Studies toward the Synthesis of an Oxazole-Based Analog of (-)-Zampanolide.

Studies are described toward the synthesis of an oxazole-based analog of (-)-zampanolide (2). Construction of (-)-dactylolide analog 22 was achieved via alcohol 5 and acid 4 through esterification and Horner-Wadsworth-Emmons (HWE)-based macrocyclization; however, attempts to attach (Z,E)-sorbamide to 22 proved unsuccessful. The C(8)-C(9) double bond of the macrocycle was prone to migration into conjugation with the oxazole ring, which may generally limit the usefulness of zampanolide analogs with aromatic moieties as tetrahydropyran replacements.

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

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.