The primary objective of this research is to continue to discover new strategies for the construction of complex carbocyclic or heterocyclic ring systems. Several new methods will be developed to meet this objective. Intramolecular cycloadditions of aza-ortho-xylylenes will be explored for the construction of the ring system of communesin B, a cytotoxic natural product that functions by disrupting microfilaments. It is hoped that anti-microfilament agents might represent a new class of anticancer agents and prove to be as effective as the well-established anti-microtubule agents. A novel method developed for the construction of indoles, a ubiquitous privileged structure found in numerous biologically active compounds, will be applied in the total synthesis of the cytotoxic, anti-microtubule agent welwistatin. This natural product has not been synthesized and is active against multiple drug resistant phenotypes. The versatility of this indole synthesis will be further demonstrated in the total synthesis of dragmacidin E. A strategy developed for the synthesis of erythrinan alkaloids that takes advantage of amidoacrolein-based methodology will be extended to a member of the homoerythrinan subclass of natural products. More importantly, additional analogs of the potent neuronal nicotinic acetylcholine antagonist, dihydro-p-erythroidine, will be prepared. The overall goal is to further define the pharmacophore and discover a subtype selective antagonist, of potential therapeutic value in the treatment of neurological diseases (for example, autism) as well as smoking cessation. A method featuring the cyclization of 2-silyloxyenals will be exploited for the first time in the rapid construction of the ring system of the potent, selective angiogenesis inhibitor, cortistatin A, an exciting new lead structure for the further development of this emerging class of anticancer agents. A completed total synthesis will permit subsequent construction of cortistatin A conjugates that will be used to discover the molecular target of this natural product. Finally, a new method of considerable promise for the construction of complex ring systems that involves the tandem vicinal difunctionalization of enecarbamates will be used to prepare gram quantities of the architecturally fascinating cytotoxin nakadomarin A. The biological investigation of this natural product has been severely restricted by its limited availability from the natural source, a marine sponge.
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