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Synthetic strategies for the synthesis and transformation of substituted pyrrolines as advanced intermediates for Rhazinilam analogues

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Publication date 2014
Author Inga Kholod, Olivier Vallat, Ana-Maria Buciumas, Reinhard Neier,
Project The hydrogenation of calix[4]pyrroles leading to the novel ligand system calix[4]pyrrolidine: Their properties and their application
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Original article (peer-reviewed)

Journal European Journal of Organic Chemistry
Volume (Issue) 35
Page(s) 7865 - 7877
Title of proceedings European Journal of Organic Chemistry

Abstract

The biaryl core structure of rhazinilam with its fixed dihedral angle is a pivotal element for its unique in vitro cytotoxic activity. Most of the related natural products are oxidized versions of rhazinilam. Replacing the sensitive pyrrole ring by a pyrrolinone ring is the basis of our initial strategy towards rhazinilam analogues. With this goal different variants of the sequence crossed Mukaiyama aldol reaction followed by the Staudinger reaction were studied. Reacting the adequately substituted acetophenone with the O-methyl-O-trimethylsilyl ketene acetal gave in good to excellent yields the pyrrolinones 8a and 8b. These intermediates could be transformed in four high-yielding steps into the pyrrolic precursors 7a-c containing all atoms necessary for the construction of the rings A, B and C of rhazinilam. Our studies illustrated a lack of stability of these intermediates. Alternative synthetic approaches towards this central biaryl core structure are described.
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