Highly enantioselective rhodium-catalyzed cross-coupling of boronic acids and racemic allyl halides

Abstract

Although Csp2–Csp2 Suzuki–Miyaura couplings (SMCs) are widely used in small-molecule synthesis, related methods that allow the incorporation of Csp3-hybridized coupling partners, particularly in an asymmetric manner, are less developed. This protocol describes catalytic asymmetric SMC reactions that provide access to enantiomerically enriched cyclic allylic products. The method couples racemic allyl halide starting materials with sp2-hybridized boronic acid derivatives and is compatible with heterocyclic coupling partners. These reactions are catalyzed by a rhodium–ligand complex and typically display very high levels of enantioselectivity (>95% enantiomeric excess (ee)). In this protocol, we detail a procedure using a dihydropyridine-derived allyl chloride for the synthesis of (−)-(S)-tert-butyl-3-(4-bromophenyl)-3,6-dihydropyridine-1(2H)-carboxylate, an intermediate in the synthesis of the anticancer drug niraparib. This procedure affords 1.17 g (86% yield) of the coupling product with 96% ee. The initial experimental setup of the reaction takes 45–50 min, and the reaction is complete within 4–5 h.

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Fig. 1: SMC: from flat to 3D molecules.
Fig. 2: Application of the Rh-catalyzed asymmetric SMC in drug synthesis.
Fig. 3
Fig. 4: Rh complex.
Fig. 5: Preparation of the boronic ester and allyl halide solutions.
Fig. 6: Reaction setup.
Fig. 7: View of the KMNO4-stained TLC plate used to examine fractions obtained by silica gel flash column chromatography.

Data availability

All data supporting this protocol are available within the article and in the Supplementary Information file.

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Acknowledgements

Financial support from the UK Engineering and Physical Sciences Research Council (EP/N022246/1) is gratefully acknowledged. J.G. thanks the European Union’s Horizon 2020 research and innovation program for a Marie Skłodowska-Curie Fellowship (GA 700108). L.v.D. is grateful to the Engineering and Physical Sciences Research Council (EPSRC) Centre for Doctoral Training in Synthesis for Biology and Medicine (EP/L015838/1) for a studentship, generously supported by AstraZeneca, Diamond Light Source, Defence Science and Technology Laboratory, Evotec, GlaxoSmithKline, Janssen, Novartis, Pfizer, Syngenta, Takeda, UCB and Vertex. F.W.G. is grateful to the National Research Fund, Luxembourg, for an AFR PhD grant (11588566), the EPSRC Doctoral Training Partnership (DTP) for a studentship (EP/N509711/1) and Vertex Pharmaceuticals for financial support.

Author information

J.G., L.v.D. and F.W.G. conducted the experiments. All authors designed the experiments, analyzed the data and edited the manuscript. S.P.F. guided the research. J.G. wrote the manuscript. All authors contributed to discussions.

Correspondence to Stephen P. Fletcher.

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Competing interests

Oxford University Innovation has filed a patent application (PCT/GB2016/051612) with S.P.F. named as an inventor. The remaining authors declare no competing interests.

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Peer review information Nature Protocols thanks David Blakemore and Choonhong Tan for their contribution to the peer review of this work.

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Key references using this protocol

Sidera, M. & Fletcher, S. P. Nat. Chem. 7, 935–939 (2015): https://www.nature.com/articles/nchem.2360

Schäfer, P., Palacin, T., Sidera, M. & Fletcher, S. P. Nat. Commun. 8, 15762 (2017): https://www.nature.com/articles/ncomms15762

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González, J., van Dijk, L., Goetzke, F.W. et al. Highly enantioselective rhodium-catalyzed cross-coupling of boronic acids and racemic allyl halides. Nat Protoc 14, 2972–2985 (2019) doi:10.1038/s41596-019-0209-8

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