The total chemical synthesis of calyciphylline A, an important alkaloid with anticancer activity, will be developed. The focus of this highly atom-economical strategy will be a ruthenium-catalyzed cascade of isomerization reactions to construct the [6.7.5] ring system of the Calyciphylline alkaloids in a single step. At this point i time, the development of a cascade of transition-metal-catalyzed isomerization reactions has never been done. Furthermore, 4 of the rings 6 rings of calyciphylline A are formed simply by isomerization reactions, highlighting an extremely efficient and highly atom-economical approach to this complex molecule with the incorporation of only two protecting groups. Additionally, this research program is designed to stimulate development of pre-existing methods in main group and transition-metal catalysis. These studies will explore novel zinc catalyzed ProPhenol alkynylations to saturated aliphatic carbamate-protected imines, as well as additions of highly functionalized alkynes to aliphatic saturated aldehydes. In addition, a general method for transition-metal-catalyzed [5+2] cycloadditions of 1,7-enynes will be explored. The methods developed within will undoubtedly attain widespread application amongst the general synthetic community. Successful completion of the proposed project would achieve the following: 1) Provide material for further biological studies in order to investigate the molecule s a potential therapeutic agent, 2) Outline a conceptual foundation for a synthetic, and highly atom-economical approach to other molecules of this type, 3) Develop new catalytic reactions involving both main group and transition-metal catalysis, 4) Culminate in the first total synthesis from this subclass of potent, structurally unique natural products.
The total chemical synthesis of calyciphylline A, an important alkaloid with anticancer activity, will be developed. The focus of this highly atom-economical strategy will be a ruthenium-catalyzed cascade of isomerization reactions. Completion of the proposed synthesis will generate larger quantities of material so that the pharmacological profile of calyciphylline A can be explored in greater detail.
| 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 |
