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However, general methods for the asymmetric synthesis of stereocenters adjacent to these strained, 3D frameworks remain scarce. Here, we report a nickel\u2010catalyzed, enantioselective reductive cross\u2010coupling between aldehydes and four\u2010membered heterocyclic alkenes to construct \u03b1\u2010hydroxy ketones bioisosteres with high efficiency and selectivity. Guided by\n                    <jats:italic>N<\/jats:italic>\n                    \u2010heterocyclic carbene (NHC) ligands, the reaction proceeds with broad functional group tolerance, affording enantioenriched products in yields of up to 94% and an enantiomeric ratio (e.r.) of 99.8:0.2. The protocol is particularly amenable to the synthesis of enantioenriched \u03b1\u2010hydroxy difluoromethylene alkanes. Mechanistic investigations revealed how strain\u2010enabled reactivity and ligand control govern chemo\u2010, regio\u2010, and stereoselectivity. The synthetic utility of the method is demonstrated through gram\u2010scale preparation and diverse downstream derivatizations, offering a versatile platform for accessing previously elusive classes of stereodefined bioisosteres.\n                  <\/jats:p>","DOI":"10.1002\/anie.202510690","type":"journal-article","created":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T08:05:41Z","timestamp":1753171541000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Nickel\u2010Catalyzed Regioselective and Enantioselective Olefin\u2013Aldehyde Cross\u2010Couplings Toward Acyloin Isosteres"],"prefix":"10.1002","volume":"64","author":[{"given":"Mingshuai","family":"Zhang","sequence":"first","affiliation":[{"name":"Key Laboratory of Marine Drugs, Ministry of Education Molecular Synthesis Center and School of Medicine and Pharmacy Ocean University of China  Yushan Road 5 Qingdao 266003 P. R. 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5720-6542","authenticated-orcid":false,"given":"Hongyu","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Marine Drugs, Ministry of Education Molecular Synthesis Center and School of Medicine and Pharmacy Ocean University of China  Yushan Road 5 Qingdao 266003 P. R. China"},{"name":"Laboratory for Marine Drugs and Bioproducts Qingdao Marine Science and Technology Center  Wenhai Middle Road 168 Qingdao 266237 P.R. China"},{"name":"College of Chemistry Chemical Engineering and Materials Science Shandong Normal University  Wenhua Road 88 Jinan 250014 P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,7,22]]},"reference":[{"key":"e_1_2_7_1_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm901241e"},{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1039\/c2md20347b"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.0c00829"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1039\/D5CC00816F"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41570-024-00623-0"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1039\/D0MD00370K"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jafc.3c00765"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.3c02239"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1039\/D4RA05694A"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1039\/c000408c"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41929-019-0417-1"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21936-4"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.orglett.0c02017"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.orglett.4c00902"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/ar900196n"},{"key":"e_1_2_7_16_1","first-page":"501","volume":"12","author":"Tanaka T.","year":"2004","journal-title":"Med. 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