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

DOI
Publisher DOI
PubMed ID
33078440
Abstract
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.
Date Issued
2021-04-01
Publication Type
Article
Subject(s)
Subjects
macrocyclization
stereoselective aza aldol reaction
total synthesis
structure-activity relationship
zampanolide
Language(s)
en
Author(s)
Altmann, Karl-Heinz
Bold, Christian Paul
Gut, Melanie
Schürmann, Jasmine
Lucena Agell, Daniel
Diaz, Jose Fernando
Additional Credits
Journal
Chemistry: a European journal
Publisher
Wiley
ISSN
1521-3765
Access(Rights)
open.access
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