Cross-coupling of two alkyl fragments is an efficient method to produce organic molecules rich in sp3-hybridized carbon centres, which are attractive candidate compounds in drug discovery. Enantioselective C(sp3)–C(sp3) coupling is challenging, especially of alkyl electrophiles without an activating group (aryl, vinyl, carbonyl). Here, we report a strategy based on nickel hydride addition to internal olefins followed by nickel-catalysed alkyl–alkyl coupling. This strategy enables the enantioselective cross-coupling of non-activated alkyl halides with alkenyl boronates to produce chiral alkyl boronates. Employing readily available and stable olefins as pro-chiral nucleophiles, the coupling proceeds under mild conditions and exhibits broad scope and high functional-group tolerance. Applications for the functionalization of natural products and drug molecules, as well as the synthesis of chiral building blocks and a key intermediate to (S)-(+)-pregabalin, are demonstrated.
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Crystallographic data for 3e′ and 4g′ have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2011678 (3e′) and CCDC 1971802 (4g′). Copies of the data can be obtained free of charge via www.ccdc.cam.ac.uk. All other data supporting the findings of this study, including experimental procedures and compound characterization, NMR, HPLC and X-ray analyses are available within the Article and its Supplementary Information.
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Supplementary information including optimization of reaction conditions (Supplementary Tables 1–6), general procedures, functional group transformations, mechanistic investigations, crystallography details, NMR spectra of compounds, references.
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Bera, S., Mao, R. & Hu, X. Enantioselective C(sp3)–C(sp3) cross-coupling of non-activated alkyl electrophiles via nickel hydride catalysis. Nat. Chem. 13, 270–277 (2021). https://doi.org/10.1038/s41557-020-00576-z
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