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Olefin functionalization/isomerization enables stereoselective alkene synthesis

Abstract

Despite tremendous efforts aimed at devising methods for stereoselective alkene synthesis, critical challenges are yet to be addressed. Direct access to a diverse range of 1-aryl(boryl)-1-methyl-functionalized tri- and tetrasubstituted trans alkenes, entities that are prevalent in many important molecules, through a catalytic manifold from readily available α-olefin substrates remains elusive. Here, we demonstrate that catalytic amounts of a non-precious N-heterocyclic carbene–Ni(I) complex in conjunction with a sterically bulky base promote site- and trans-selective union of monosubstituted olefins with a wide array of electrophilic reagents to deliver tri- and tetrasubstituted alkenes in up to 92% yield and >98% regio- and stereoselectivity. The protocol is amenable to the preparation of carbon- and heteroatom-substituted C=C bonds, providing distinct advantages over existing transformations. Utility is highlighted through concise stereoselective synthesis of biologically active compounds.

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Fig. 1: The importance of designing catalytic reactions that deliver stereodefined tri- and tetrasubstituted alkenes.
Fig. 2: Mechanistic and computational studies.
Fig. 3: Trans-selective synthesis of tri- and tetrasubstituted alkenes.
Fig. 4: Access to boron-containing olefins and application to synthesis of biologically active compounds.

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Data availability

All data are available from the corresponding authors upon reasonable request. Crystallographic data for the structure reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition number CCDC 2018464 (7d). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

This research was supported by the National University of Singapore Academic Research Fund Tier 1: R-143-000-A77-114 (M.J.K.) and by the National Institutes of Health grant no. R35GM137797 (O.G.). O.G. is grateful to the University of Maryland College Park for start-up funds and computational resources from UMD Deepthought2 and MARCC/BlueCrab HPC clusters and XSEDE (grant nos. CHE160082 and CHE160053). We thank G.K. Tan for X-ray crystallographic analysis.

Author information

Authors and Affiliations

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Contributions

C.-F.L. and H.W. contributed equally to this work and are listed in alphabetical order in the author list. C.-F.L., H.W. and H.Z. developed the method and carried out the mechanistic studies. R.T.M. carried out the DFT calculations. O.G. directed the DFT studies. M.J.K. directed the investigations and wrote the manuscript with revisions provided by the other authors.

Corresponding authors

Correspondence to Osvaldo Gutierrez or Ming Joo Koh.

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Peer review information Nature Catalysis thanks the anonymous reviewers for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Preliminary studies on the boron variant of the Ni-catalysed tandem reaction.

a, Control experiments revealed that borylation likely occurs, affording observed intermediate 11g′, prior to C=C bond migration. b, A tentative mechanistic pathway involving formation of a putative nickel-boryl species IX to promote boryl-Heck reaction. Under typical circumstances where catalytic amounts of LiOt-Bu were used, DMPU likely served as a hydride acceptor to afford the corresponding Ni-alkoxide VIII and turn over the catalytic cycle. In other instances, more base might be needed to regenerate the active Ni-tert-butoxide species (VIII, R = t-Bu). G, functional group; pin, pinacolato; DMPU, N,N′-dimethylpropyleneurea; IPr, 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene.

Supplementary information

Supplementary Information

Supplementary Tables 1 and 2, Figs. 1–4, Methods and References.

Supplementary Data 1

Crystallographic data for compound 7d.

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Liu, CF., Wang, H., Martin, R.T. et al. Olefin functionalization/isomerization enables stereoselective alkene synthesis. Nat Catal 4, 674–683 (2021). https://doi.org/10.1038/s41929-021-00658-2

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