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(+)-Crocacin D


The crocacins are a group of compounds which are regularly found in the extracts of the Chondromyces crocatus and Chondromyces pediculatus strains and represent a second novel group of modified peptides from C. crocatus. Crocacin D shows higher biological activity against Saccharomyces cerevisiae as well as higher toxicity in L929 mouse fibroblast cell cultures, when compared to crocacins A-C. To provide material for more extensive biological evaluation, along with access to novel analogues, we have undertaken the total synthesis of the polyketide (+)-crocacin D, the most active compound in this series. Crocacin D, a dipeptide of glycine and 6-aminohexenoic acid, shows four consecutive stereocenters, three E-double bonds and a Z-enamide moiety, that is probably responsible for the pharmacological activity of the crocacins and represents the major synthetic challenge.

The total synthesis of (+)-crocacin D is described. The convergent asymmetric synthesis relies on the use of a Stille cross-coupling between an E-vinyl stannane with an E-vinyl iodide to establish the (E,E)-dienamide moiety followed by a mild and efficient copper-catalyzed coupling between (+)-crocacin C and a Z-vinyl iodide to establish the challenging Z-enamide function.

  1. “Total synthesis of (+)-crocacin D”. Dias, L.C.; de Oliveira, L.G.; Vilcachagua, J.D.; Nigsch, F. Journal of Organic Chemistry 2005, 70 , 2225-2234.

  2. "Total Synthesis of (+)-crocacin C". Dias, L.C.; de Oliveira, L.G. Organic Letters 2001, 3, 3951-3954.

 

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