The goal of this project is to develop transition metal carbene complex- based approaches to polycyclic systems. This methodology will allow for the rapid construction of a variety of polycyclic frameworks, many of which are found in biologically active natural products. Many of the ring systems accessible with this methodology are not readily accessible with existing methodology. Current efforts are focused on the further expansion of this methodology, as well as on the application of these strategies to the preparation of several medicinally relevant targets. Of particular interest is the construction of the 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 will be constructed and used to probe the nature of the binding of phorbol esters to the diacylglycerol binding site of protein kinase C, their biological receptor. Structure/activity studies of this type are currently not feasible due to the absence of general routes to the phorbol skeleton. In addition, an approach to the DNA alkylating subunit of CC-1065 and the duocarmycins will be developed. This approach is expected to provide general access to a variety of derivatives of CC-1065 and the duocarmycins that will enhance our understanding of the mechanism of action of these powerful antitumor agents.
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