Multisite modifications of arenes using ketones as removable handles enabled by Pd and norbornene cooperative catalysis | Nature Synthesis

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Natural products serve as crucial sources for new drugs and play an indispensable role in drug discovery. Late-stage functionalization of natural products is an efficient method for diversifying their structures, fine-tuning their biological properties and rapidly constructing molecular libraries. Polysubstituted arenes serve as structural cores in pharmaceuticals derived from natural products. However, programmable multisite arene modification remains a largely unmet challenge. Here, using commercially available and easy-to-synthesize aryl ketones as substrates, we present the programmable multifunctionalization of natural products via a palladium- and norbornene-catalysed Catellani-type reaction. Given the ease of installing an acyl group and using it as a relay, this protocol enables the incorporation of a variety of bioactive molecules into natural products via successive acylation and deacylation processes. Furthermore, this strategy was applied to the construction of a molecular library based on dehydroabietic acid. Multiple molecules with substantially increased activity were obtained through antimicrobial activity screening.

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The data supporting the findings of this study are available within the article and its Supplementary Information files. The crystallographic data for compound 5u have been deposited at the Cambridge Crystallographic Data Centra (CCDC 2371740). These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif.

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L.L. thanks the National Key Research and Development Program of China (2023YFD1800102). H.-X.D. and Y.Y. thank the National Natural Science Foundation of China (22171276, 21920102003). H.-X.D. and H.X. thank the Science and Technology Commission of Shanghai Municipality (17JC1405000, 21ZR1475400, 23ZR1474400 and 18431907100). H.-X.D. thanks the Program of Shanghai Academic Research Leader (19XD1424600). X.W. and Z.-Y.W. thank the Shanghai Postdoctoral Excellence Program (2023706 and 2022699) for financial support.

These authors contributed equally: Kai-Liang Tao, Xing Wang, Huan Liu.

School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China

Kai-Liang Tao, Wen-Qing Chen, Yi Sun, Yang Ye & Hui-Xiong Dai

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

Xing Wang, Huan Liu, Yun-Qian Zhang, Yu-Xi Li, Zhen-Yu Wang, Yang Ye, Hui Xu & Hui-Xiong Dai

School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China

Huan Liu & Lefu Lan

University of Chinese Academy of Sciences, Beijing, China

Huan Liu, Yun-Qian Zhang, Yu-Xi Li, Yang Ye & Hui-Xiong Dai

The First Affiliated Hospital of Anhui Medical University, Hefei, China

Lefu Lan

State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China

Hui-Xiong Dai

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K.-L.T. and X.W. discovered and developed these reactions. W.-Q.C., Y.S., Y.-Q.Z., Y.-X.L., Z.-Y.W. and H.X. helped perform the experiments determing the substrates’ scope and synthetic applications. H.L. and L.L. designed and conducted the antimicrobial evaluation. H.-X.D. conceived the concept and directed the project. H.-X.D. and H.X. prepared this paper. Y.Y. and H.-X.D. directed the research.

Correspondence to Hui Xu, Lefu Lan or Hui-Xiong Dai.

The authors declare no competing interests.

Nature Synthesis thanks the anonymous reviewers for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Tables 1–23, material chart, discussion, antimicrobial evaluation, experimental procedures and NMR spectra.

Crystallographic data for compound 5u, CCDC 2371740.

Structure factors for compound 5u, CCDC 2371740.

Reflection intensities for compound 5u, CCDC 2371740.

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Tao, KL., Wang, X., Liu, H. et al. Multisite modifications of arenes using ketones as removable handles enabled by Pd and norbornene cooperative catalysis. Nat. Synth (2024). https://doi.org/10.1038/s44160-024-00673-8

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Received: 10 June 2024

Accepted: 24 September 2024

Published: 25 October 2024

DOI: https://doi.org/10.1038/s44160-024-00673-8

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