A Highly Stereoselective Total Synthesis of (–)-Dictyostatin

The sponge-derived macrolide (-)-dictyostatin (1) has been reported to exhibit paclitaxel-like effects on cellular microtubules and to inhibit human cancer cell proliferation (even of paclitaxel-resistant cancer cell lines) at low nanomolar concentrations, with activity somewhat superior to the already very active discodermolide.1 Although four total syntheses of (-)-dictyostatin were recently completed,2 the development of a practical and flexible synthesis remains an important goal, particularly as its natural supply is extremely scarce. Here we report a highly stereoselective total synthesis of (-)-dictyostatin, achived by coupling two key-fragments,3 C1-C9 (2) and C10-C26 (3), followed by Yamaguchi macrolactonization and global deprotection. The reported synthetic route offers the possibility of introducing variations in the dictyostatin skeleton, which will allow for the preparation of novel analogs. We thank the Ministero dell’Università e della Ricerca for financial support (PRIN prot. 2008J4YNJY) and for a PhD fellowship (Borsa di dottorato ‘Progetto giovani’ to C. Zanato). L. Pignataro thanks Milan University for a postdoctoral fellowship (‘Assegno di ricerca’). Z. Hao (Lanzhou University, PRC) thanks the China Scholarship Council for a PhD mobility grant. We thank Master student A. Ambrosi for the scale-up of several intermediates.