The goal of this project is to develop a Fischer carbene based approach to the synthesis of polycyclic systems. If successful, this new methodology will allow for the rapid construction of several complex biologically active target structures. The initial phase of this research will involve a general study of the reactivity of in situ generated Fischer vinylcarbene complexes. Trapping of these reactive transition-metal complexes with substituted olefins or other unsaturated moieties should provide rapid access to a variety of novel ring systems. Of particular interest is the application of this methodology to the construction of the basic tricyclic ring skeleton of the tigliane and daphnane diterpenes. Members of these classes of compounds have been widely studied, primarily because of their ability to promote tumor formation. Analogs of the phorbol esters to the diacylglycerol binding site of protein kinase C. Structure/activity studies of this type are currently not feasible due to the absence of general routes to the phorbol skeleton. In addition, analogs of sphingosine, which has been found to function as a protein kinase C inhibitor, will be synthesized to determine the chemical nature of its relationship to the protein kinase C activating phorbol esters. We hope that through these studies we will be able to develop a better understanding of the biochemical control mechanisms that regulate the activity of protein kinase C.
