Syntheses of TRH analogs and the natural product (+)-nemorensic acid

Thyrotropin releasing hormone (TRH) represents an ideal model for exploring the relationship between the predicted and actual biological activity of unique peptide conformations. For this reason, conformationally restricted TRH analogs are designed to probe ligand and receptor interaction. In connection with the efforts to build constrained peptidomimetics, new routes for the synthesis of bicyclic lactam based peptide mimetics are developed. In the first project, a general strategy for the construction of bicyclic lactam peptidomimetics with control of bridgehead stereochemistry and the stereocenters on the lactam ring is achieved. This strategy uses an anodic oxidation to selectively functionalize proline derivatives and then an olefin metathesis to build the desired lactam constraint. The route described provides a versatile approach for synthesizing six- and seven-membered ring lactams without the sidechain on the central amino acid. It is also compatible with the synthesis of lactams with different bridgehead stereochemistry and the N-terminus stereochemistry. The building blocks are then incorporated into partially constrained TRH analogs and biological studies are conducted. In the second project, a general synthetic approach to construct a bicyclic lactam with a nitrogen atom at the bridgehead is developed. The synthesis uses azaproline and an unsaturated amino acid as building blocks. Reductive amination completes the ring closure and provides the desired peptidomimetics in an efficient way.; The second part of this dissertation describes an asymmetric total synthesis of natural product (+)-nemorensic acid with the anodic coupling of a ketene dithioacetal to an oxygen nucleophile as a key step. The anodic oxidation reverses the polarity of the electron-rich olefin and generates a bond between two nucleophilic centers. The anodic oxidation route avoids problems with existing synthetic routes by completely reversing the direction used to synthesize the key tetrahydrofuran ring of the natural product. The result is an efficient, highly stereoselective synthesis of (+)-nemorensic acid. The synthesis demonstrates that radical cations generated from anodic oxidation are powerful synthetic tools for building complex molecules.