Total synthesis of apoptolidin: completion of the synthesis and analogue synthesis and evaluation.
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.
Nicolaou
K C
KC
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
Li
Yiwei
Y
Sugita
Kazuyuki
K
Monenschein
Holger
H
Guntupalli
Prasuna
P
Mitchell
Helen J
HJ
Fylaktakidou
Konstantina C
KC
Vourloumis
Dionisios
D
Giannakakou
Paraskevi
P
O'Brate
Aurora
A
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006027:Glycosides / Q000138:chemical synthesis / Q000737:chemistry; D006801:Humans; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D010051:Ovarian Neoplasms / Q000188:drug therapy; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D006027:Glycosides; D018942:Macrolides; C114125:apoptolidin