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However, the application of Lewis base catalysis in such reactions remains underexplored, and the strategy for the cycloaddition of acceptor\u2013acceptor BCBs remains unknown. Herein, we report the first formal (4\u00a0+\u00a02) cycloaddition of acceptor\u2013acceptor BCBs, which serve as a four\u2010atom component, for the selective synthesis of pharmaceutically valuable oxa\u2010bicyclo[3.1.1]heptanes (oxa\u2010BCHeps) enabled by\n                    <jats:italic>N<\/jats:italic>\n                    \u2010heterocyclic carbene (NHC) catalysis. BCBs and carbonyl compounds, such as aldehydes and ketones, with various functional groups, are well\u2010tolerated under mild conditions, yielding oxa\u2010BCHeps with up to 87% yield, competing with at least five side reactions. The versatility of this synthetic method is further demonstrated through derivatization of the (4\u00a0+\u00a02) cycloadducts and late\u2010stage functionalization of pharmaceuticals. The reaction mechanism and the origins of the chemoselectivity were investigated by means of density functional theory calculations.\n                  <\/jats:p>","DOI":"10.1002\/anie.202507590","type":"journal-article","created":{"date-parts":[[2025,6,13]],"date-time":"2025-06-13T05:39:30Z","timestamp":1749793170000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Catalytic Activation of Acceptor\u2013Acceptor Bicyclobutanes Enabled by Lewis Base Catalysis"],"prefix":"10.1002","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6313-4546","authenticated-orcid":false,"given":"Jin\u2010Lan","family":"Zhou","sequence":"first","affiliation":[{"name":"State Key Laboratory of Chemo and Biosensing, Advanced Catalytic Engineering Research Center of the Ministry of Education, College of Chemistry and Chemical Engineering Hunan University  Changsha Hunan 410082 P.R. 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