CYCLOPENTANNELATION IN TOTAL SYNTHESIS

University Of Hawaii At Manoa, Honolulu HI

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Abstract

A concise and efficient total synthesis of roseophilin has been proposed. Roseophilin is a unique and very unusual ansa-bridged azafulvene natural product which has been isolated from the culture broths of Streptomyces griseoviridis. The natural product shows activity against several human tumor cell lines in submicromolar concentration and is therefore an attractive lead compound for pharmaceutical development, the more so since this compound may represent an unusual mechanism of action. The chemical synthesis which is being proposed makes use of a method for creating the central ring structure which is ideally suited to this target. Application of this non-obvious strategy makes it possible to assemble the entire core structure in ten linear steps. In this way, total synthesis become an efficient means for preparing both the natural material and also for preparing functional analogs of the natural product. The enantioselective version of the key cyclization reaction will be developed in a general context and then applied to the roseophilin synthesis. Since the absolute stereochemistry of the natural product has not been determined, the question will be answered through total synthesis. The key structure which is embedded within the roseophilin tricyclic core, the cross-conjugated cyclopentenone, is also present in a number of other pharmacologically active natural products, therefore the proposed research is broad in scope. One of the long-term goals of this work is to apply the enantioselective version of the key cyclization reaction to the syntheses of these structures.