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These compounds belong to a class of heptapeptide natural products containing four non-proteinogenic amino acids, \u03b1-(hydroxymethyl)serine, (2S,3S)-\u03b1,\u03b2-diaminobutyric acid, dehydropiperazic acid, and E-dehydroisoleucine (E-\u0394-Ile). These natural products have received significant attention as drug leads to develop structurally unique antibacterial agents against M. tuberculosis. However, no total synthesis has been reported since their isolation in 1981 owing to their characteristic structural features. Herein, we report the first total synthesis of antrimycins A and D. The total synthesis features the use of an (\u03b1-phosphono)-N-Cbz-glycine ester as a synthetic equivalent of E-\u0394-Ile, enabling its stereoselective construction and incorporation into the peptide chain.<\/jats:p>","DOI":"10.1021\/acs.orglett.6c03818","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T03:01:30Z","timestamp":1790910090000},"page":"12989-12993","source":"Crossref","is-referenced-by-count":0,"title":["Total Synthesis\nof Antrimycins A and D"],"prefix":"10.1021","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6725-8610","authenticated-orcid":true,"given":"Yoko","family":"Yasuno","sequence":"first","affiliation":[{"name":"Osaka Metropolitan University , , 3-3-138 Sugimoto , Sumiyoshi, ,","place":["Osaka, Japan, 558-8585"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akito","family":"Nishimura","sequence":"additional","affiliation":[{"name":"Osaka Metropolitan University , , 3-3-138 Sugimoto , Sumiyoshi, ,","place":["Osaka, Japan, 558-8585"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusaku","family":"Tamura","sequence":"additional","affiliation":[{"name":"Osaka Metropolitan University , , 3-3-138 Sugimoto , Sumiyoshi, ,","place":["Osaka, Japan, 558-8585"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibuki","family":"Fujiwara","sequence":"additional","affiliation":[{"name":"Osaka Metropolitan University , , 3-3-138 Sugimoto , Sumiyoshi, ,","place":["Osaka, Japan, 558-8585"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4072-3804","authenticated-orcid":true,"given":"Atsushi","family":"Nakayama","sequence":"additional","affiliation":[{"name":"Osaka Metropolitan University , , 3-3-138 Sugimoto , Sumiyoshi, ,","place":["Osaka, Japan, 558-8585"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motoko","family":"Shinohara","sequence":"additional","affiliation":[{"name":"Fujita Health University , , 1-98 Dengakugakubo , Kutsukake-cho, , ,","place":["Toyoake, Aichi, Japan, 470-1192"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0888-8564","authenticated-orcid":true,"given":"Yusuke","family":"Minato","sequence":"additional","affiliation":[{"name":"Fujita Health University , , 1-98 Dengakugakubo , Kutsukake-cho, , ,","place":["Toyoake, Aichi, Japan, 470-1192"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayoshi","family":"Arai","sequence":"additional","affiliation":[{"name":"The University of Osaka , , 1-6 Yamadaoka , , ,","place":["Suita, Osaka, Japan, 565-0871"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9145-1533","authenticated-orcid":true,"given":"Tetsuro","family":"Shinada","sequence":"additional","affiliation":[{"name":"Osaka Metropolitan University , , 3-3-138 Sugimoto , Sumiyoshi, ,","place":["Osaka, Japan, 558-8585"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"key":"2026101608471452000_cit1","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1039\/D3NP00041A","article-title":"Dehydroamino Acid Residues in Bioactive\nNatural Products","volume":"41","author":"Wang","year":"2024","journal-title":"Nat. Prod. Rep."},{"key":"2026101608471452000_cit2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s00726-014-1846-4","article-title":"\u03b1,\u03b2-Dehydroamino\nAcids in Naturally Occurring Peptides","volume":"47","author":"Siod\u0142ak","year":"2015","journal-title":"Amino\nAcids"},{"key":"2026101608471452000_cit3","doi-asserted-by":"publisher","first-page":"4625","DOI":"10.1039\/D4OB00507D","article-title":"Efficient\nSynthetic Methods for \u03b1,\u03b2-Dehydroamino Acids as Useful\nand Environmentally Benign Building Blocks in Biological and Materials\nScience","volume":"22","author":"Mori","year":"2024","journal-title":"Org. Biomol. Chem."},{"key":"2026101608471452000_cit4","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1016\/j.trechm.2022.04.008","article-title":"Dehydroalanine Modification\nSees the Light: a Photochemical Conjugate Addition Strategy","volume":"4","author":"Peng","year":"2022","journal-title":"Trends Chem."},{"key":"2026101608471452000_cit5","doi-asserted-by":"publisher","first-page":"3653","DOI":"10.1039\/C8OB03155J","article-title":"Dehydroamino Acids: Chemical Multi-Tools\nfor Late-Stage\nDiversification","volume":"17","author":"Bogart","year":"2019","journal-title":"Org. Biomol. Chem."},{"key":"2026101608471452000_cit6","doi-asserted-by":"publisher","first-page":"1613","DOI":"10.7164\/antibiotics.34.1613","article-title":"Antrimycin, A New Peptide\nAntibiotic","volume":"34","author":"Shimada","year":"1981","journal-title":"J. Antibiot."},{"key":"2026101608471452000_cit7","doi-asserted-by":"publisher","first-page":"1615","DOI":"10.7164\/antibiotics.34.1615","article-title":"The Structure\nof Antrimycin","volume":"34","author":"Morimoto","year":"1981","journal-title":"J. Antibiot."},{"key":"2026101608471452000_cit8","doi-asserted-by":"publisher","first-page":"378","DOI":"10.7164\/antibiotics.35.378","article-title":"Minor Congeners of\nAntrimycin: Application of Secondary\nIon Mass Spectrometry (SIMS) to Structure Determination","volume":"35","author":"Morimoto","year":"1982","journal-title":"J. Antibiot."},{"key":"2026101608471452000_cit9","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1080\/00021369.1982.10865166","article-title":"Isolation and Structures of New Peptide\nAntibiotics, Cirratiomycin\nA and B","volume":"46","author":"Shiroza","year":"1982","journal-title":"Agric. Biol. Chem."},{"key":"2026101608471452000_cit10","doi-asserted-by":"publisher","first-page":"1891","DOI":"10.1271\/bbb1961.46.1891","article-title":"The Structures of Cirratiomycin\nA and B, the New Peptide Antibiotics","volume":"46","author":"Shiroza","year":"1982","journal-title":"Agric.\nBiol. Chem."},{"key":"2026101608471452000_cit11","doi-asserted-by":"publisher","first-page":"1186","DOI":"10.1039\/c39920001186","article-title":"The Total Synthesis of Antrimycin Dv","author":"Schmidt","year":"1992","journal-title":"J. Chem.\nSoc., Chem. Commun."},{"key":"2026101608471452000_cit12","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1055\/s-1993-25947","article-title":"The Total Synthesis\nof Antrimycin Dv; II: Synthesis of Tetrahydropyridazinecarboxylic\nAcid and Its Incorporation into Peptides","volume":"1993","author":"Schmidt","year":"1993","journal-title":"Synthesis"},{"key":"2026101608471452000_cit13","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1055\/s-1993-25948","article-title":"The Total Synthesis\nof Antrimycin Dv; III: Construction of the Protected\nHexapeptide and Deprotection","volume":"1993","author":"Schmidt","year":"1993","journal-title":"Synthesis"},{"key":"2026101608471452000_cit14","doi-asserted-by":"publisher","first-page":"2151","DOI":"10.1246\/bcsj.67.2151","article-title":"Dehydrooligopeptides.\nXVI. Convenient Syntheses of\nTwo Kinds of Antrimycins Av and Dv Containing Dehydrovaline Residues","volume":"67","author":"Nakamura","year":"1994","journal-title":"Bull. Chem. Soc. 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Ed."},{"key":"2026101608471452000_cit21","doi-asserted-by":"publisher","first-page":"4564","DOI":"10.1002\/anie.201916517","article-title":"Solid-Phase Total Synthesis of Yaku\u2018amide\nB Enabled by Traceless\nStaudinger Ligation","volume":"59","author":"Itoh","year":"2020","journal-title":"Angew. Chem., Int. Ed."},{"key":"2026101608471452000_cit22","doi-asserted-by":"publisher","DOI":"10.1002\/ajoc.202300227","article-title":"Rhodium-Catalyzed\nC\u2013H Alkylation for the Stereoselective Synthesis of \u03b2,\u03b2-Disubstituted\nDehydroamino-Acid Motifs","volume":"12","author":"Nanjo","year":"2023","journal-title":"Asian J. Org. Chem."},{"key":"2026101608471452000_cit23","doi-asserted-by":"publisher","first-page":"1478","DOI":"10.1039\/C5CC08458J","article-title":"The Stereoselective\nConstruction of E- and Z-\u0394-Ile\nfrom E-Dehydroamino\nAcid Ester: the Synthesis of the Phomopsin A Tripeptide Side Chain","volume":"52","author":"Yasuno","year":"2016","journal-title":"Chem. Commun."},{"key":"2026101608471452000_cit24","doi-asserted-by":"publisher","first-page":"1884","DOI":"10.1002\/ejoc.201300112","article-title":"Stereoselective\nSynthesis of (E)-\u03b1,\u03b2-Dehydroamino Acid\nEsters","volume":"2013","author":"Yasuno","year":"2013","journal-title":"Eur. J. Org. Chem."},{"key":"2026101608471452000_cit25","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.1002\/psc.1054","article-title":"Chemistry\nof \u03b1-Hydroxymethylserine: Problems and Solutions","volume":"14","author":"Stasiak","year":"2008","journal-title":"J. Pept. Sci."},{"key":"2026101608471452000_cit26","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1016\/j.bmc.2018.12.004","article-title":"The Effect\nof Replacing the Ester Bond with an Amide Bond and of Overall Stereochemistry\non the Activity of Daptomycin","volume":"27","author":"Moreira","year":"2019","journal-title":"Bioorg. Med.\nChem."},{"key":"2026101608471452000_cit27","doi-asserted-by":"publisher","first-page":"6899","DOI":"10.1021\/jo034441n","article-title":"Lipase TL-Mediated Kinetic Resolution\nof 5-Benzyloxy-1-tert-butyldimethylsilyloxy-2-pentanol\nat Low Temperature: Concise Asymmetric Synthesis of Both Enantiomers\nof a Piperazic Acid Derivative","volume":"68","author":"Aoyagi","year":"2003","journal-title":"J. Org. Chem."},{"key":"2026101608471452000_cit28a","doi-asserted-by":"publisher","first-page":"2977","DOI":"10.1039\/c3cc00178d","article-title":"Total Synthesis of\nPadanamides A and B","volume":"49","author":"Long","year":"2013","journal-title":"Chem. Commun."},{"key":"2026101608471452000_cit28b","doi-asserted-by":"publisher","first-page":"4394","DOI":"10.1021\/jo00042a016","article-title":"Use of N-Fmoc Amino Acid Chlorides and Activated 2-(Fluorenylmethoxy)-5(4H)-oxazolones in Solid-Phase Peptide Synthesis. Efficient\nSyntheses of Highly N-Alkylated Cyclic Hexapeptide Oxytocin Antagonists\nRelated to L-365,209","volume":"57","author":"Perlow","year":"1992","journal-title":"J. Org. Chem."},{"key":"2026101608471452000_cit29","doi-asserted-by":"publisher","first-page":"1378","DOI":"10.1002\/anie.200462207","article-title":"A Mild\nand Selective Method for the Hydrolysis of Esters with Trimethyltin\nHydroxide","volume":"44","author":"Nicolaou","year":"2005","journal-title":"Angew. Chem., Int. Ed."},{"key":"2026101608471452000_cit30","doi-asserted-by":"publisher","first-page":"11354","DOI":"10.1002\/anie.201205747","article-title":"Pd-PEPPSI-IPentCl: A Highly Effective Catalyst\nfor the Selective Cross-Coupling\nof Secondary Organozinc Reagents","volume":"51","author":"Pompeo","year":"2012","journal-title":"Angew. Chem.,\nInt. Ed."}],"container-title":["Organic Letters"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.orglett.6c03818","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/orlef7\/article-pdf\/28\/41\/12989\/68731330\/acs.orglett.6c03818.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/orlef7\/article-pdf\/28\/41\/12989\/68731330\/acs.orglett.6c03818.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T13:03:56Z","timestamp":1792155836000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/orlef7\/article\/28\/41\/12989\/5443649\/Total-Synthesis-of-Antrimycins-A-and-D"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,1]]},"references-count":31,"journal-issue":{"issue":"41","published-online":{"date-parts":[[2026,10,1]]},"published-print":{"date-parts":[[2026,10,16]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.orglett.6c03818","relation":{},"ISSN":["1523-7060","1523-7052"],"issn-type":[{"value":"1523-7060","type":"print"},{"value":"1523-7052","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,1]]}}}