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 _sp_3

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DIFUNCTIONALIZATION OF BICYCLO[1.1.0]BUTANES ENABLED BY MERGING C−C CLEAVAGE AND RUTHENIUM-CATALYSED REMOTE C−H ACTIVATION Article Open access 17 February 2025 ASYMMETRIC SYNTHESIS OF

ATROPISOMERS FEATURING CYCLOBUTANE BORONIC ESTERS FACILITATED BY RING-STRAINED B-ATE COMPLEXES Article Open access 30 December 2024 ENANTIOSELECTIVE SYNTHESIS OF 2-SUBSTITUTED

BICYCLO[1.1.1]PENTANES VIA SEQUENTIAL ASYMMETRIC IMINE ADDITION OF BICYCLO[1.1.0]BUTANES AND SKELETAL EDITING Article 28 January 2025 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

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bicyclo[1.1.1]pentyl-1 derivatives. _J. Org. Chem._ 58, 5603–5604 (1993). CAS  Google Scholar  Download references 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 AUTHORS AND AFFILIATIONS * Department of Chemistry, Emory University, Atlanta, GA, USA Zachary J. Garlets & Huw M. L. Davies *

Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA Jacob N. Sanders & K. N. Houk * Novartis Institutes for Biomedical Research Inc., Cambridge, MA,

USA Hasnain Malik & Christian Gampe Authors * Zachary J. Garlets View author publications You can also search for this author inPubMed Google Scholar * Jacob N. Sanders View author

publications You can also search for this author inPubMed Google Scholar * Hasnain Malik View author publications You can also search for this author inPubMed Google Scholar * Christian

Gampe View author publications You can also search for this author inPubMed Google Scholar * K. N. Houk View author publications You can also search for this author inPubMed Google Scholar *

Huw M. L. Davies View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS 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. CORRESPONDING AUTHOR Correspondence to Huw M. L. Davies. ETHICS DECLARATIONS 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. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Garlets, Z.J., Sanders, J.N., Malik, H. _et al._ Enantioselective

C–H functionalization of bicyclo[1.1.1]pentanes. _Nat Catal_ 3, 351–357 (2020). https://doi.org/10.1038/s41929-019-0417-1 Download citation * Received: 08 April 2019 * Accepted: 09 December

2019 * Published: 27 January 2020 * Issue Date: April 2020 * DOI: https://doi.org/10.1038/s41929-019-0417-1 SHARE THIS ARTICLE Anyone you share the following link with will be able to read

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