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The optimized synthetic route features a Zn<jats:sup>II<\/jats:sup>\u2010mediated intramolecular Horner\u2013Wadsworth\u2013Emmons (HWE) reaction resulting in a highly stereoselective formation of the strained 12\u2010membered macrolactone of lactimidomycin on a 423\u2005mg scale. The presence of the <jats:italic>E<\/jats:italic>,<jats:italic>Z<\/jats:italic>\u2010diene functionality was found to be key for effective macrocyclizations as a complete removal of these unsaturation units resulted in exclusive formation of the dimer rather than monocyclic enoate. The synthetic route features a late\u2010stage installation of the glutarimide functionality via an asymmetric catalytic Mukaiyama aldol reaction, which allows for a quick generation of lactimidomycin homolog <jats:bold>55<\/jats:bold> containing two additional carbons in the glutarimide side chain. Similar to lactimidomycin, this analog was found to possess cytotoxicity against MDA\u2010MB\u2010231 breast cancer cells (GI<jats:sub>50<\/jats:sub>=1\u20133\u2009\u03bcM) using in vitro 2D and 3D assays. Although lactimidomycin was found to be the most potent compound in terms of anticancer activity, <jats:bold>55<\/jats:bold> as well as truncated analogues <jats:bold>50<\/jats:bold>\u2013<jats:bold>52<\/jats:bold> lacking the glutarimide side\u2010chain were found to be significantly less toxic against human mammary epithelial cells.<\/jats:p>","DOI":"10.1002\/chem.201503527","type":"journal-article","created":{"date-parts":[[2015,11,18]],"date-time":"2015-11-18T07:37:59Z","timestamp":1447832279000},"page":"19159-19167","source":"Crossref","is-referenced-by-count":12,"title":["Synthesis and Biological Evaluation of Lactimidomycin and Its Analogues"],"prefix":"10.1002","volume":"21","author":[{"given":"Brian J.","family":"Larsen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhankui","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"Lachacz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaroslav","family":"Khomutnyk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew B.","family":"Soellner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pavel","family":"Nagorny","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2015,11,18]]},"reference":[{"key":"e_1_2_6_1_2","unstructured":"\u00a0"},{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.7164\/antibiotics.45.1433"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.7164\/antibiotics.53.1130"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.7164\/antibiotics.55.141"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.201000370"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00253-010-3025-1"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/ja.2010.150"},{"key":"e_1_2_6_8_2","first-page":"14728","volume":"109","author":"Lee S.","year":"2012","journal-title":"Proc. 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