Premium
Synthesis of Morpholine‐Based Analogues of (−)‐Zampanolide and Their Biological Activity
Author(s) -
Bold Christian Paul,
Gut Melanie,
Schürmann Jasmine,
LucenaAgell Daniel,
Gertsch Jürg,
Díaz José Fernando,
Altmann KarlHeinz
Publication year - 2021
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202003996
Subject(s) - morpholine , chemistry , moiety , stereochemistry , natural product , aldehyde , intramolecular force , hemiaminal , epoxide , derivative (finance) , organic chemistry , catalysis , financial economics , economics
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.