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Cu-catalyzed enantioselective allylic alkylation with organolithium reagents


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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Figure 1: Pd- and Cu-catalyzed AAA methodologies.
Figure 2: Cu-catalyzed AAA using organolithium compounds; preferred chiral ligands for different combinations of allylic substrates and organolithium reagents.
Figure 3: Examples of Cu-catalyzed AAA reactions.
Figure 4: Examples of Cu-catalyzed AAA reactions.
Figure 5
Figure 6: Taking a solution of allyl halide with a syringe to transfer to the reaction vessel.
Figure 7
Figure 8
Figure 9
Figure 10
Figure 11: HPLC traces of phenacyl ester of (S)-Arundic acid 4.

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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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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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Correspondence to Ben L Feringa.

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The authors declare no competing financial interests.

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Hornillos, V., Guduguntla, S., Fañanás-Mastral, M. et al. Cu-catalyzed enantioselective allylic alkylation with organolithium reagents. Nat Protoc 12, 493–505 (2017).

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