Fostriecin (1), a novel secondary metabolite of Streptomyces pulveraceus, is a selective inhibitor of protein phosphatase 2A (PP2A), and displays antitumor activity against a diverse panel of tumor cell lines and in vivo toward lymphoid leukwmias. Because of its important biological activity, fostriecin has attracted many synthetic chemists. Our synthetic strategy is to control the stereocenters using the existing stereogenic centers as much as possible. Our retrosynthetic analysis is as follows: The stereogenic center at C11 would be constructed by 1,3-asymmetric induction using C9 chiral center. The stereochemistry at C5 would be controlled by the chiral center at C8 via 1,4-asymmetric induction. A catalytic asymmetric dihydroxylation of homoallylic alcohol 8 is the only asymmetric reaction using external chiral reagent. Another noteworthy feature is the construction of a labile (Z,Z,E)-triene unit, which would be synthesized by the reduction of the more stable dieneyne at the later stage of the synthesis. In this scenario, one of the most difficult transformations would be the 1,4-chiral induction. We have developed an efficient and highly diastereoselective 1,4-asymmetric induction based on the novel methodology using cobalt-alkyne complex. Using this reaction as a key step, we have accomplished a synthesis of protected dephosphofostriecin 2, a key intermediate in Imanishi's synthesis of fostriecin in a highly stereo-selective manner.
