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Merging allylic C–H bond activation and C–C bond cleavage en route to the formation of a quaternary carbon stereocenter in acyclic systems

Nature Protocols volume 12, pages 74–87 (2017)Cite this article

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Abstract

This protocol describes a diastereoselective approach for the synthesis of complex molecular architectures containing two stereogenic centers in a 1,4 relationship, one of which being an all-carbon quaternary stereogenic center. Such molecules could be intermediates in the synthesis of steroids, for example. Conceived as a single-flask synthetic sequence from ω-ene cyclopropanes, the protocol involves a concerted allylic C–H and C–C bond activation promoted by the Negishi reagent (Cp2Zr(η2-butene)). This zirconium-promenade-based procedure affords bifunctionalized products in high diastereomeric ratios after reaction of ω-ene cyclopropanes with the Negishi complex, followed by a thermal treatment and sequential addition of two different electrophiles. The method proves to be particularly efficient when carbonyl compounds are used as first electrophiles and hydrogen or elemental halides are used as second electrophiles. In addition, it offers the opportunity to create new C–C bonds via remote functionalization of a (sp3)–C–H bond, a result of a copper or copper/palladium transmetalation step that extends the scope of the process to alkyl, acyl and aromatic halide compounds as second electrophiles. The typical described protocol allows the synthesis of the highly diastereo-enriched 2-((1R*,2S*)-2-butyl-2 propylcyclopropyl)ethanol and may provide a new entry to access complex molecular segments of natural products such as steroids or C30 botryococcene. It requires a simple reaction setup and takes ∼18.5 h to run the reaction and 2 h for isolation and purification.

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Figure 1: The zirconium-promenade-based strategy used for the synthesis of multifunctionalized acylic molecules (4) of synthetic interest from diastereopure ω-ene cyclopropane (1).
Figure 2: Positive impact of the addition of THF and subsequent thermal treatment in the diastereoselectivity of the transformation providing 4a from 1a.
Figure 3: Scope and limitations of the process regarding electrophiles E1–X and E2–X.
Figure 4: Appearance of the (E,Z)-allyl-alkylzirconocene complex suspension in Et2O.
Figure 5: Appearance of the THF/Et2O (80:20, (vol/vol)) solution of the (E,Z)-allyl-alkylzirconocene complex.
Figure 6: Sequence relative to the change of the thermometer.
Figure 7: Change of color observed during the isomerization of the (Z)-allyl-alkylzirconocene species into its E isomer.
Figure 8: Immersion of the alkoxy-alkylzirconocene species in an NaCl/ice bath.
Figure 9: Typical column chromatography used for purification.

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Acknowledgements

This research was supported by the European Research Council under the European Community's Seventh Framework Program (ERC grant agreement no. 338912). We thank Z. Nairoukh and R. Liu for their assistance and particularly for taking the pictures.

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  1. The Mallat Family Laboratory of Organic Chemistry, Schulich Faculty of Chemistry and the Lise Meitner-Minerva Center for Computational Quantum Chemistry, Technion-Israel Institute of Technology, Haifa, Israel

    Alexandre Vasseur & Ilan Marek

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A.V. planned, conducted and analyzed the experiments. I.M. conceived and directed the project, and wrote the manuscript, with contributions from A.V. Both authors contributed to discussions.

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Correspondence to Ilan Marek.

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Vasseur, A., Marek, I. Merging allylic C–H bond activation and C–C bond cleavage en route to the formation of a quaternary carbon stereocenter in acyclic systems. Nat Protoc 12, 74–87 (2017). https://doi.org/10.1038/nprot.2016.161

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