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HYA024 strain. This naturally occurring substance was reported to show remarkable cytotoxic activity against human cancer cell lines HeLa and DG\u201075 and in vivo antitumor activity against murine leukemia P388 cell line. Herein, the total synthesis, stereochemical revision, and biological assessment of iriomoteolide\u20102a are reported in detail. Total synthesis of the proposed structure <jats:bold>1<\/jats:bold> of iriomoteolide\u20102a featured a late\u2010stage convergent assembly of three components by a Suzuki\u2013Miyaura coupling, an esterification, and a ring\u2010closing metathesis. However, the NMR data of synthetic <jats:bold>1<\/jats:bold> were not identical to those of the natural product. Careful analysis of the NMR data of the authentic material and synthesis\/NMR analysis of appropriately designed model compounds led to consideration of four possible stereoisomers <jats:bold>2<\/jats:bold>\u2013<jats:bold>5<\/jats:bold> as candidates for the correct structure. Accordingly, total syntheses of <jats:bold>2<\/jats:bold>\u2013<jats:bold>5<\/jats:bold> were achieved by taking advantage of the convergent strategy, and comparison of the NMR spectra of synthetic <jats:bold>2<\/jats:bold>\u2013<jats:bold>5<\/jats:bold> with those of the natural product led to the conclusion that <jats:bold>5<\/jats:bold> shows the correct relative configuration of iriomoteolide\u20102a. The absolute configuration of this natural product was finally established through chiral HPLC analysis of synthetic <jats:bold>5<\/jats:bold>\/<jats:italic>ent<\/jats:italic>\u2010<jats:bold>5<\/jats:bold> with the authentic sample. The antiproliferative activity of the synthetic compounds was assessed against HeLa and A549 cells to show that, in contrast to expectation, synthetic <jats:bold>5<\/jats:bold> and <jats:italic>ent<\/jats:italic>\u2010<jats:bold>5<\/jats:bold> were only marginally active in these cell lines. This work clearly underscores the vital role of total synthesis in the establishment of the structure and biological activity of natural products.<\/jats:p>","DOI":"10.1002\/chem.201900813","type":"journal-article","created":{"date-parts":[[2019,3,18]],"date-time":"2019-03-18T15:35:41Z","timestamp":1552923341000},"page":"8528-8542","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Total Synthesis, Stereochemical Revision, and Biological Assessment of Iriomoteolide\u20102a"],"prefix":"10.1002","volume":"25","author":[{"given":"Keita","family":"Sakamoto","sequence":"first","affiliation":[{"name":"Department of Applied Chemistry Faculty of Science and Engineering Chuo University  1-13-27 Kasuga Bunkyo-ku Tokyo 112-8551 Japan"},{"name":"Graduate School of Life Sciences Tohoku University  2-1-1 Katahira Aoba-ku Sendai 980-8577 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akihiro","family":"Hakamata","sequence":"additional","affiliation":[{"name":"Graduate School of Life Sciences Tohoku University  2-1-1 Katahira Aoba-ku Sendai 980-8577 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arihiro","family":"Iwasaki","sequence":"additional","affiliation":[{"name":"Department of Chemistry Faculty of Science and Technology Keio University  3-14-1 Hiyoshi Kohoku-ku Yokohama 223-8522 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5343-5890","authenticated-orcid":false,"given":"Kiyotake","family":"Suenaga","sequence":"additional","affiliation":[{"name":"Department of Chemistry Faculty of Science and Technology Keio University  3-14-1 Hiyoshi Kohoku-ku Yokohama 223-8522 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masashi","family":"Tsuda","sequence":"additional","affiliation":[{"name":"Center for Advanced Marine Core Research and Department of, Agriculture and Marine Science Kochi University  Nankoku Kochi 783-8502 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5343-9023","authenticated-orcid":false,"given":"Haruhiko","family":"Fuwa","sequence":"additional","affiliation":[{"name":"Department of Applied Chemistry Faculty of Science and Engineering Chuo University  1-13-27 Kasuga Bunkyo-ku Tokyo 112-8551 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,5,17]]},"reference":[{"key":"e_1_2_6_1_1","unstructured":"For recent reviews on marine macrolides 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typical acyclic and cyclic systems stereochemical interactions of stereogenic centers flanking three or more bonds are almost negligible in1H and13C\u2005NMR spectroscopy (ref.\u2005[39g]). However it appears that some macrocyclic systems are exceptions to this empirical rule; for example we have observed long-range stereochemical communication between remote stereogenic centers in a 14-membered macrolactone system of neopeltolide (ref.\u2005[8c])."},{"key":"e_1_2_6_132_1","unstructured":"Compound 24-epi-24was obtained as the minor diastereomer of24."},{"key":"e_1_2_6_133_1","unstructured":"\u00a0"},{"key":"e_1_2_6_134_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo9614349"},{"key":"e_1_2_6_135_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo961205m"},{"key":"e_1_2_6_136_1","unstructured":"Compoundent-8was prepared in a similar manner to that of8(ref.\u2005[36])."},{"key":"e_1_2_6_137_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja0526867"},{"key":"e_1_2_6_138_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja011257f"},{"key":"e_1_2_6_139_1","doi-asserted-by":"publisher","DOI":"10.1039\/a809656b"},{"key":"e_1_2_6_140_1","unstructured":"Antiproliferative activity of compounds1\u20134was also moderate against A549 cells. For details see Table\u2005S7 in the Supporting Information."},{"key":"e_1_2_6_141_1","unstructured":"DinoflagellateAmphidiniumsp. HYA024 strain is also known to produce iriomoteolides-1a -1b -1c -3a -4a and -5a:"},{"key":"e_1_2_6_142_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo070414b"},{"key":"e_1_2_6_143_2","doi-asserted-by":"publisher","DOI":"10.1021\/np0702537"},{"key":"e_1_2_6_144_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo702440s"},{"key":"e_1_2_6_145_2","doi-asserted-by":"publisher","DOI":"10.3987\/COM-13-12841"},{"key":"e_1_2_6_146_1","unstructured":"For reviews of structural reassignment of natural products by means of total synthesis see:"},{"key":"e_1_2_6_147_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200460864"},{"key":"e_1_2_6_147_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.200460864"},{"key":"e_1_2_6_148_2","doi-asserted-by":"publisher","DOI":"10.1039\/b809658a"},{"key":"e_1_2_6_149_2","doi-asserted-by":"publisher","DOI":"10.3390\/md7030314"},{"key":"e_1_2_6_150_1","unstructured":"\u00a0"},{"key":"e_1_2_6_151_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja066772y"},{"key":"e_1_2_6_152_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja305864z"},{"key":"e_1_2_6_153_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201204303"},{"key":"e_1_2_6_154_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201303713"},{"key":"e_1_2_6_155_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.joc.6b00290"}],"container-title":["Chemistry \u2013 A European Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/chem.201900813","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/chem.201900813","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/chem.201900813","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T17:34:02Z","timestamp":1760290442000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/chem.201900813"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,5,17]]},"references-count":174,"journal-issue":{"issue":"36","published-print":{"date-parts":[[2019,6,26]]}},"alternative-id":["10.1002\/chem.201900813"],"URL":"https:\/\/doi.org\/10.1002\/chem.201900813","archive":["Portico"],"relation":{},"ISSN":["0947-6539","1521-3765"],"issn-type":[{"value":"0947-6539","type":"print"},{"value":"1521-3765","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,5,17]]},"assertion":[{"value":"2019-02-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-05-17","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}