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Building C(sp3)-rich complexity by combining cycloaddition and C–C cross-coupling reactions


Prized for their ability to rapidly generate chemical complexity by building new ring systems and stereocentres1, cycloaddition reactions have featured in numerous total syntheses2 and are a key component in the education of chemistry students3. Similarly, carbon–carbon (C–C) cross-coupling methods are integral to synthesis because of their programmability, modularity and reliability4. Within the area of drug discovery, an overreliance on cross-coupling has led to a disproportionate representation of flat architectures that are rich in carbon atoms with orbitals hybridized in an sp2 manner5. Despite the ability of cycloadditions to introduce multiple carbon sp3 centres in a single step, they are less used6. This is probably because of their lack of modularity, stemming from the idiosyncratic steric and electronic rules for each specific type of cycloaddition. Here we demonstrate a strategy for combining the optimal features of these two chemical transformations into one simple sequence, to enable the modular, enantioselective, scalable and programmable preparation of useful building blocks, natural products and lead scaffolds for drug discovery.

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Financial support for this work was provided by Leo Pharma and the US National Institutes of Health (NIH)/National Institute of General Medical Sciences (NIGMS; grant GM-118176). Shenzhen Haiwei M&E Co. Ltd supported a fellowship to T.–G.C.; the Uehara Memorial Foundation supported a research fellowship to S.A.; the Basque Government supported a fellowship to I.B.; Nankai University supported Y.L. and C.B.; the University of Science and Technology of China supported J.T.; and the Swiss National Science Foundation supported an Early Postdoc Mobility Fellowship to D.K. We thank L. Buzzetti for the synthesis of intermediates; D.-H. Huang and L. Pasternack for assistance with nuclear magnetic resonance spectroscopy; and A.L. Rheingold, M. Gembicky and C.E. Moore for X-ray crystallographic analysis.

Author information

T.–G.C., T.Q. and P.S.B. conceived the work. T.–G.C., L.M.B., Y.L., J.T., D.K., I.B., S.A., C.B., J.S.C., M.S., H.F., F.G.F., H.-W.C., L.H., T.Q. and P.S.B. designed the experiments and analysed the data. T.–G.C., L.M.B., Y.L., J.T., D.K., I.B., S.A. and C.B. performed the experiments. M.S., H.F., F.G.F., H.-W.C. and L.H. performed the experiments described in Fig. 3f. P.S.B. wrote the manuscript. T.–G.C., L.M.B., Y.L., J.T., D.K., I.B., S.A., C.B., J.S.C. and T.Q. assisted in writing and editing the manuscript.

Competing interests

M.S., H.F., F.G.F., H.-W.C. and L.H. are employees of Eisai Inc. This work was part-funded by Leo Pharma.

Correspondence to Phil S. Baran.

Extended data figures and tables

Extended Data Fig. 1 Complete substrate scope of [4+2] cycloadditions/cross-couplings.

See Supplementary Information for synthetic details. R1, R2 = (Het)Aryl, alkyl, alkenyl, alkynyl. X-ray structure data are available for compounds 11, 19, 23, 25, 28, 44, 45 and 49.

Extended Data Fig. 2 Complete substrate scope of [3+2], [2+2] and [2+1] sections.

See Supplementary Information for synthetic details. R1, R2 = (Het)Aryl, alkyl, alkenyl, alkynyl. X-ray structure data are available for compounds C2 and 65.

Supplementary information

Supplementary Information

This file contains Supplementary Text and Data – see contents pages for details.

Supplementary Data

This file contains NMR Spectra data.

Supplementary Data

This zipped file contains the crystallographic data files for the compounds used.

Supplementary Data

This zipped file contains the checkcif files for the compounds used.

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Further reading

Fig. 1: Combining the logic of cycloaddition and C–C cross-coupling.
Fig. 2: Substrate scope of combining cycloaddition and C–C cross-coupling.
Fig. 3: Applications of combining cycloaddition and C–C cross-coupling.
Extended Data Fig. 1: Complete substrate scope of [4+2] cycloadditions/cross-couplings.
Extended Data Fig. 2: Complete substrate scope of [3+2], [2+2] and [2+1] sections.


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