The overall objective of our research program involves the development of general, broadly applicable methods that makes use of organosulfur compounds for the construction of novel nitrogen containing heterocycles. Emphasis will be placed on new domino cyclization/cycloaddition cascade reactions of organosulfur derivatives for the construction of a variety of biologically interesting molecules. Among the reactions to be studied are cycloaddition reactions of mesoionic thio-substituted betaines, Diels-Alder reactions of thio-substituted heteroaromatics and new applications of the Pummerer reaction for heterocyclic synthesis. The project will also focus on using a variety of novel thio reagents for intramolecular cyclization. A number of inter and intramolecular variations of the tandem sequence will be explored which will provide access to the structural frameworks contained within the Amaryllidaceae, Aspidosperma, Erythrina, Pyrrolizidine, Quinolizidine, Sceletium and Vinca alkaloids. These complex nitrogen containing substrates are of interest as synthetic targets due to the wide range of biological properties they exhibit. A variety of pharmacological effects, including sedative, hypotensive, neuromuscular blocking, CNS depressant and skin disorder properties are associated with these compounds. The various synthetic strategies outlined in the proposal will lead to the rapid assembly of the basic core skeleton of various alkaloids and will provide quantities of material for detailed biological assay. The generation of biologically active compounds by new synthetic methods remains an important part of both health related and chemical research.
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