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Despite the immense progress toward achieving stereoselective Pictet\u2013Spengler reaction with aldehydes, the analogous reaction with ketones is still underdeveloped. Exploiting KslB, a Pictet\u2013Spenglerase from the biosynthesis of kitasetaline, we develop a general, diastereoselective, and protecting\u2010group free method for the construction of densely functionalized THBCs with \u03b1\u2010quaternary center by coupling tryptophan derivatives and \u03b1\u2010keto acids. We determine the stereochemistry of kitasetalic acid, KslB's physiological product and a key biosynthetic intermediate toward kitasetaline, and established that KslB's selectivity is opposite to what is achieved chemically. Our investigations of KslB show its high activity (total turnover number &gt;438000), substrate promiscuity, and tolerance for high substrate concentrations (0.1\u00a0M). Additionally, a TrpB\u2010KslB cascade enables the construction of complex tricyclic products from simple indoles in one\u2010pot. X\u2010ray structural characterization of KslB sheds light on potential active site interactions to account for its stereoselectivity and ability to accept ketone substrates.<\/jats:p>","DOI":"10.1002\/anie.202502367","type":"journal-article","created":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T16:17:01Z","timestamp":1744301821000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["A Ketone\u2010Accepting Pictet\u2013Spenglerase for the Asymmetric Construction of 1,1\u2010Disubstituted Tetrahydro\u2010\u00df\u2010carboline Alkaloids"],"prefix":"10.1002","volume":"64","author":[{"given":"Ruiying","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of Chemistry Rice University BioScience Research Collaborative  Houston Texas 77005 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nour","family":"Wasfy","sequence":"additional","affiliation":[{"name":"Department of Chemistry Rice University BioScience Research Collaborative  Houston Texas 77005 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Mori","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences The University of Tokyo  Tokyo Japan"},{"name":"Collaborative Research Institute for Innovative Microbiology The University of Tokyo  Tokyo Japan"},{"name":"FOREST Japan Science and Technology Agency  Saitama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan","family":"Hoang","sequence":"additional","affiliation":[{"name":"Department of Chemistry Rice University BioScience Research Collaborative  Houston Texas 77005 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ikuro","family":"Abe","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences The University of Tokyo  Tokyo Japan"},{"name":"Collaborative Research Institute for Innovative Microbiology The University of Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"Renata","sequence":"additional","affiliation":[{"name":"Department of Chemistry Rice University BioScience Research Collaborative  Houston Texas 77005 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,5,2]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201008071"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja046259p"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1021\/ol802887h"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/slct.202203368"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ejoc.202200088"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.orglett.1c04316"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.0c05804"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/ange.202201788"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202213831"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tetlet.2011.08.071"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/adsc.201100050"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.orglett.2c00368"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1039\/D1SC00882J"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja076179w"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/ol800256j"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja9024885"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1021\/ol101651t"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2019.12.003"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-1119(00)00578-3"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14883"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/acscatal.0c04704"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41429-018-0074-7"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10295-019-02151-z"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.02355-12"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2015.06.006"},{"key":"e_1_2_8_26_1","volume":"146","author":"Zheng Z.","year":"2024","journal-title":"J. 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