Enantioselective C–H functionalization of bicyclo[1.1.1]pentanes

Abstract

Bicyclo[1.1.1]pentanes (BCPs) are highly strained carbocycles that have fascinated the chemical community for decades because of their unique structure. Despite the immense interest in this scaffold and extensive synthetic efforts, the construction of BCP derivatives still relies substantially on the manipulation of dimethyl bicyclo[1.1.1]pentane-1,3-dicarboxylate. Furthermore, BCPs that contain a proximal stereocentre are underrepresented in the literature and their generation requires stoichiometric chiral auxiliaries. Here we explore enantioselective C–H functionalization of BCPs as a conceptually innovative strategy that provides access to chiral substituted BCPs. For this purpose, enantioselective intermolecular sp3 C–H insertion reactions of donor/acceptor diazo compounds catalysed by the chiral dirhodium complex, Rh2(TCPTAD)4, were employed to forge new C–C bonds at the tertiary position of a variety of BCPs. This work also establishes that highly strained molecules can undergo direct C–H insertion without losing the integrity of their carbocyclic framework.

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Fig. 1: Applications and synthesis of BCPs related to the current work.
Fig. 2: Structures and applications of other dirhodium catalysts for site-selective functionalization of unactivated C–H bonds.
Fig. 3: Evaluation of the optimization catalysts for C–H functionalization of BCPs.
Fig. 4: Scope of the reaction with respect to substrates and aryldiazoacetates.
Fig. 5: Synthesis of analogues of known biologically active compounds and a comparison of solubility and microsomal stability.
Fig. 6: Computational analysis of C–H insertion into BCPs.

Data availability

Crystallographic data for the structures reported in this Letter have been deposited at the Cambridge Crystallographic Data Centre, under deposition nos. 1906391 and 1906395. Copies of the data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif. Complete experimental procedures and compound characterization data are available in the Supplementary Information; any other data is available from the authors on request.

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Acknowledgements

This work was supported by the NSF under the Center for C–H Functionalization (grant no. CHE-1700982) and the NIGMS of the NIH under award nos. F32GM130020 (Z.J.G.) and F32GM122218 (J.N.S.). The content is solely the responsibility of the authors and does not necessarily represent the views of the NSF or NIH. Additional financial support was provided by Novartis. Instrumentation used in this work was supported by the National Science Foundation (grant nos. CHE 1531620 and CHE 1626172). Computational resources were provided by the UCLA Institute for Digital Research and Education (IDRE). We wish to thank the members of the NSF Center for C–H Functionalization (grant no. CHE-1700982), especially J.Du. Bois . and N. Chiappini, for helpful discussions regarding this work. We thank J. Bacsa and T. Pickel at the Emory X-ray Crystallography Facility for the X-ray structural analysis. We thank S. Skolnik and J. Poirier at the Novartis Institutes for BioMedical Research for carrying out solubility and logD measurements.

Author information

Z.J.G. performed the synthetic experiments. J.N.S. and K.N.H. conducted the computational studies. H.M. and C.G. evaluated the biologically relevant compounds and conducted the comparison studies. Z.J.G. and H.M.L.D. designed and analysed the synthetic experiments and prepared the manuscript. All authors contributed to the final draft of the manuscript.

Correspondence to Huw M. L. Davies.

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Competing interests

H.M.L.D. is a named inventor on a patent entitled ‘Dirhodium catalyst compositions and synthetic processes related thereto’ (US 8,974,428, issued 10 March 2015). The other authors declare no competing interests.

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Supplementary information

Supplementary Information

Supplementary Methods, Figs. 1–3, Tables 1–16 and references.

Compound 8d

Crystallographic Data for Compound 8d.

Compound 29

Crystallographic Data for Compound 29.

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Garlets, Z.J., Sanders, J.N., Malik, H. et al. Enantioselective C–H functionalization of bicyclo[1.1.1]pentanes. Nat Catal (2020). https://doi.org/10.1038/s41929-019-0417-1

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