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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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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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.
The authors declare no competing interests.
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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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