore the medicinal properties of these natural products, while shedding light on their biosynthetic origin.

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Fig. 1: Proposed biosynthesis of DBCOD lignans and a redox-neutral photocatalytic approach to mimic non-canonical oxidative cyclizations.
Fig. 2: Retrosynthetic analysis of a stage 2 DBCOD.
Fig. 3: Forward synthesis of stage 2 DBCODs.
Fig. 4: The atroposelective Suzuki cyclization proceeds by a stereoselective transmetalation that relays the point chirality at C6 and C9 of 22 into the P-configured axis of chirality in 23.
Fig. 5: Synthesis of kadsulignan E and heteroclitin J by 5-membered ring spirocyclization.
Fig. 6: Synthesis of kadsuphilin N by 11-membered ring cyclization.

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Data availability

All data generated or analysed during this study, including characterization data for all compounds produced in this work, are included in this published article and its Supplementary Information files. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 1916278 (22), 1916279 (S17), 1916280 (8) and 2026509 (46). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

We thank T. Maris from the University of Montreal for help with X-ray crystallography and N. Moitessier and J. Plescia from McGill University for help with ozonolysis. Financial support was provided by the Natural Sciences and Engineering Research Council of Canada (Discovery Grant to J.-P.L.), the Fonds de Recherche du Québec Nature et Technologies (FRQNT) (Team Grant to J.-P.L.) and the FRQNT Center for Green Chemistry and Catalysis.

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  1. Department of Chemistry, McGill University, Montreal, Quebec, Canada

    Zheng Huang & Jean-Philip Lumb

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  1. Zheng Huang
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Contributions

Z.H. and J.-P.L. conceived and designed the experiments. Z.H. performed the experiments. Z.H. and J.-P.L. analysed the data. Z.H. and J.-P.L. co-wrote the manuscript.

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Correspondence to Jean-Philip Lumb.

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Supplementary information

Supplementary information

The Supplementary Information contains Supplementary Figs. 1–14, Discussion and Tables 1–12 associated with the manuscript, as well as procedural details for and characterization data of all newly prepared compounds, including their NMR spectra and, where appropriate, their X-ray data

Supplementary Data 1

Crystallographic data for compound 8. CCDC reference 1916280

Supplementary Data 2

Crystallographic data for compound 22. CCDC reference 1916278

Supplementary Data 3

Crystallographic data for compound 46. CCDC reference 2026509

Supplementary Data 4

Crystallographic data for compound S17. CCDC reference 1916279

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Huang, Z., Lumb, JP. Mimicking oxidative radical cyclizations of lignan biosynthesis using redox-neutral photocatalysis. Nat. Chem. 13, 24–32 (2021). https://doi.org/10.1038/s41557-020-00603-z

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