Journal
CHEMISTRY-A EUROPEAN JOURNAL
Volume 21, Issue 26, Pages 9370-9379Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.201501370
Keywords
aeruginosin; CH activation; marine natural products; palladium catalysis; total synthesis
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Funding
- Region Rhone-Alpes (ARC Sante)
- Fondation Pierre Potier pour le Developpement de la Chimie des Substances Naturelles et ses Applications
- Institut Universitaire de France
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A general and scalable access to the aeruginosin family of marine natural products, exhibiting potent inhibitory activity against serine proteases, is reported. This was enabled by the strategic use of two recently implemented Pd-catalyzed C(sp(3))H activation reactions. The first method allowed us to obtain the common 2-carboxy-6-hydroxyoctahydroindole (Choi) core of the target molecules on a large scale, whereas the second method provided a rapid and divergent access to various hydroxyphenyllactic (Hpla) subunits, including halogenated ones. This unique strategy, together with an optimization of the fragment coupling sequence allowed the synthesis of four aeruginosins, that is, 98A-C and 298A from the chiral pool. Among them, aeruginosin 298A was synthesized on an unprecedentedly large scale. In addition, halogenated aeruginosins 98A and 98C were synthesized for the first time, thanks to a fine-tuning of the final hydrogenation step.
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