{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T15:03:18Z","timestamp":1790348598561,"version":"4.1.0"},"reference-count":40,"publisher":"American Chemical Society (ACS)","issue":"38","license":[{"start":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T00:00:00Z","timestamp":1789171200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T00:00:00Z","timestamp":1789171200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T00:00:00Z","timestamp":1789171200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100006407","name":"Natural Science Foundation of Henan Province","doi-asserted-by":"publisher","award":["252300421384"],"award-info":[{"award-number":["252300421384"]}],"id":[{"id":"10.13039\/501100006407","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013066","name":"Key Scientific Research Project of Colleges and Universities in Henan Province","doi-asserted-by":"publisher","award":["26A150021"],"award-info":[{"award-number":["26A150021"]}],"id":[{"id":"10.13039\/501100013066","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021233","name":"Henan Key Laboratory of Organic Functional Molecules and Drug Innovation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100021233","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NMPA Key Laboratory for Research and Evaluation of Innovative Drug"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Bicyclo[2.1.1]hexanes (BCHs), three-dimensional benzene bioisosteres characterized by high sp3 carbon content, hold great promise for diverse applications in medicinal chemistry. While racemic BCH synthesis has advanced significantly, highly enantioselective approaches are still comparatively scarce. Here, we report an enantioselective [2\u03c0+2\u03c3] cycloaddition of \u03b2-fluoroalkyl-\u03b1,\u03b2-unsaturated ketones with bicyclo[1.1.0]butanes (BCBs) catalyzed by a chiral (R)-3,3\u2032-(3,5-(CF3)2-C6H3)2-BINOL\u2013boron complex. This approach overcomes major limitations of existing metal-catalyzed and photochemical methods. This transformation provides BCH derivatives featuring CF3- or C2F5-bearing stereocenters in moderate to high yields with excellent diastereo- and enantioselectivities (up to &amp;gt;20:1 dr and &amp;gt;99% ee). This mild catalytic protocol exhibits a broad substrate scope and enables the rapid construction of complex fluoroalkyl-containing BCH scaffolds.<\/jats:p>","DOI":"10.1021\/acs.orglett.6c03773","type":"journal-article","created":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T16:01:45Z","timestamp":1789228905000},"page":"12148-12153","source":"Crossref","is-referenced-by-count":0,"title":["Chiral Boron\nComplex-Catalyzed Asymmetric [2\u03c0+2\u03c3]\nCycloaddition of \u03b2-Fluoroalkyl-\u03b1,\u03b2-Unsaturated\nKetones with Bicyclo[1.1.0]butanes"],"prefix":"10.1021","volume":"28","author":[{"given":"Cai-Guang","family":"Li","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Science, Henan Normal University , , , ,","place":["Xinxiang, Henan, China, 453007"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling-Yun","family":"Shang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science, Henan Normal University , , , ,","place":["Xinxiang, Henan, China, 453007"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang-Ling","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science, Henan Normal University , , , ,","place":["Xinxiang, Henan, China, 453007"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6236-1256","authenticated-orcid":true,"given":"Junbiao","family":"Chang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science, Henan Normal University , , , ,","place":["Xinxiang, Henan, China, 453007"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1342-6217","authenticated-orcid":true,"given":"Guo-Li","family":"Chai","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science, Henan Normal University , , , ,","place":["Xinxiang, Henan, China, 453007"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,12]]},"reference":[{"key":"2026092510113147900_cit1a","doi-asserted-by":"publisher","first-page":"734","DOI":"10.1038\/s41557-025-01746-7","article-title":"Enantioselective photocatalytic\nsynthesis of bicyclo[2.1.1]hexanes as ortho-disubstituted\nbenzene bioisosteres with improved biological activity","volume":"17","author":"Garrido-Garcia","year":"2025","journal-title":"Nat. Chem."},{"key":"2026092510113147900_cit1b","doi-asserted-by":"publisher","first-page":"6752","DOI":"10.1021\/jm901241e","article-title":"Escape from Flatland: Increasing\nSaturation as an Approach to Improving Clinical Success","volume":"52","author":"Lovering","year":"2009","journal-title":"J. Med. Chem."},{"key":"2026092510113147900_cit1c","doi-asserted-by":"publisher","first-page":"3414","DOI":"10.1021\/jm300094u","article-title":"Application of the Bicyclo[1.1.1]pentane\nMotif as a Nonclassical Phenyl Ring Bioisostere in the Design of a\nPotent and Orally Active \u03b3-Secretase Inhibitor","volume":"55","author":"Stepan","year":"2012","journal-title":"J. Med. Chem."},{"key":"2026092510113147900_cit1d","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1038\/s41557-023-01135-y","article-title":"A catalytic alkene insertion approach\nto bicyclo[2.1.1]hexane bioisosteres","volume":"15","author":"Agasti","year":"2023","journal-title":"Nat. Chem."},{"key":"2026092510113147900_cit2a","doi-asserted-by":"publisher","first-page":"5776","DOI":"10.1039\/D5CS01224D","article-title":"Catalytic\nstrain-release\nenabled cycloaddition of carbonyl activated bicyclo[1.1.0]butanes","volume":"55","author":"Wang","year":"2026","journal-title":"Chem. Soc. Rev."},{"key":"2026092510113147900_cit2b","doi-asserted-by":"publisher","first-page":"5572","DOI":"10.1039\/D6CS00010J","article-title":"Recent advances in the strain-release\ndriven reactions of bicyclobutanes: an emerging landscape in organic\nsynthesis","volume":"55","author":"Deswal","year":"2026","journal-title":"Chem. Soc. Rev."},{"key":"2026092510113147900_cit2c","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1038\/s44160-024-00659-6","article-title":"Palladium-catalysed\n[2\u03c3+2\u03c0] cycloaddition reactions of bicyclo[1.1.0]butanes\nwith aldehydes","volume":"4","author":"Qin","year":"2025","journal-title":"Nat. Synth."},{"key":"2026092510113147900_cit2d","doi-asserted-by":"publisher","first-page":"5096","DOI":"10.1021\/acscatal.3c00305","article-title":"Pyridine-Boryl Radical-Catalyzed [2\u03c0+2\u03c3]\nCycloaddition of Bicyclo[1.1.0]-butanes with Alkenes","volume":"13","author":"Liu","year":"2023","journal-title":"ACS Catal."},{"key":"2026092510113147900_cit2e","doi-asserted-by":"publisher","first-page":"7988","DOI":"10.1021\/jacs.2c02976","article-title":"Strain-Release [2\u03c0+2\u03c3]\nCycloadditions for the Synthesis of Bicyclo[2.1.1]hexanes Initiated\nby Energy Transfer","volume":"144","author":"Guo","year":"2022","journal-title":"J. Am. Chem. Soc."},{"key":"2026092510113147900_cit2f","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1038\/s41586-022-04636-x","article-title":"Intermolecular [2\u03c0+2\u03c3]-photo-cycloaddition\nenabled by triplet energy transfer","volume":"605","author":"Kleinmans","year":"2022","journal-title":"Nature"},{"key":"2026092510113147900_cit3a","doi-asserted-by":"publisher","first-page":"1903","DOI":"10.31635\/ccschem.025.202505825","article-title":"Catalytic\nAsymmetric\nStrategies for Bicyclo[1.1.0]butane Transformations: Advances and\nApplications","volume":"7","author":"Xiao","year":"2025","journal-title":"CCS Chem."},{"key":"2026092510113147900_cit3b","doi-asserted-by":"publisher","first-page":"8078","DOI":"10.1021\/acscatal.5c01900","article-title":"Recent Advances in\nCatalytic Asymmetric Transformations of Bicyclobutane: A Versatile\nBuilding Block for Enantiopure Bioisosteric Molecules","volume":"15","author":"Koo","year":"2025","journal-title":"ACS Catal."},{"key":"2026092510113147900_cit3c","doi-asserted-by":"publisher","first-page":"734","DOI":"10.1038\/s41557-025-01746-7","article-title":"Enantioselective photocatalytic synthesis\nof bicyclo[2.1.1]hexanes as ortho-disubstituted benzene\nbioisosteres with improved biological activity","volume":"17","author":"Garrido-Garcia","year":"2025","journal-title":"Nat. Chem."},{"key":"2026092510113147900_cit4","doi-asserted-by":"publisher","first-page":"24466","DOI":"10.1021\/jacs.3c08404","article-title":"Enantioselective Intermolecular [\u03c02+\u03c32]\nPhotocycloaddition Reactions of 2(1H)-Quinolones and Bicyclo[1.1.0]butanes","volume":"145","author":"de Robichon","year":"2023","journal-title":"J. Am. Chem. Soc."},{"key":"2026092510113147900_cit5","doi-asserted-by":"publisher","first-page":"8372","DOI":"10.1021\/jacs.3c14077","article-title":"Enantioselective [2\u03c0+2\u03c3] Cycloadditions of Bicyclo[1.1.0]butanes\nwith Vinylazaarenes through Asymmetric Photoredox Catalysis","volume":"146","author":"Fu","year":"2024","journal-title":"J. Am. Chem. Soc."},{"key":"2026092510113147900_cit6a","doi-asserted-by":"publisher","first-page":"27830","DOI":"10.1021\/jacs.4c10153","article-title":"Divergent Enantioselective\nAccess to Diverse Chiral Compounds from Bicyclo[1.1.0]butanes and\n\u03b1,\u03b2-Unsaturated Ketones under Catalyst Control","volume":"146","author":"Jeong","year":"2024","journal-title":"J. Am. Chem. Soc."},{"key":"2026092510113147900_cit6b","doi-asserted-by":"publisher","first-page":"34427","DOI":"10.1021\/jacs.4c10968","article-title":"Catalytic\nIntermolecular Asymmetric [2\u03c0+2\u03c3] Cycloadditions of Bicyclo[1.1.0]butanes:\nPractical Synthesis of Enantioenriched Highly Substituted Bicyclo[2.1.1]hexanes","volume":"146","author":"Li","year":"2024","journal-title":"J. Am. Chem. Soc."},{"key":"2026092510113147900_cit7a","doi-asserted-by":"publisher","first-page":"31400","DOI":"10.1021\/jacs.4c13596","article-title":"Enantioselective\n[2\u03c0+2\u03c3] Photo-cycloaddition Enabled by Bro\u0337nsted\nAcid Catalyzed Chromophore Activation","volume":"146","author":"Plachinski","year":"2024","journal-title":"J. Am.\nChem. Soc."},{"key":"2026092510113147900_cit7b","doi-asserted-by":"publisher","first-page":"11667","DOI":"10.1021\/jacs.5c01506","article-title":"Enantioselective Dearomative [2\u03c0\n+ 2\u03c3] Photocycloaddition of Naphthalene Derivatives with Bicyclo[1.1.0]butanes\nEnabled by Gd(III) Catalysis","volume":"147","author":"Shen","year":"2025","journal-title":"J. Am. Chem. Soc."},{"key":"2026092510113147900_cit8","doi-asserted-by":"publisher","first-page":"4634","DOI":"10.1021\/acscatal.5c00303","article-title":"Lewis Acid-\nCatalyzed Asymmetric [2\u03c3+2\u03c0] Cycloaddition Reactions of\nBicyclo[1.1.0]butanes and Vinyl Azido\/Diazo Compounds","volume":"15","author":"Ren","year":"2025","journal-title":"ACS Catal."},{"key":"2026092510113147900_cit9a","doi-asserted-by":"publisher","first-page":"18799","DOI":"10.1021\/acscatal.4c06660","article-title":"Zwitterionic \u03c0-Allyl-Pd\nSpecies\nEnabled [2\u03c3+2\u03c0] Cycloaddition Reactions of Vinylbicyclo[1.1.0]butanes\n(VBCBs) with Alkenes, Carbonyls, and Imines","volume":"14","author":"Li","year":"2024","journal-title":"ACS Catal."},{"key":"2026092510113147900_cit9b","doi-asserted-by":"publisher","first-page":"111072","DOI":"10.1016\/j.cclet.2025.111072","article-title":"Palladium-catalyzed\nenantioselective [2\u03c3+2\u03c0] cycloadditions of vinyl-carbonyl-bicyclo[1.1.0]butanes\nwith arylidenemalononitriles","volume":"37","author":"Qin","year":"2026","journal-title":"Chin. Chem. Lett."},{"key":"2026092510113147900_cit10a","doi-asserted-by":"publisher","first-page":"9361","DOI":"10.1038\/s41467-025-64399-7","article-title":"Organocatalytic\nenantioselective [2\u03c0+2\u03c3] cycloaddition reactions of bicyclo[1.1.0]\nbutanes with \u03b1,\u03b2-unsaturated aldehydes","volume":"16","author":"Geng","year":"2025","journal-title":"Nat. Commun."},{"key":"2026092510113147900_cit10b","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1002\/cjoc.70355","article-title":"Chemo-, Diastereo-, and Enantioselective (3+2) Cycloadditons\nof Bicyclobutanes with Enals Enabled by Synergistic Palladium and\nOrganocatalysis","volume":"44","author":"Wu","year":"2026","journal-title":"Chin. J. Chem."},{"key":"2026092510113147900_cit11","doi-asserted-by":"publisher","first-page":"101809","DOI":"10.1016\/j.checat.2026.101809","article-title":"Asymmetric [2\u03c0+2\u03c3] cycloaddition\nof bicyclo[1.1.0]butanes enabled by chiral tetracoordinated boron\ncatalysis","author":"Wang","year":"2026","journal-title":"Chem. Catal."},{"key":"2026092510113147900_cit12a","doi-asserted-by":"publisher","first-page":"13755","DOI":"10.1021\/jacs.5c20918","article-title":"Enantioselective\n[2\u03c0+2\u03c3] Cycloaddition to Bicyclo[2.1.1]hexanes Enabled\nby an Artificial Photoenzyme","volume":"148","author":"Li","year":"2026","journal-title":"J. Am. Chem. Soc."},{"key":"2026092510113147900_cit12b","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1039\/D5QO01029B","article-title":"Enantioselective polar\n[2\u03c3+2\u03c0] cycloadditions of bicyclo[1.1.0]butanes and ortho-quinone methides enabled by chiral phosphoric acid\ncatalysis","volume":"13","author":"Xu","year":"2026","journal-title":"Org. Chem. Front."},{"key":"2026092510113147900_cit13a","doi-asserted-by":"publisher","first-page":"115476","DOI":"10.1016\/j.ejmech.2023.115476","article-title":"Highlights on U.S.\nFDA-approved fluorinated drugs over the past five years (2018\u20132022)","volume":"256","author":"Ali","year":"2023","journal-title":"Eur. J. Med. Chem."},{"key":"2026092510113147900_cit13b","doi-asserted-by":"publisher","first-page":"5822","DOI":"10.1021\/acs.jmedchem.7b01788","article-title":"Fluorine and Fluorinated Motifs in the Design and Application\nof Bioisosteres for Drug Design","volume":"61","author":"Meanwell","year":"2018","journal-title":"J. Med. Chem."},{"key":"2026092510113147900_cit13c","doi-asserted-by":"publisher","first-page":"8315","DOI":"10.1021\/acs.jmedchem.5b00258","article-title":"Applications of Fluorine in Medicinal Chemistry","volume":"58","author":"Gillis","year":"2015","journal-title":"J. Med. Chem."},{"key":"2026092510113147900_cit13d","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1039\/B610213C","article-title":"Fluorine in\nmedicinal chemistry","volume":"37","author":"Purser","year":"2008","journal-title":"Chem. Soc. Rev."},{"key":"2026092510113147900_cit14","doi-asserted-by":"publisher","first-page":"7003","DOI":"10.1021\/acs.joc.5c00455","article-title":"Strain-Release-Driven\nAlder-Ene Reaction of Bicyclo[1.1.0]butanes with \u03b2-Fluoroalkyl-\u03b1,\u03b2-Unsaturated\nKetones","volume":"90","author":"Xu","year":"2025","journal-title":"J. Org. Chem."},{"key":"2026092510113147900_cit15a","doi-asserted-by":"publisher","first-page":"6982","DOI":"10.1021\/acs.orglett.3c02463","article-title":"Chiral-Boron-Complex Catalyzed Asymmetric\nInverse-Electron-Demand Aza-Diels-Alder Reaction of \u03b2-Trifluoromethyl\n\u03b1,\u03b2-Unsaturated Ketones with Cyclic N-Sulfonyl Ketimines","volume":"25","author":"Chai","year":"2023","journal-title":"Org. Lett."},{"key":"2026092510113147900_cit15b","doi-asserted-by":"publisher","first-page":"16566","DOI":"10.1021\/acs.joc.3c02106","article-title":"Chiral-Boron-Complex-Catalyzed Asymmetric [3 + 2] Cycloaddition of\n\u03b2-Trifluoromethyl \u03b1,\u03b2-Unsaturated Ketones with N,N\u2032-Cyclic\nAzomethine Imines","volume":"88","author":"Liu","year":"2023","journal-title":"J. Org. Chem."},{"key":"2026092510113147900_cit15c","doi-asserted-by":"publisher","first-page":"11607","DOI":"10.1021\/acs.joc.4c01319","article-title":"Chiral-Boron Complex-Catalyzed Asymmetric [3 + 2] Cycloaddition of\n2\u2032-Hydroxychalcones with N-2,2,2-Trifluoroethylisatin Ketimines","volume":"89","author":"Chai","year":"2024","journal-title":"J. Org. Chem."},{"key":"2026092510113147900_cit15d","doi-asserted-by":"publisher","first-page":"8023","DOI":"10.1021\/acs.orglett.0c02978","article-title":"Chiral Hydroxytetraphenylene\u2013Boron\nComplex Catalyzed Asymmetric Diels\u2013Alder Cycloaddition of 2\u2032-Hydroxychalcones","volume":"22","author":"Chai","year":"2020","journal-title":"Org. Lett."},{"key":"2026092510113147900_cit15e","doi-asserted-by":"publisher","first-page":"6449","DOI":"10.1021\/acs.orglett.2c02597","article-title":"Chiral-Boron-Complex-Catalyzed\nAsymmetric [3 + 2] Cycloaddition of 2\u2032-Hydroxychalcones with\nN,N\u2032-Cyclic Azomethine Imines","volume":"24","author":"Chai","year":"2022","journal-title":"Org. Lett."},{"key":"2026092510113147900_cit16a","doi-asserted-by":"publisher","first-page":"798","DOI":"10.1021\/jacs.5b12778","article-title":"Asymmetric Syntheses\nof the Flavonoid Diels\u2013Alder Natural Products Sanggenons C\nand O","volume":"138","author":"Qi","year":"2016","journal-title":"J. Am. Chem. Soc."},{"key":"2026092510113147900_cit16b","doi-asserted-by":"publisher","first-page":"458","DOI":"10.1021\/acs.joc.5b02248","article-title":"Chiral Boron\nComplex-Promoted Asymmetric Diels\u2013Alder Cycloaddition and Its\nApplication in Natural Product Synthesis","volume":"81","author":"Li","year":"2016","journal-title":"J.\nOrg. Chem."},{"key":"2026092510113147900_cit16c","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1021\/acs.orglett.5b03285","article-title":"Enantioselective\nTotal Syntheses of Kuwanon X, Kuwanon Y, and Kuwanol A","volume":"18","author":"Gao","year":"2016","journal-title":"Org. Lett."}],"container-title":["Organic Letters"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.orglett.6c03773","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/orlef7\/article-pdf\/28\/38\/12148\/68491994\/acs.orglett.6c03773.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/orlef7\/article-pdf\/28\/38\/12148\/68491994\/acs.orglett.6c03773.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T14:31:22Z","timestamp":1790346682000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/orlef7\/article\/28\/38\/12148\/5428902\/Chiral-Boron-Complex-Catalyzed-Asymmetric-2-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,12]]},"references-count":40,"journal-issue":{"issue":"38","published-online":{"date-parts":[[2026,9,12]]},"published-print":{"date-parts":[[2026,9,25]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.orglett.6c03773","relation":{},"ISSN":["1523-7060","1523-7052"],"issn-type":[{"value":"1523-7060","type":"print"},{"value":"1523-7052","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,12]]}}}