Carbocyclic rings are structural units present in most pharmacologically active compounds. As a consequence, the development of cyclization reactions for the efficient construction of molecules containing these units is essential. Several well-known ring-forming processes (e.g. the Diels-Alder and Robinson annulation reactions) have been highly developed and extensively utilized. Other processes which might be complimentary to these and perhaps more general in scope have seen comparatively little development. We propose a systematic study of intramolecular reductive coupling reactions in an effort to examine their scope for the construction of carbocyclic rings. The first part of the proposal outlines fundamental research in carbocyclic ring-forming reactions. A variety of difunctional organic substrates will be investigated for their ability to undergo intramolecular reductive coupling reactions. A number of metal-based reductants will be utilized to effect these cyclizations. The goal of these studies is to determine the conditions under which effective cyclization will occur, as well as to assess the chemo- and stereoselectivity of the processes developed. The second phase of the study will focus on the use of chelation-control in these intramolecular reductive coupling reactions to bring about the cyclization with complete stereochemical control. Once again, several systems will be evaluated for their effectiveness in this process. Nearly all of the proposed substrates can be prepared in optically active form, and thus this represents an extremely efficient process for the synthesis of chiral carbocyclic materials from acyclic substrates.
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