Total synthesis of fostriecin

Protein phosphatases 1 and 2A (PP1 and PP2A) have been implicated in the regulation of cells' entry into mitosis. Fostriecin (1) has shown ten thousand fold selectivity in the inhibition of PP2A over PP1. Selective phosphatase inhibitors such as fostriecin aid in the study of each of the individual phophatases. To this end we have undertaken the total synthesis of fostriecin. Two different retrosynthetic strategies were devised. Both strategies envision a chelation-controlled addition of an anionic unit to a methyl ketone to couple the fragments and set the stereochemistry at the tertiary carbinol center found in fostriecin. The two strategies differ, however, in their disconnection of the triene unit. The first strategy proposes the addition of the entire tail at once and the second-generation retrosynthesis cuts the triene moiety between the two cis-olefins. To date, a novel synthetic pathway was devised and a formal total synthesis of fostriecin was executed. This progress will allow the construction of analogues of fostriecin to further understand what structural elements are necessary for binding to individual phosphatases.