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Here, we report a modular and enantioselective synthetic strategy featuring a biomimetic macrocyclization\u2013aromatization cascade that enables rapid access to natural and unnatural RMs. Using this route, we generated a small panel of minimal RMs, introducing covalent warheads, double bonds for macrocycle rigidification, and modifications at the C15 position, a position that has not been modified before. We also synthesized macrocyclic peptide\u2010RM hybrids, offering a platform for rapid diversification. We evaluated all analogs for inhibitory activity against Hsp90\u03b1 and Hsp90\u03b2 and for disruption of the KRas<jats:sup>G12C<\/jats:sup>\u2013CRAF protein\u2013protein interaction (PPI). We found that introduction of polar groups at C15 improved Hsp90 activity relative to the representative RM de\u2010<jats:italic>O<\/jats:italic>\u2010methyllasiodiplodin, dependent on stereochemistry, whereas introduction of larger groups at C15 or introduction of a trans double bond into the macrocycle reduced activity. Two analogs with poor Hsp90 inhibitory activity exhibited dose\u2010dependent inhibition of the KRas<jats:sup>G12C<\/jats:sup>\u2013CRAF PPI. This work demonstrates that strategic modifications of a minimal RM scaffold through modular chemical insight can provide foundational structure\u2013activity relationships for the class.<\/jats:p>","DOI":"10.1002\/chem.202501509","type":"journal-article","created":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T13:55:06Z","timestamp":1746626106000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Convergent Approach to Resorcinolic Macrolides to Expand Structural Diversity"],"prefix":"10.1002","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4424-0375","authenticated-orcid":false,"given":"Jesus M. 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