Natural products serve as an abundant source in the search for anticancer agents due to unparalleled structural diversity and accompanying molecular modes of action. In May of 2011, Bo Yeon Kim, Hiroyuki Osada, Jong Seog Ahn, and co-workers reported the isolation and structural elucidation of a biologically intriguing natural product, fusarisetin A, from a soil fungus, Fusarium sp. FN080326, which displays significant inhibition of acinar morphogenesis as well as cell migration and invasion without apparent cytotoxicity. From a structural perspective, fusarisetin A exhibits a 6,6,5,5,5-fused pentacyclic ring system bearing 10 stereogenic centers, which poses a remarkable challenge for synthetic chemists.

　　　  A team of scientists from the State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Jun Deng, Bo Zhu, Zhaoyong Lu, and Haixin Yu, led by Prof. Ang Li (www.bnpc.labs.gov.cn/LiAng/), accomplished the first total synthesis of (–)-fusarisetin A within 6 months (J. Am. Chem. Soc. 2012, 134, 920). The physical properties of the synthetic sample matched those reported for the natural material, except for the sign of its optical rotation. Thus, the absolute configuration of naturally occurring fusarisetin A was reassigned to the enantiomeric form of the original one based on the total synthesis. From a chemical point of view, the 13-step total synthesis featured a Lewis acid-promoted intramolecular Diels-Alder reaction, a palladium-catalyzed O to C allylic rearrangement, a chemoselective Wacker oxidation, and a Dieckmann condensation/hemi-ketalization cascade. The reported synthetic strategy and methods are expected to be applicable to the construction of other structurally or biosynthetically related natural products, as well as designed analogues of fusarisetin A, and thus to facilitate the exploration of its mechanism of action on molecular level.

The Total Synthesis of (−)-Fusarisetin A. (Image by Ang Li @ SIOC)