Total synthesis of apoptolidin: completion of the synthesis and analogue synthesis and evaluation |
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Authors: | Nicolaou K C Li Yiwei Sugita Kazuyuki Monenschein Holger Guntupalli Prasuna Mitchell Helen J Fylaktakidou Konstantina C Vourloumis Dionisios Giannakakou Paraskevi O'Brate Aurora |
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Institution: | Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. kcn@scripps.edu |
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Abstract: | The total synthesis of apoptolidin (1) is reported together with the design, synthesis, and biological evaluation of a number of analogues. The assembly of key fragments 6 and 7 to vinyl iodide 3 via dithiane coupling technology was supplemented by a second generation route to this advanced intermediate involving a Horner-Wadsworth-Emmons coupling of fragments 22 and 25. The final stages of the synthesis featured a Stille coupling between vinyl iodide 3 and vinylstannane 2, a Yamaguchi lactonization, a number of glycosidations, and final deprotection. The developed synthetic technology was applied to the construction of several analogues including 74, 75, and 77 which exhibit significant bioactivity against tumor cells. |
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