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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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.
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.
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