Synthesis of Morpholine-Based Analogs of (-)-Zampanolide and Their Biological Activity.

Altmann, Karl-Heinz; Bold, Christian Paul; Gut, Melanie; Schürmann, Jasmine; Lucena Agell, Daniel; Diaz, Jose Fernando; Gertsch, Jürg (2021). Synthesis of Morpholine-Based Analogs of (-)-Zampanolide and Their Biological Activity. Chemistry: a European journal, 27(19), pp. 5936-5943. Wiley 10.1002/chem.202003996

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We describe the convergent synthesis of three prototypical examples of a new class of analogs of the complex, cytotoxic marine macrolide (-)-zampanolide, which 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 two possible routes departing from two different pairs of enantiomeric epoxides, one proved to be clearly superior. Of the three morpholino-zampanolides investigated, the N- acetyl and the N- benzoyl derivative 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.

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