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Enantioselective dearomative prenylation of indole derivatives

Nature Catalysis volume 1, pages 601–608 (2018)Cite this article

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Abstract

Prenylation is a ubiquitous process common to almost all living organisms, and a key transformation in organic synthesis. Dearomative prenylation reactions of tryptophan derivatives lead to various prenylated indoline alkaloids with diverse biological activities. However, enantioselective dearomative prenylations without a pre-installed stereogenic centre in the substrate have not been reported. Here, we show that a small molecule-based catalytic system derived from a commercially available palladium precursor and a chiral phosphoramidite ligand (allylphos) can catalyse the enantioselective dearomative prenylation of indole derivatives, which tolerates a much broader substrate scope than those of known enzymatic dearomative prenylation processes. Enantioselective dearomative geranylation and farnesylation reactions also proceed smoothly under the standard conditions. The concise total or formal syntheses of a series of natural products can be realized using this catalytic system. The mechanistic investigations provide deep insights for the further design of chiral ligands and catalysts for asymmetric reactions.

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Fig. 1: Structures and syntheses of prenylated molecules.
Fig. 2: Substrate scope of the dearomative prenylation reaction.
Fig. 3: Total syntheses of (−)-flustramine B, pseudophrynaminol and mollenine A.
Fig. 4: Substrate scope for the cascade approach towards the preparation of prenylated indole alkaloids.
Fig. 5: Mechanistic studies.

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Acknowledgements

We thank the National Key Research and Development Program of China (2016YFA0202900), National Basic Research Program of China (973 Program 2015CB856600), National Natural Science Foundation of China (21332009 and 21572252), Strategic Priority Research Program (XDB20000000) and Key Research Program of Frontier Sciences (QYZDYSSWSLH012) of the Chinese Academy of Sciences, and the Science and Technology Commission of Shanghai Municipality (16XD1404300) for generous financial support, and X. Leng and J. Sun (SIOC) for X-ray crystallographic analysis.

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  1. These authors contributed equally: Hang-Fei Tu, Xiao Zhang.

Authors and Affiliations

  1. State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

    Hang-Fei Tu, Xiao Zhang, Chao Zheng, Min Zhu & Shu-Li You

  2. Collaborative Innovation Center of Chemical Science and Engineering, Tianjin, China

    Shu-Li You

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Contributions

H.-F.T. and X.Z. were involved in the discovery, design and development of the enantioselective dearomative prenylation of indole derivatives. X.Z. synthesized allylphos. H.-F.T. performed the total syntheses of the natural products. H.-F.T. and C.Z. performed the mechanistic studies. M.Z. was involved in the synthesis of substrates. S.-L.Y. conceived and supervised the project. H.-F.T., C.Z. and S.-L.Y. wrote the manuscript with revisions suggested by all authors.

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Correspondence to Shu-Li You.

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Supplementary information

Supplementary Information

Supplementary Methods, Supplementary Figures 1–3, Supplementary Tables 1–17, Supplementary References

Crystallographic data

CIF for compound C1; CCDC reference: 1822391

Crystallographic data

CIF for compound C2; CCDC reference: 1822392

Crystallographic data

CIF for compound 22; CCDC reference: 1822393

Crystallographic data

CIF for compound (R)-L1; CCDC reference: 1822394

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Tu, HF., Zhang, X., Zheng, C. et al. Enantioselective dearomative prenylation of indole derivatives. Nat Catal 1, 601–608 (2018). https://doi.org/10.1038/s41929-018-0111-8

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