Abstract

This protocol describes a method for the catalytic enantioselective synthesis of tertiary and quaternary carbon stereogenic centers, which are widely present in pharmaceutical and natural products. The method is based on the direct reaction between organolithium compounds, which are cheap, readily available and broadly used in chemical synthesis, and allylic electrophiles, using chiral copper catalysts. The methodology involves the asymmetric allylic alkylation (AAA) of allyl bromides, chlorides and ethers with organolithium compounds using catalyst systems based on Cu–Taniaphos and Cu–phosphoramidites. The protocol contains a complete description of the reaction setup, a method based on 1H-NMR, gas chromatography–mass spectrometry (GC—MS) and chiral HPLC for assaying the regioselectivity and enantioselectivity of the product, and isolation, purification and characterization procedures. Six Cu-catalyzed AAA reactions between different organolithium reagents and allylic systems are detailed in the text as representative examples of these procedures. These reactions proceed within 1–10 h, depending on the nature of the allylic substrate (bromide, chloride, or ether and disubstituted or trisubstituted) or the chiral ligand used (Taniaphos or phosphoramidite). However, the entire protocol, including workup and purification, generally requires an additional 4–7 h to complete.

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Acknowledgements

This work was supported financially by the European Research Council (Advanced Investigator Grant no. 227897 to B.L.F.). The Netherlands Organization for Scientific Research (NWO-CW); funding from the Ministry of Education, Culture and Science (Gravitation program 024.001.035); The Royal Netherlands Academy of Arts and Sciences (KNAW); and NRSC-Catalysis are gratefully acknowledged.

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Author notes

    • Martín Fañanás-Mastral
    •  & Pieter H Bos

    Present addresses: Department of Organic Chemistry and Center for Research in Biological Chemistry and Molecular Materials (CIQUS), University of Santiago de Compostela, Santiago de Compostela, Spain (M.F.-M.); Department of Biological Sciences, Columbia University, New York, New York, USA (P.H.B.).

Affiliations

  1. Stratingh Institute for Chemistry, Faculty of Mathematics and Natural Sciences, University of Groningen, Groningen, The Netherlands.

    • Valentín Hornillos
    • , Sureshbabu Guduguntla
    • , Martín Fañanás-Mastral
    • , Manuel Pérez
    • , Pieter H Bos
    • , Alena Rudolph
    • , Syuzanna R Harutyunyan
    •  & Ben L Feringa

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Contributions

V.H. and B.L.F. wrote the manuscript. All authors contributed to designing the experiments, analyzing the data and editing the manuscript. B.L.F. guided the research.

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The authors declare no competing financial interests.

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Correspondence to Ben L Feringa.

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https://doi.org/10.1038/nprot.2016.179

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