Stereoselective synthesis of heterocycles for building natural products and peptidomimetics

Anodic oxidation reactions have proven to be valuable tools for reversing the polarity of enol ethers and initiating radical cation based oxidative cyclization reactions. This approach is compatible with the use of alcohol nucleophile as trapping group thus providing a unique pathway to form tetrahydrofuran and tetrahydropyran derivatives. By studying a series of cyclization reactions, it was found that the trapping of enol ether radical cations was primarily controlled by stereoelectronic factors. The stereoelectronic difference between competing transition states for five-membered ring formation was larger than that for six membered-ring formation so cyclizations generating tetrahydrofuran rings led to higher levels of stereoselectivity. Based on the observation, a sequential Wittig reaction - anodic cyclization strategy was successfully used to effect an efficient, stereoselective synthesis of the tetrahydrofuran-containing natural product Linalool oxide. When a larger ketene dithioacetal was used as initiating group, mechanistic studies suggested that steric factors determined the stereo selectivity of this reaction. It was also found that a Wittig reaction - anodic oxidation strategy could be successfully applied to the synthesis of a tetrahydropyran building block for constructing the C10–C16 portion of Bryostatin. This synthesis capitalized on an intramolecular electron transfer reaction that allowed for the anodic coupling of an enol ether to an intramolecular oxygen nucleophile in spite of the presence of a thioacetal functional group that oxidized at a lower potential than the enol ether. Further study showed that the thioacetal group could be used to selectively oxidize a spatially closer enol ether in the presence of a second enol ether. An effort to use the methodology developed to synthesize the complex polyether natural product Thyrisferol was also undertaken. A good foundation has been laid for future efforts along these lines.; In the second part of the thesis, a method for the stereoselective synthesis of the C-terminal ring of the bicyclic lactam peptidomimetics has been developed. This synthesis first converted the available 2,3-disubstituted pentenoic acid derivatives into cyclic N-acyliminium ion precursors with the use of a hydroboration - Swern oxidation sequence. Then a family of 3-phenyl-5-vinyl substituted prolines were synthesized in a stereocontrolled fashion.