Cu-catalyzed enantioselective allylic alkylation with organolithium reagents

Journal name:
Nature Protocols
Volume:
12,
Pages:
493–505
Year published:
DOI:
doi:10.1038/nprot.2016.179
Published online

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.

At a glance

Figures

  1. Pd- and Cu-catalyzed AAA methodologies.
    Figure 1: Pd- and Cu-catalyzed AAA methodologies.
  2. Cu-catalyzed AAA using organolithium compounds; preferred chiral ligands for different combinations of allylic substrates and organolithium reagents.
    Figure 2: Cu-catalyzed AAA using organolithium compounds; preferred chiral ligands for different combinations of allylic substrates and organolithium reagents.

    (a) General scheme for reactions of allylic substrates with organolithium compounds. (b) Reaction of allyl bromides with primary alkyllithium reagents using Taniaphos. (c) Reaction of allyl bromides, chlorides or ethers with primary alkyllithium reagents using (S,S,S)-L2. (d) Reaction of allyl chlorides with secondary alkyllithium reagents using (S,R,R)-L3. (e) Reaction of trisubstituted (E)-allyl bromides with primary alkyllithium reagents using (S,R,R)-L4. (f) Reaction of trisubstituted (Z)-allyl bromides with primary alkyllithium reagents using (R,R,R)-L5. Red color: leaving groups; blue color: alkyl groups arising from the organolithium reagents: if R2 = H, L1, L2 or L3 is used. If R2 = CH3, L4 or L5 is used.

  3. Examples of Cu-catalyzed AAA reactions.
    Figure 3: Examples of Cu-catalyzed AAA reactions.

    (Top) Reaction of cinnamyl bromide with n-BuLi. (Center) Reaction of 1b with MeLi. (Bottom) Reaction using a highly sensitive ester-substituted allylic substrate 1c with n-BuLi

  4. Examples of Cu-catalyzed AAA reactions.
    Figure 4: Examples of Cu-catalyzed AAA reactions.

    (Top) Cu-catalyzed AAA involving a secondary alkyllithium compound with an allyl chloride. (Bottom) Enantioselective copper/phosphoramidite-catalyzed synthesis of quaternary carbon atoms using n-hexyllithium.

  5. Example of copper-catalyzed AAA of an allyl ether with organolithium reagents.
    Figure 5: Example of copper-catalyzed AAA of an allyl ether with organolithium reagents.
  6. Taking a solution of allyl halide with a syringe to transfer to the reaction vessel.
    Figure 6: Taking a solution of allyl halide with a syringe to transfer to the reaction vessel.
  7. Reaction vessel immersed in the cooling bath at -80 [deg]C.
    Figure 7: Reaction vessel immersed in the cooling bath at −80 °C.
  8. Taking a solution of commercial organolithium compound with a syringe under a N2 atmosphere.
    Figure 8: Taking a solution of commercial organolithium compound with a syringe under a N2 atmosphere.
  9. Preparing a solution of the organolithium compound.
    Figure 9: Preparing a solution of the organolithium compound.
  10. Adding the organolithium solution using a syringe pump.
    Figure 10: Adding the organolithium solution using a syringe pump.
  11. HPLC traces of phenacyl ester of (S)-Arundic acid 4.
    Figure 11: HPLC traces of phenacyl ester of (S)-Arundic acid 4.

    (a) The trace for the racemic ester. (b) The trace for the enantiopure ester. mAU, milliabsorbance units; Pk, peak.

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Author information

  1. 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.).

    • Martín Fañanás-Mastral &
    • Pieter H Bos

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

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.

Competing financial interests

The authors declare no competing financial interests.

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