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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Gertsch, Jürg

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1521-3765

Publisher:

Wiley

Language:

English

Submitter:

Barbara Franziska Järmann-Bangerter

Date Deposited:

21 Jan 2021 14:21

Last Modified:

21 Oct 2021 02:30

Publisher DOI:

10.1002/chem.202003996

PubMed ID:

33078440

Uncontrolled Keywords:

macrocyclization stereoselective aza aldol reaction total synthesis structure-activity relationship zampanolide

BORIS DOI:

10.48350/150918

URI:

https://boris.unibe.ch/id/eprint/150918

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