Decalin-containing drugs have profoundly impacted medical therapies. The prevalence of biologically-potent decalin has stimulated numerous decalin synthases particularly through annulations to cyclic enones. Despite the development of several impressive decalin-forming strategies there is a pressing need for asymmetric decalin syntheses capable of installing diverse functionality and substitution patterns that directly correlate with decalin-containing drugs. The focus of this proposal is to develop new, asymmetric decalin syntheses capable of installing diverse functionality and substituents with equal efficiency. Key to achieving this aim are several counter- intuitive reactions that employ alpha, beta-unsaturated nitriles that allow reactions and selectivities that are practically inaccessible for carbonyl compounds. Incorporating the advantages of nitriles within domino reactions is expected to provide a highly convergent synthesis of substituted decalins. The ideal of this methodology is the assembly of two new carbon-carbon bonds and four new stereocenters in a single synthetic operation-bond constructions analogous to the exceptionally powerful Diels-Alder reaction. The strategy is illustrated in the synthesis of potameogetonin as a potential AIDs inhibitor. Synthesizing potamogetonin not only illustrates the rapid construction of decalin- containing drugs but will determine whether more flexible terpenoids, labdanes in particular, are better AIDs inhibitors than their more rigid analogs. The four specific aims of this proposal are: Domino addition alkylations to unsaturated oxonitriles Asymmetric additions to unsaturated nitriles Michael additions to unsaturated nitriles Synthesizing potamogetonin as a potential HIV inhibitor Fulfilling these aims will advance knowledge of both nitrile-based reactions and NNRTI inhibitors.
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