Synthesis of Morpholine‐Based Analogues of (−)‐Zampanolide and Their Biological Activity

• Published in: Chemistry : a European journal Vol. 27; no. 19; pp. 5936 - 5943
• Main Authors: Bold, Christian Paul, Gut, Melanie, Schürmann, Jasmine, Lucena‐Agell, Daniel, Gertsch, Jürg, Díaz, José Fernando, Altmann, Karl‐Heinz
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 01.04.2021; Wiley Subscription Services, Inc
• Subjects: Aldehydes; Antineoplastic Agents; Biological activity; Biological Products - pharmacology; Chemistry; Chemistry, Multidisciplinary; Construction; Cytotoxicity; macrocyclization; Macrolides - pharmacology; Molecular Structure; Morpholine; Morpholines - pharmacology; Natural products; Nucleophiles; Physical Sciences; Science & Technology; Stereoisomerism; stereoselective aza aldol reaction; Stereoselectivity; structure–activity relationships; Synthesis; total synthesis; zampanolide; (-)-DACTYLOLIDE; ASYMMETRIC-SYNTHESIS; DRUG DISCOVERY; stereoselective aza aldol reaction; zampanolide; activity relationships; MARINE NATURAL-PRODUCTS; STANNYLCUPRATION; macrocyclization; BINDING-AFFINITY; CONSTRUCTION; structure– AXIALLY DISSYMMETRIC MOLECULES; AGENTS; total synthesis; ENANTIOSELECTIVE TOTAL-SYNTHESIS; structure-activity relationships
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.202003996

We describe the convergent synthesis of three prototypical examples of a new class of analogues of the complex, cytotoxic marine macrolide (−)‐zampanolide that incorporate an embedded N‐substituted morpholine moiety in place of the natural tetrahydropyran ring. The final construction of the macrolactone core was based on a high‐yielding intramolecular HWE olefination, while the hemiaminal‐linked side chain was elaborated through a stereoselective, BINAL‐H‐mediated addition of (Z,E)‐sorbamide to a macrocyclic aldehyde precursor. The synthesis of the common functionalized morpholine building block involved two consecutive epoxide openings with tosylamide and the product of the first opening reaction, respectively, as nucleophiles. Of the three morpholino‐zampanolides investigated, the N‐acetyl and the N‐benzoyl derivatives both exhibited nanomolar antiproliferative activity, thus being essentially equipotent with the natural product. In contrast, the activity of the N‐tosyl derivative was significantly reduced. Opening up activity: A synthetic approach has been developed towards a new class of analogues of the marine macrolide (−)‐zampanolide. The morpholine core replacing the tetrahydropyran ring was elaborated from epoxides and tosyl amide. The macrocycle was closed by a HWE reaction, and a stereoselective aza‐aldol reaction installed the sorbamide‐derived side chain. Two analogues showed nm antiproliferative activity.