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Herein, we report a biocatalytic C\u2013H oxidation strategy that leverages an engineered P450BM3 platform for the selective C18-methyl hydroxylation of sclareol. Through five rounds of directed evolution, variant Ox18M3\u20133 was developed, elevating the regioselectivity from 4% to &amp;gt;99% alongside a 2.2-fold increase in catalytic activity. The site-specific enzymatic hydroxylation facilitated the first synthesis of the complex heptacyclic tumor stemness inhibitor spiromyrrhene B in 10 steps (longest linear sequence) from sclareol, underscoring the benefits of merging precision biocatalysis with classical synthesis to streamline access to bioactive natural products.<\/jats:p>","DOI":"10.1021\/jacs.6c16907","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T17:01:36Z","timestamp":1790096496000},"page":"42812-42821","source":"Crossref","is-referenced-by-count":0,"title":["Selective C18-Methyl\nOxidation of Sclareol via an\nEngineered P450 Enables the Synthesis of Spiromyrrhene B"],"prefix":"10.1021","volume":"148","author":[{"given":"Chenhao","family":"Zhang","sequence":"first","affiliation":[{"name":"Fudan University , , ,","place":["Shanghai, China, 201203"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shugong","family":"Liu","sequence":"additional","affiliation":[{"name":"Fudan University , , ,","place":["Shanghai, China, 201203"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanwen","family":"Chen","sequence":"additional","affiliation":[{"name":"Fudan University , , ,","place":["Shanghai, China, 201203"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Shi","sequence":"additional","affiliation":[{"name":"Fudan University , , ,","place":["Shanghai, China, 201203"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liran","family":"Chen","sequence":"additional","affiliation":[{"name":"Fudan University , , ,","place":["Shanghai, China, 201203"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3806-3114","authenticated-orcid":true,"given":"Dao-Feng","family":"Chen","sequence":"additional","affiliation":[{"name":"Fudan University , , ,","place":["Shanghai, China, 201203"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2710-7743","authenticated-orcid":true,"given":"Fuzhuo","family":"Li","sequence":"additional","affiliation":[{"name":"Fudan University , , ,","place":["Shanghai, China, 201203"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,22]]},"reference":[{"key":"2026100711104178400_cit1","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1038\/s41570-023-00534-6","article-title":"Strategic application of C\u2013H oxidation in natural\nproduct total synthesis","volume":"7","author":"Bakanas","year":"2023","journal-title":"Nat. Rev. Chem."},{"key":"2026100711104178400_cit2","doi-asserted-by":"publisher","first-page":"562","DOI":"10.1039\/C5NP00122F","article-title":"Trends in applying\nC\u2013H oxidation to the total synthesis of\nnatural products","volume":"33","author":"Qiu","year":"2016","journal-title":"Nat. Prod. Rep."},{"key":"2026100711104178400_cit3","doi-asserted-by":"publisher","first-page":"8925","DOI":"10.1039\/C8CS00716K","article-title":"Recent applications of C\u2013H\nfunctionalization in complex natural product synthesis","volume":"47","author":"Abrams","year":"2018","journal-title":"Chem. Soc. Rev."},{"key":"2026100711104178400_cit4","doi-asserted-by":"publisher","first-page":"2710","DOI":"10.1039\/D0QO00656D","article-title":"Spiromyrrhenes A\u2013D:\nunprecedented diterpene\u2013sesquiterpene\nheterodimers as intermolecular [4 + 2] cycloaddition products from Resina Commiphora that inhibit tumor stemness in esophageal\ncancer","volume":"7","author":"Hu","year":"2020","journal-title":"Org. Chem. Front."},{"key":"2026100711104178400_cit5","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1021\/np50083a006","article-title":"Azadirachtins H and I: two new tetranortriterpenoids\nfrom Azadirachta indica","volume":"55","author":"Govindachari","year":"1992","journal-title":"J.\nNat. Prod."},{"key":"2026100711104178400_cit6","doi-asserted-by":"publisher","first-page":"1412","DOI":"10.1021\/acs.jnatprod.8b00723","article-title":"Indole diterpenoids\nfrom an endophytic Penicillium sp","volume":"82","author":"Ariantari","year":"2019","journal-title":"J. Nat. Prod."},{"key":"2026100711104178400_cit7","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1248\/cpb.46.178","article-title":"Novel skeletal diterpenoids from\nthe Japanese liverwort Pallavicinia subciliata","volume":"46","author":"Toyota","year":"1998","journal-title":"Chem. Pharm. 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