INTRAMOLECULAR CYCLOPENTENE ANNULATION

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The proposed research addresses not only the implementation of a new and general synthetic method into the compendium of procedures available for the synthesis of complex natural products of biological significance, but also the development of some novel aspects of two reactions which were used during the former endeavor. Our strategy involves the intramolecular addition of a carbenoid, a nitrene, or any equivalent species to a conjugated diene in a 1,4-mode, at least formally, to produce ring annulated cyclopentenes or dihydropyroles. We focus on the construction of carbon skeletons containing especially any quaternary centers rather than on any final functionalizations which will be adversed later on preformed skeletons via simple differentiated functionalities in energetically feasible and practical manner. This approach avoids multi-step syntheses with intermediates containing complex substitution patterns and eliminates any protective/deprotective operations. With the above philosophy in mind we wish to investigate various topological permutations of the diene-carbenoid system to maximize the generality of the cyclopentene dihydropyrrole annulation. We intend to expand this methodology to heterocyclic compounds since we have already established the carbocyclic cyclopentene annulation as a general method of access to cyclopentanoid terpenes. Finally, we will investigate novel uses of the Simons-Smith and the Reformatsky reactions which we have used during our syntheses of terpenes and which spurred certain tangential interests to the point where both warrant independent investigations. The major aims of our projected research are as summarized: a. Continuing application of cyclopentene annulation to the synthesis of terpenes; b. Investigations of non-pyrolytic alternatives to the vinylcyclopropane rearrangement; c. Implementation of the intramolecular variant of the Simons-Smith reaction as means of novel carbon-carbon bond formation; d. Initiation of nitrene-diene additions; e. Investigation of novel uses of the Reformatsky reaction in synthesis. The overall significance of the proposed research rests in the provision of several efficient general synthetic methods which can be applied to the preparation of various medicinal agents currently in demand.