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The key step in the synthesis of this precursor was a stereoselective aldol reaction of a formal Evans acetate aldol product with crotonaldehyde. As demonstrated by X\u2010ray crystallography, the binding mode of C(13)\/C(13\u2032)\u2010bis(desmethyl)disorazole\u2005Z to tubulin is virtually identical with that of the natural product disorazole\u2005Z. Likewise, C(13)\/C(13\u2032)\u2010bis(desmethyl)disorazole\u2005Z inhibits tubulin assembly with at least the same potency as disorazole\u2005Z and it appears to be a more potent cell growth inhibitor.<\/jats:p>","DOI":"10.1002\/anie.202212190","type":"journal-article","created":{"date-parts":[[2022,10,25]],"date-time":"2022-10-25T04:59:46Z","timestamp":1666673986000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Synthesis and Biological Evaluation of C(13)\/C(13\u2032)\u2010Bis(desmethyl)disorazole\u2005Z**"],"prefix":"10.1002","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3810-8407","authenticated-orcid":false,"given":"Christian Paul","family":"Bold","sequence":"first","affiliation":[{"name":"Department of Chemistry and Applied Biosciences Institute of Pharmaceutical Sciences ETH Z\u00fcrich  Vladimir-Prelog-Weg 4 8093 Z\u00fcrich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7314-8696","authenticated-orcid":false,"given":"Daniel","family":"Lucena\u2010Agell","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Biol\u00f3gicas Margarita Salas Consejo Superior de Investigaciones Cient\u00edficas  Ramiro de Maeztu 9 28040 Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2215-4639","authenticated-orcid":false,"given":"Mar\u00eda \u00c1ngela","family":"Oliva","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Biol\u00f3gicas Margarita Salas Consejo Superior de Investigaciones Cient\u00edficas  Ramiro de Maeztu 9 28040 Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2743-3319","authenticated-orcid":false,"given":"Jos\u00e9 Fernando","family":"D\u00edaz","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Biol\u00f3gicas Margarita Salas Consejo Superior de Investigaciones Cient\u00edficas  Ramiro de Maeztu 9 28040 Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0747-9734","authenticated-orcid":false,"given":"Karl\u2010Heinz","family":"Altmann","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Applied Biosciences Institute of Pharmaceutical Sciences ETH Z\u00fcrich  Vladimir-Prelog-Weg 4 8093 Z\u00fcrich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,12,20]]},"reference":[{"key":"e_1_2_7_1_1","doi-asserted-by":"publisher","DOI":"10.1002\/jlac.199419940802"},{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.7164\/antibiotics.48.31"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2003.10.029"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.108.147330"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.0c07094"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.accounts.8b00537"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1039\/b813799b"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja0443068"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja509973r"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201501922"},{"key":"e_1_2_7_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201501922"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.orglett.1c01123"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.7b09843"},{"key":"e_1_2_7_13_1","unstructured":"\u00a0"},{"key":"e_1_2_7_14_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1747-0285.2005.00313.x"},{"key":"e_1_2_7_15_2","doi-asserted-by":"publisher","DOI":"10.1351\/pac200779040753"},{"key":"e_1_2_7_16_2","doi-asserted-by":"publisher","DOI":"10.1021\/ol2015994"},{"key":"e_1_2_7_17_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.joc.8b02137"},{"key":"e_1_2_7_18_1","unstructured":"H.Irschik R.Jansen F.Sasse European Patent Application EP 1743897A1 2007. This is the earliest publication on disorazole\u2005Z (1) that can be found in SciFinder. However the compound is first mentioned in the 2001 annual report of the Helmholtz Institute for Infection Research Braunschweig Germany."},{"key":"e_1_2_7_19_1","unstructured":"The absolute and relative configuration of1has not been explicitly reported in the literature. Kalesse in Ref.\u2005[21] pointed out that the configuration at C(13)\/C(13\u2032) was unknown at the time. However based on the structural data on the complex of tubulin and1in Ref.\u2005[19] it was safe to assume that the configuration of this stereocenter isR."},{"key":"e_1_2_7_20_1","doi-asserted-by":"crossref","unstructured":"B. Aicher K. Hirschfelder R. Jansen H. Irschik P. Schmidt J. Engel E. Guenther R. M\u00fcller M. Teifel Mol. 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Altmann unpublished results."},{"key":"e_1_2_7_31_1","unstructured":"Similar observations have been reported by Hoveyda for the attempted synthesis of disorazole C1through esterification\/macrolactonisation-based cyclodimerization.[9]"},{"key":"e_1_2_7_32_1","unstructured":"\u00a0"},{"key":"e_1_2_7_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4039(96)02395-7"},{"key":"e_1_2_7_34_2","doi-asserted-by":"publisher","DOI":"10.1021\/ol990004c"},{"key":"e_1_2_7_35_1","unstructured":"For a very low-yielding (2\u2009%) attempt at the construction of the marinomycin macrocycle through cyclodimerizing Suzuki coupling see:"},{"key":"e_1_2_7_36_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja068053p"},{"key":"e_1_2_7_37_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201601832"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1021\/ol201548m"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo070159v"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1039\/C7SC01625E"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tet.2016.08.029"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo5027639"},{"key":"e_1_2_7_43_1","unstructured":"A.De Lera B.Dominguez United States Patent Application US 6534545 B1 2003."},{"key":"e_1_2_7_44_1","unstructured":"\u00a0"},{"key":"e_1_2_7_45_2","doi-asserted-by":"publisher","DOI":"10.1039\/c39870001625"},{"key":"e_1_2_7_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tet.2005.06.080"},{"key":"e_1_2_7_47_1","unstructured":"\u00a0"},{"key":"e_1_2_7_48_2","doi-asserted-by":"publisher","DOI":"10.3891\/acta.chem.scand.27-0888"},{"key":"e_1_2_7_49_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo01294a058"},{"key":"e_1_2_7_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4020(01)97963-3"},{"key":"e_1_2_7_51_1","unstructured":"Both the intermediate aldehyde formed by Ley\u2013Griffith oxidation of15as well as acid7were found to be unstable on silica gel and were thus used crude in the subsequent steps."},{"key":"e_1_2_7_52_1","doi-asserted-by":"publisher","DOI":"10.1021\/ol005777b"},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.joc.7b00023"},{"key":"e_1_2_7_54_1","unstructured":"If the hydroxy group was protected as a PMB-ether the subsequent reaction with crotonaldehyde (11) produced a complex product mixture. 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These data are provided free of charge by the joint Cambridge Crystallographic Data Centre and Fachinformationszentrum KarlsruheAccess Structures service."},{"key":"e_1_2_7_62_1","unstructured":"\u00a0"},{"key":"e_1_2_7_63_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja991191c"},{"key":"e_1_2_7_64_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja3001776"},{"key":"e_1_2_7_65_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201002916"},{"key":"e_1_2_7_65_2","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201002916"},{"key":"e_1_2_7_66_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja105704m"},{"key":"e_1_2_7_67_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo00170a070"},{"key":"e_1_2_7_68_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4039(00)99640-0"},{"key":"e_1_2_7_69_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tet.2005.09.055"},{"key":"e_1_2_7_70_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tetlet.2010.10.092"},{"key":"e_1_2_7_71_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.197805221"},{"key":"e_1_2_7_71_2","doi-asserted-by":"publisher","DOI":"10.1002\/ange.19780900718"},{"key":"e_1_2_7_72_1","doi-asserted-by":"publisher","DOI":"10.1246\/bcsj.52.1989"},{"key":"e_1_2_7_73_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr800278z"},{"key":"e_1_2_7_74_1","doi-asserted-by":"publisher","DOI":"10.1039\/b805299a"},{"key":"e_1_2_7_75_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-14-0012"},{"key":"e_1_2_7_76_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2005.09.010"},{"key":"e_1_2_7_77_1","unstructured":"\u00a0"},{"key":"e_1_2_7_78_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.6372095"},{"key":"e_1_2_7_79_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.52.4.613"},{"key":"e_1_2_7_80_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-10-0644"},{"key":"e_1_2_7_81_1","doi-asserted-by":"publisher","DOI":"10.1002\/chem.202103520"},{"key":"e_1_2_7_82_1","unstructured":"For a discussion of the correlation (or lack thereof) between tubulin binding constants and inhibition of microtubule assembly by tubulin polymerization inhibitors see Ref.\u2005[56]."},{"key":"e_1_2_7_83_1","unstructured":"No biological data for any disorazole lacking the characteristic side chain have been published in the literature so far. Ref.\u2005[13b] states that the removal of the side chains from disorazole C1\u201cdestroys activity\u201d but no actual data are presented."}],"container-title":["Angewandte Chemie International Edition"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.202212190","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/anie.202212190","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.202212190","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,19]],"date-time":"2023-08-19T05:47:36Z","timestamp":1692424056000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/anie.202212190"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,20]]},"references-count":88,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2023,1,26]]}},"alternative-id":["10.1002\/anie.202212190"],"URL":"https:\/\/doi.org\/10.1002\/anie.202212190","archive":["Portico"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.26434\/chemrxiv-2022-jwlzk","asserted-by":"object"}]},"ISSN":["1433-7851","1521-3773"],"issn-type":[{"value":"1433-7851","type":"print"},{"value":"1521-3773","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,20]]},"assertion":[{"value":"2022-08-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-12-20","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e202212190"}}