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Catalytic enantioselective desymmetrizing functionalization of alkyl radicals via Cu(i)/CPA cooperative catalysis

Nature Catalysis volume 3, pages 401–410 (2020)Cite this article

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Abstract

In contrast with abundant methods for the asymmetric functionalization of alkyl radicals to generate stereogenic centres at reaction sites, catalytic enantioselective desymmetrizing functionalization of alkyl radicals for forging multiple stereocentres—including positions that are remote from the reaction sites—with both high enantio- and diastereoselectivity remains largely unexplored. The major challenge for such reactions is the high reactivity of open-shell alkyl radicals. Here, we describe a strategy to address this challenge: the use of Cu(ii) phosphate to immediately associate with the in situ-generated reactive alkyl radical species, creating a compact and confined chiral microenvironment for effective stereocontrol. With this strategy, we have developed a general and efficient catalytic enantioselective desymmetrizing functionalization of alkene-tethered 1,3-diols. It provides various tetrahydrofurans and analogues bearing multiple stereocentres with remarkably high levels of enantio- and diastereocontrol. Density functional theory calculations and mechanistic experiments revealed a reaction mechanism involving an enantiodetermining outer-sphere C–O bond formation step.

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Fig. 1: Motivation and development of catalytic enantioselective desymmetrizing functionalization of alkyl radicals.
Fig. 2: Substrate scope to access two congested quaternary stereocentres with different radicals.
Fig. 3: Mechanistic studies of the catalytic enantioselective desymmetrizing functionalization reactions involving radical species.
Fig. 4: DFT-computed free energy profile of the favoured C–O bond formation process.
Fig. 5: DFT-computed enantioselectivity-determining C–O bond formation transition states.

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Data availability

Data relating to the materials and methods, optimization studies, experimental procedures, mechanistic studies and DFT calculations, high-performance liquid chromatography spectra, NMR spectra and mass spectrometry are available in the Supplementary Information. Crystallographic data for compounds 3A′, 6 and 8A are available free of charge from the Cambridge Crystallographic Data Centre under reference numbers 1916711 (3A′), 1922870 (6) and 1916714 (8A). All other data are available from the authors upon reasonable request.

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Acknowledgements

Financial support from the National Natural Science Foundation of China (21722203 and 21831002 to X.-Y.L., 21702182 and 2187308 to X.H. and 21801116 to Z.-L.L.), Shenzhen Special Funds (JCYJ20170412152435366 and JCYJ20170307105638498 to X.-Y.L.), Shenzhen Nobel Prize Scientists Laboratory Project (C17783101 to X.-Y.L.) and ‘Fundamental Research Funds for the Central Universities’ (2019QNA3009, X.H.) are gratefully acknowledged. Calculations were performed on the high-performance computing system at the Department of Chemistry, Zhejiang University.

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  1. These authors contributed equally: Yong-Feng Cheng, Ji-Ren Liu, Qiang-Shuai Gu, Zhang-Long Yu.

Authors and Affiliations

  1. Shenzhen Grubbs Institute, Southern University of Science and Technology, Shenzhen, China

    Yong-Feng Cheng, Zhang-Long Yu, Jian Wang, Jun-Qian Bian, Han-Tao Wen, Xiao-Jing Wang & Xin-Yuan Liu

  2. Department of Chemistry, Southern University of Science and Technology, Shenzhen, China

    Yong-Feng Cheng, Qiang-Shuai Gu, Zhang-Long Yu, Jian Wang, Zhong-Liang Li, Jun-Qian Bian, Han-Tao Wen, Xiao-Jing Wang & Xin-Yuan Liu

  3. Department of Chemistry, Zhejiang University, Hangzhou, China

    Ji-Ren Liu & Xin Hong

  4. Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen, China

    Qiang-Shuai Gu & Zhong-Liang Li

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Contributions

X.-Y.L. conceived of and supervised the project. Y.-F.C., Z.-L.Y., J.W., Q.-S.G. and Z.-L.L. designed the experiments and analysed the data. Y.-F.C., Z.-L.Y., J.W., J.-Q.B., H.-T.W. and X.-J.W. performed the experiments. J.-R.L. and X.H. designed and performed the DFT calculations. X.-Y.L., X.H. and Q.-S.G. wrote the paper. All authors discussed the results and commented on the manuscript.

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Correspondence to Xin-Yuan Liu.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–9, Tables 1–4, methods and references.

Supplementary Data 1

Cartesian coordinates for calculated species.

Compound 3A′

Crystallographic data for compound 3A′.

Compound 6

Crystallographic data for compound 6.

Compound 8A

Crystallographic data for compound 8A.

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Cheng, YF., Liu, JR., Gu, QS. et al. Catalytic enantioselective desymmetrizing functionalization of alkyl radicals via Cu(i)/CPA cooperative catalysis. Nat Catal 3, 401–410 (2020). https://doi.org/10.1038/s41929-020-0439-8

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