Efficient syntheses of 25,26-dihydrodictyostatin and 25,26-dihydro-6-epi-dictyostatin, two potent new microtubule-stabilizing agents

The dictyostatins are powerful microtubule-stabilizing agents that have shown antiproliferative activity against a variety of human cancer cell lines. Two highly active analogs of dictyostatin, 25,26-dihydrodictyostatin and 25,26-dihydro-6-epi-dictyostatin, were prepared by a new streamlined total synthesis route. Three complete carbon fragments were prepared to achieve maximum convergency. These were coupled by a Horner-Wadsworth-Emmons reaction sequence and an esterification. A late stage Nozaki-Hiyama-Kishi reaction was then used to form the 22-membered macrolide. The stereoselectivity of this reaction depended on the configurations of the nearby stereocenter at C6.