While nature's production of molecular agents, especially those with biological activity, are achieved in a relatively short number of chemical transformations, synthetic chemists'approaches to molecules are not as streamlined and thus neither as efficient nor effective. Emulation of nature's biosynthetic processes will provide valuable lessons for advancing the capability of chemists to access molecular structures of importance. The development of a biomimetic process, where sequential catalytic manipulations are achieved through utilization of multiple catalysts without isolation of intermediates, should enhance the chemist's ability to approach architectures of biologically active molecules in a more effective fashion. In this proposal, the applicability of cascade catalysis will be tested in the context of the phorbol architecture, specifically in the total synthesis of 12-deoxy phorbol. Phorbol, a potent tumor promoter, has been one of the most important natural products that has been used in studies to decipher the mechanism of the carcinogenesis. More recently, its derivatives have demonstrated anti-tumor, analgesic, and anti-HIV activities. Due to these significant biological implications, access to phorbol and its congeners have become very important. """"""""The proposed synthesis will take advantage of cascade catalysis to access the desired molecular architecture in a short, efficient, and deliberate manner with control of enantio- and diastereoselectivity. The modular nature of the synthesis will allow the devised strategy to be applicable towards a wide range of the molecular structures within the phorbol family. Relevance to public health: 12-deoxy phorbol ester derivatives have demonstrated potential as anti-tumor agents. Studies of efficient synthetic access to the parent structure, 12-deoxy phorbol, will prove beneficial towards development of anti-tumor medicines.
| Kim, Hahn; MacMillan, David W C (2008) Enantioselective organo-SOMO catalysis: the alpha-vinylation of aldehydes. J Am Chem Soc 130:398-9 |
