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Betamethasone dipropionate, clobetasol propionate, and beclomethasone dipropionate are particularly noteworthy for their synthetic intractability. Despite five decades of research, these 16<jats:italic>\u03b2<\/jats:italic>\u2010methylcorticoids have remained challenging synthetic targets owing to insurmountable issues of reactivity, selectivity, and cost efficiency associated with all previously explored strategies. We herein report our practicability\u2010oriented strategy toward the unified stereoselective synthesis of 16<jats:italic>\u03b2<\/jats:italic>\u2010methylcorticoids in 12.6\u201314.0\u2009% overall yield from commercially available 9<jats:italic>\u03b1<\/jats:italic>\u2010hydroxyandrost\u20104\u2010ene\u20103,17\u2010dione (9<jats:italic>\u03b1<\/jats:italic>\u2010OH\u2010AD). In this approach, the chiral C16<jats:italic>\u03b2<\/jats:italic>\u2010Me and C17<jats:italic>\u03b1<\/jats:italic>\u2010OH groups of the corticosteroid D ring were installed via a substrate\u2010controlled diastereo\u2010 and enantioselective Mn\u2010catalyzed oxidation\u2010reduction hydration of \u0394<jats:sup>4,9(11),16<\/jats:sup>\u2010triene\u20103,20\u2010dione. The C1\u2212C2 double bond of the corticosteroid A ring was constructed using an unprecedented engineered 3\u2010ketosteroid\u2010\u0394<jats:sup>1<\/jats:sup>\u2010dehydrogenase (MK4\u2010KstD)\u2010catalyzed regioselective \u0394<jats:sup>1<\/jats:sup>\u2010dehydrogenation of \u0394<jats:sup>4,9(11)<\/jats:sup>\u2010diene\u20103,21\u2010dione. This strategy provides a general method and a key precursor for the divergent synthesis of a variety of glucocorticoids and related steroidal drugs.<\/jats:p>","DOI":"10.1002\/anie.202313952","type":"journal-article","created":{"date-parts":[[2023,11,23]],"date-time":"2023-11-23T16:15:02Z","timestamp":1700756102000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Divergent Chemo\u2010 and Biocatalytic Route to 16<i>\u03b2<\/i>\u2010Methylcorticoids: Asymmetric Synthesis of Betamethasone Dipropionate, Clobetasol Propionate, and Beclomethasone Dipropionate"],"prefix":"10.1002","volume":"63","author":[{"given":"Jianhai","family":"Wei","sequence":"first","affiliation":[{"name":"Engineering Center of Catalysis and Synthesis for Chiral Molecules Fudan University  Shanghai 200433 China"},{"name":"Shanghai Engineering Center of Industrial Catalysis for Chiral Drugs Fudan University  Shanghai 200433 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yajiao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Engineering Center of Catalysis and Synthesis for Chiral Molecules Fudan University  Shanghai 200433 China"},{"name":"Shanghai Engineering Center of Industrial Catalysis for Chiral Drugs Fudan University  Shanghai 200433 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minjie","family":"Liu","sequence":"additional","affiliation":[{"name":"Engineering Center of Catalysis and Synthesis for Chiral Molecules Fudan University  Shanghai 200433 China"},{"name":"Shanghai Engineering Center of Industrial Catalysis for Chiral Drugs Fudan University  Shanghai 200433 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingtang","family":"Ning","sequence":"additional","affiliation":[{"name":"Engineering Center of Catalysis and Synthesis for Chiral Molecules Fudan University  Shanghai 200433 China"},{"name":"Shanghai Engineering Center of Industrial Catalysis for Chiral Drugs Fudan University  Shanghai 200433 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiran","family":"Cao","sequence":"additional","affiliation":[{"name":"Engineering Center of Catalysis and Synthesis for Chiral Molecules Fudan University  Shanghai 200433 China"},{"name":"Shanghai Engineering Center of Industrial Catalysis for Chiral Drugs Fudan University  Shanghai 200433 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6734-3388","authenticated-orcid":false,"given":"Fen\u2010Er","family":"Chen","sequence":"additional","affiliation":[{"name":"Engineering Center of Catalysis and Synthesis for Chiral Molecules Fudan University  Shanghai 200433 China"},{"name":"Shanghai Engineering Center of Industrial Catalysis for Chiral Drugs Fudan University  Shanghai 200433 China"},{"name":"College of Chemistry and Chemical Engineering Jiangxi Normal University  Nanchang 330022 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,12,20]]},"reference":[{"key":"e_1_2_7_1_1","unstructured":"\u00a0"},{"key":"e_1_2_7_2_2","doi-asserted-by":"publisher","DOI":"10.1517\/13543776.2010.493876"},{"key":"e_1_2_7_3_2","doi-asserted-by":"publisher","DOI":"10.1080\/17512433.2017.1318062"},{"key":"e_1_2_7_4_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr068203e"},{"key":"e_1_2_7_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2023.101916"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1468-3083.2012.04525.x"},{"key":"e_1_2_7_7_1","unstructured":"\u00a0"},{"key":"e_1_2_7_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)02125-0"},{"key":"e_1_2_7_9_2","doi-asserted-by":"publisher","DOI":"10.1111\/pde.14812"},{"key":"e_1_2_7_10_2","volume":"3","author":"Ciapponi A.","year":"2021","journal-title":"Am. 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