Total Synthesis of Calyciphylline A - A Potent Cytotoxic Alkaloid

Stanford University, Stanford CA

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Abstract

DESCRIPTION (provided by applicant): 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.