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While directed enantioselective methyl C(sp3)\u2013H activation is well-established, achieving analogous reactivity at methylene sites\u2500which would enable the direct editing of molecular scaffolds\u2500remains a formidable goal, particularly with earth-abundant 3d metals. Here, we report the first nickel(II)-catalyzed enantioselective alkynylation of \u03b2-methylene C(sp3)\u2013H bonds. This transformation is enabled by an air-stable Ni(II) salt and a bulky chiral phosphoric acid ligand, (R)-TCYP, delivering a broad range of \u03b2-alkynylated amides in up to 98% yield and 99% ee. Notably, this system achieves preferential methylene C\u2013H activation in the presence of methyl groups, overcoming the intrinsic selectivity of directed C(sp3)\u2013H activation. Mechanistic studies, including the isolation and full characterization of a chiral Ni(II)-metallacyclic intermediate via X-ray diffraction, reveal that the C\u2013H cleavage step is both the rate- and enantio-determining step.<\/jats:p>","DOI":"10.1021\/jacs.6c11377","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T04:01:59Z","timestamp":1785902519000},"page":"34976-34984","source":"Crossref","is-referenced-by-count":1,"title":["Overriding Intrinsic\nSite-Selectivity in Nickel(II)-Catalyzed\nEnantioselective Methylene C(sp3)\u2013H Alkynylation"],"prefix":"10.1021","volume":"148","author":[{"given":"Fei","family":"Yao","sequence":"first","affiliation":[{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-Yi","family":"Bi","sequence":"additional","affiliation":[{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8159-9999","authenticated-orcid":true,"given":"Wenkui","family":"Yuan","sequence":"additional","affiliation":[{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0375-955X","authenticated-orcid":true,"given":"Bing-Feng","family":"Shi","sequence":"additional","affiliation":[{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"2026081910213697000_cit1a","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1021\/jacs.5b08707","article-title":"Evolution of C\u2013H bond functionalization from\nmethane to methodology","volume":"138","author":"Hartwig","year":"2016","journal-title":"J. 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