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However, the as yet poor understanding of structure\/activity relationships and the fact that one family member proved systemically toxic for unknown reasons render a more detailed assessment of these potential lead compounds difficult. To help overcome these issues, a collective total synthesis was devised. The key steps consisted of a ring closing alkyne metathesis (RCAM) reaction to forge a common macrocyclic intermediate followed by a hydroxy\u2010directed ruthenium catalyzed <jats:italic>trans<\/jats:italic>\u2010hydrostannation of the propargyl alcohol site thus formed. The resulting alkenyltin derivative served as the central node of the synthesis blueprint, which could be elaborated into the natural products themselves as well as into a set of non\u2010natural analogues according to the concept of diverted total synthesis. The recorded biological data confirmed the potency of the compounds and showed the lack of any noticeable cytotoxicity. The \u201cnorthern\u201d allylic alcohol subunit was recognized as an integral part of the pharmacophore, yet it provides opportunities for chemical modification.<\/jats:p>","DOI":"10.1002\/anie.202408725","type":"journal-article","created":{"date-parts":[[2024,6,12]],"date-time":"2024-06-12T10:29:56Z","timestamp":1718188196000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Collective and Diverted Total Synthesis of the Strasseriolides: A Family of Macrolides Endowed with Potent Antiplasmodial and Antitrypanosomal Activity"],"prefix":"10.1002","volume":"63","author":[{"given":"Daniel","family":"Isak","sequence":"first","affiliation":[{"name":"Max-Planck-Institut f\u00fcr Kohlenforschung  45470 M\u00fclheim\/Ruhr Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leyah A.","family":"Schwartz","sequence":"additional","affiliation":[{"name":"Max-Planck-Institut f\u00fcr Kohlenforschung  45470 M\u00fclheim\/Ruhr Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saskia","family":"Schulthoff","sequence":"additional","affiliation":[{"name":"Max-Planck-Institut f\u00fcr Kohlenforschung  45470 M\u00fclheim\/Ruhr Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guiomar","family":"P\u00e9rez\u2010Moreno","sequence":"additional","affiliation":[{"name":"Instituto de Parasitologia y Biomedicina \u201cL\u00f3pez-Neyra\u201d Consejo Superior de Investigaciones Cient\u00edficas  Avenida del Conocimiento 17 18016 Armilla Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Bosch\u2010Navarrete","sequence":"additional","affiliation":[{"name":"Instituto de Parasitologia y Biomedicina \u201cL\u00f3pez-Neyra\u201d Consejo Superior de Investigaciones Cient\u00edficas  Avenida del Conocimiento 17 18016 Armilla Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dolores","family":"Gonz\u00e1lez\u2010Pacanowska","sequence":"additional","affiliation":[{"name":"Instituto de Parasitologia y Biomedicina \u201cL\u00f3pez-Neyra\u201d Consejo Superior de Investigaciones Cient\u00edficas  Avenida del Conocimiento 17 18016 Armilla Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0098-3417","authenticated-orcid":false,"given":"Alois","family":"F\u00fcrstner","sequence":"additional","affiliation":[{"name":"Max-Planck-Institut f\u00fcr Kohlenforschung  45470 M\u00fclheim\/Ruhr 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ref.\u2005[9]."},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.orglett.1c04340"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.joc.2c01595"},{"key":"e_1_2_7_14_1","unstructured":"For the concept of diverted total synthesis see:"},{"key":"e_1_2_7_15_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo0610053"},{"key":"e_1_2_7_16_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201000775"},{"key":"e_1_2_7_17_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200904761"},{"key":"e_1_2_7_18_1","unstructured":"For some collective total synthesis projects from this group 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see:"},{"key":"e_1_2_7_27_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.200601136"},{"key":"e_1_2_7_28_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.200901449"},{"key":"e_1_2_7_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201100180"},{"key":"e_1_2_7_30_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201300393"},{"key":"e_1_2_7_31_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja508846g"},{"key":"e_1_2_7_32_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201501608"},{"key":"e_1_2_7_33_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.joc.7b02871"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.1c08040"},{"key":"e_1_2_7_35_1","first-page":"613","volume":"102","author":"Lee D.","year":"2020","journal-title":"Org. React."},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201204513"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1229713"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.8b09782"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.accounts.0c00759"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja993838z"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja971570a"},{"key":"e_1_2_7_42_1","unstructured":"The configuration of the newly formed alcohol was confirmed by Mosher ester analysis see the Supporting Information."},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo01311a037"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja00327a022"},{"key":"e_1_2_7_45_1","unstructured":"A larger excess of the Grignard reagent the use of MeLi instead of MeMgBr or a different ratio between CuI and MeMgBr lead to competing allene formation by SN2\u2032 reaction and unproductive cleavage of the acetate group off the substrate."},{"key":"e_1_2_7_46_1","unstructured":"Although terminal as well as silylated alkynes can be used they are less reactive; a direct comparison is found in ref. 56."},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja0492900"},{"key":"e_1_2_7_48_1","unstructured":"For successful applications by our laboratory see:"},{"key":"e_1_2_7_49_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202011472"},{"key":"e_1_2_7_50_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202105732"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja00398a058"},{"key":"e_1_2_7_52_1","unstructured":"They report an overall yield of 28\u2009% for cleavage of the TBDPS group from their alcohol presursor with TBAF oxidation to the corresponding aldehyde with PCC and the subsequent Evans aldol step mediated by Bu2BOTf\/Et3N."},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja9716721"},{"key":"e_1_2_7_54_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo001387r"},{"key":"e_1_2_7_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tet.2010.02.010"},{"key":"e_1_2_7_56_1","doi-asserted-by":"publisher","DOI":"10.1039\/c1cs15071e"},{"key":"e_1_2_7_57_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200600636"},{"key":"e_1_2_7_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4039(98)01433-6"},{"key":"e_1_2_7_59_1","doi-asserted-by":"publisher","DOI":"10.1039\/p19810002527"},{"key":"e_1_2_7_60_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202015243"},{"key":"e_1_2_7_61_1","doi-asserted-by":"publisher","DOI":"10.1021\/ol800341z"},{"key":"e_1_2_7_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/0040-4039(94)88017-4"},{"key":"e_1_2_7_63_1","doi-asserted-by":"publisher","DOI":"10.3762\/bjoc.15.53"},{"key":"e_1_2_7_64_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202303345"},{"key":"e_1_2_7_65_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-1996-5474"},{"key":"e_1_2_7_66_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-1987-27863"},{"key":"e_1_2_7_67_1","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201500437"},{"key":"e_1_2_7_68_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-1980-29214"},{"key":"e_1_2_7_69_1","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201203965"},{"key":"e_1_2_7_70_1","unstructured":"The chosen route bears overall similarity to the route described by Rychnovsky and co-workers who also start from citronellal and end with a homoenolate cross coupling reaction; 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for details see the Supporting Information."},{"key":"e_1_2_7_86_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201311080"},{"key":"e_1_2_7_87_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.5b01475"},{"key":"e_1_2_7_88_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.6b12517"},{"key":"e_1_2_7_89_1","doi-asserted-by":"publisher","DOI":"10.1002\/chem.202101901"},{"key":"e_1_2_7_90_1","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201702470"},{"key":"e_1_2_7_91_1","doi-asserted-by":"publisher","DOI":"10.1016\/0040-4039(91)80222-R"},{"key":"e_1_2_7_92_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.0c01700"},{"key":"e_1_2_7_93_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200462207"},{"key":"e_1_2_7_94_1","unstructured":"For applications in total synthesis by our group see:"},{"key":"e_1_2_7_95_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200601859"},{"key":"e_1_2_7_96_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201005850"},{"key":"e_1_2_7_97_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.orglett.3c03066"},{"key":"e_1_2_7_98_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200906122"}],"container-title":["Angewandte Chemie International Edition"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.202408725","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T00:27:28Z","timestamp":1741739248000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/anie.202408725"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,29]]},"references-count":98,"journal-issue":{"issue":"36","published-print":{"date-parts":[[2024,9,2]]}},"alternative-id":["10.1002\/anie.202408725"],"URL":"https:\/\/doi.org\/10.1002\/anie.202408725","archive":["Portico"],"relation":{},"ISSN":["1433-7851","1521-3773"],"issn-type":[{"value":"1433-7851","type":"print"},{"value":"1521-3773","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,29]]},"assertion":[{"value":"2024-05-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-07-29","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e202408725"}}