Amphidinolide N is one of 34 distinct macrolides isolated from the dinoflagellate Amphidinium sp. from the Okinawan coral reefs and represents, by far, the most potent member of this large family of natural products. It possesses a level of anti cancer activity that rivals some of the most potent therapeutics agents that are currently available for the treatment of cancer. While considerable progress has been made in the synthesis and biological evaluation of several pharmaceutically relevant amphidinolides, a synthesis of amphidinolide N has not been approached successfully and the full structural elucidation of the molecule still remains unknown. Our approach to the total chemical synthesis of amphidinolide N is envisioned to feature a unique Pd-catalyzed asymmetric allylic alkylation to construct a trans-tetrahydrofuran ring. Additionally, a key Ru-catalyzed alkene-alkyne coupling will join two large sub fragments of the target molecule together. This research program is designed to further stimulate the development of preexisting methods in both main group and transition metal catalysis. The convergent strategy, described above, emanated from the novel methodologies that are currently under development in our laboratory. They have provided a unique opportunity to further explore and exploit their potential use in complex molecular settings. Successful completion of the proposed project would achieve the following: 1) Complete the total chemical synthesis of amphidinolide N, 2) Establish the absolute and relative stereochemistry of the molecule, and 3) Provide material for further biological studies in order to investigate the molecule as a potential therapeutic agent.

Public Health Relevance

Drug discovery is a process that involves the development and design of new chemical entities as potential candidates for therapeutic agents. The chemical synthesis of complex natural products constitutes a major subdivision of organic chemistry that not only highlights the current state of the art, but also stimulates innovation, and identifies new challenges that need to be addressed. The target molecule, Amphidinolide N, possesses a level of anti cancer activity that rivals some of the most potent anti cancer agents on the market and therefore, the evolution of such a molecular entity into a potential drug requires detailed understanding of both the structure of the molecule as well as its function in a biological system.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F04-A (20))
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Lees, Robert G
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Stanford University
Schools of Arts and Sciences
United States
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Trost, Barry M; Stivala, Craig E; Fandrick, Daniel R et al. (2016) Total Synthesis of (-)-Lasonolide A. J Am Chem Soc 138:11690-701
Trost, Barry M; Stivala, Craig E; Hull, Kami L et al. (2014) A concise synthesis of (-)-lasonolide A. J Am Chem Soc 136:88-91