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These analogs were derived from 13\u2010desmethylene\u2010(\u2212)\u2010zampanolide (DM\u2010ZMP), which is an equally potent cancer cell growth inhibitor as ZMP. Key steps in the synthesis of all compounds were the formation of the dioxabicyclo[15.3.1]heneicosane core by an intramolecular HWE reaction (67\u201395\u2009% yield) and a stereoselective aza\u2010aldol reaction with an (\n                    <jats:italic>S<\/jats:italic>\n                    )\u2010BINOL\u2010derived sorbamide transfer complex, to establish the C(20) stereocenter (24\u201371\u2009% yield). As the sole exception, for the 5\u2010desmethyl macrocycle, ring\u2010closure relied on macrolactonization; however, elaboration of the macrocyclization product into the corresponding zampanolide analog was unsuccessful. All modifications led to reduced cellular activity and lowered microtubule\u2010binding affinity compared to DM\u2010ZMP, albeit to a different extent. For compounds incorporating the reactive enone moiety of ZMP, IC\n                    <jats:sub>50<\/jats:sub>\n                    values for cancer cell growth inhibition varied between 5 and 133\u2005nM, compared to 1\u201312\u2005nM for DM\u2010ZMP. Reduction of the enone double bond led to a several hundred\u2010fold loss in growth inhibition. The cellular potency of 2,3\u2010dihydro\u201013\u2010desmethylene zampanolide, as the most potent analog identified, remained within a ninefold range of that of DM\u2010ZMP.\n                  <\/jats:p>","DOI":"10.1002\/chem.202300703","type":"journal-article","created":{"date-parts":[[2023,4,14]],"date-time":"2023-04-14T09:00:14Z","timestamp":1681462814000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Synthesis and Structure\u2010Activity Relationship Studies of C(13)\u2010Desmethylene\u2010(\u2212)\u2010Zampanolide Analogs"],"prefix":"10.1002","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7246-7166","authenticated-orcid":false,"given":"Tobias M.","family":"Br\u00fctsch","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"},{"name":"Current address: 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