Catalytic enantioselective 1,6-conjugate additions of propargyl and allyl groups

Abstract

Conjugate (or 1,4-) additions of carbanionic species to α,β-unsaturated carbonyl compounds are vital to research in organic and medicinal chemistry, and there are several chiral catalysts that facilitate the catalytic enantioselective additions of nucleophiles to enoates1. Nonetheless, catalytic enantioselective 1,6-conjugate additions are uncommon, and ones that incorporate readily functionalizable moieties, such as propargyl or allyl groups, into acyclic α,β,γ,δ-doubly unsaturated acceptors are unknown2. Chemical transformations that could generate a new bond at the C6 position of a dienoate are particularly desirable because the resulting products could then be subjected to further modifications. However, such reactions, especially when dienoates contain two equally substituted olefins, are scarce3 and are confined to reactions promoted by a phosphine–copper catalyst (with an alkyl Grignard reagent4,5, dialkylzinc or trialkylaluminium compounds6,7), a diene–iridium catalyst (with arylboroxines)8,9, or a bisphosphine–cobalt catalyst (with monosilyl-acetylenes)10. 1,6-Conjugate additions are otherwise limited to substrates where there is full substitution at the C4 position11. It is unclear why certain catalysts favour bond formation at C6, and—although there are a small number of catalytic enantioselective conjugate allyl additions12,13,14,15—related 1,6-additions and processes involving a propargyl unit are non-existent. Here we show that an easily accessible organocopper catalyst can promote 1,6-conjugate additions of propargyl and 2-boryl-substituted allyl groups to acyclic dienoates with high selectivity. A commercially available allenyl–boron compound or a monosubstituted allene may be used. Products can be obtained in up to 83 per cent yield, >98:2 diastereomeric ratio (for allyl additions) and 99:1 enantiomeric ratio. We elucidate the mechanistic details, including the origins of high site selectivity (1,6- versus 1,4-) and enantioselectivity as a function of the catalyst structure and reaction type, by means of density functional theory calculations. The utility of the approach is highlighted by an application towards enantioselective synthesis of the anti-HIV agent (−)-equisetin.

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Figure 1: Possible conjugate addition pathways, the initial experiment and a plausible catalytic cycle.
Figure 2: Catalytic enantioselective 1,6-propargyl conjugate additions.
Figure 3: Catalytic diastereo- and enantioselective multicomponent 1,6-conjugate addition of 2-B(pin)-substituted allyl moieties.
Figure 4: Mechanistic considerations.
Figure 5: Functionalizations and demonstration of utility.

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Acknowledgements

This research was supported by the United States National Institutes of Health, Institute of General Medical Sciences (GM-47480) and the National Science Foundation (CHE-1362763). We are grateful to A. Iimuro for experimental assistance.

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Contributions

F.M. and X.L. were involved in the discovery and development of the optimal catalysts, the corresponding methods and their various applications; S.T. and Y.S. performed the computational investigations, developed the models for the observed levels and patterns in selectivity; X.S. developed efficient routes for preparation of the dienoates. A.H.H. directed the investigations and wrote the manuscript with revisions provided by the other authors.

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Correspondence to Amir H. Hoveyda.

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The authors declare no competing financial interests.

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Meng, F., Li, X., Torker, S. et al. Catalytic enantioselective 1,6-conjugate additions of propargyl and allyl groups. Nature 537, 387–393 (2016). https://doi.org/10.1038/nature19063

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