A program of research is proposed whose goal is to utilize N-sulfonyloxy amines (NSA) as precursors for iminium ions that can undergo intramolecular cyclization to azacyclic products. The proposed research will investigate a different approach to iminium ion formation using N-oxidized precursors, rather than C-oxidized precursors used in normal Mannich-based methods of iminium ion formation. It is not our intention to offer a replacement for Mannich-based generation of iminium ions, since it is often the most successful and best entry into iminium ion cyclizations. However, in some cases Mannich-based chemistry is less successful or less convenient for the generation of iminium ions. It is precisely for these cases that new methods of iminium ion formation must be found. Our studies on NSA over the last several years have been used to pinpoint how NSA might offer unique solutions in these problem areas. As a result, new strategies for the synthesis of azacyclic natural products could emerge. We wish to demonstrate that cationic carbon to nitrogen migration in NSA provides a new conceptual approach to the preparation and trapping of iminium ions. Two particular migration reactions of NSA, ring expansion and hydride migration, will be used as focal points for the construction of azacyclic compounds. These two processes, in appropriate substrates, yield iminium ions which can undergo subsequent intramolecular trapping and azacycle formation. Three specific rearrangement processes provide the focus for the work. (a) Tandem carbon to nitrogen ring expansion- intramolecular cyclization will be investigated as a means of producing multicyclic products directly. (b) Hydride rearrangement in tertiary amine NSA derivatives will be examined as a route to simple endocyclic iminium ions. (c) Hydride rearrangement in hydroxamic acid NSA derivatives will be utilized to generate N-acyl iminium ions. A major driving force for these efforts is the potent physiological activity of many of the products. A wide spectrum of activities including cardiotonic effects, tissue necrosis, anticarcinogenic behavior, and antibiotic activity can be found in the alkaloid products. Iminium ions thus play an important role in the synthesis of a large number of important physiologically active agents. The utilization of NSA for azacyclic synthesis proposed here is a new methodology. Fresh synthetic strategies to physiologically active azacyclic targets are developed with particular emphasis on systems that are problematic by traditional synthetic strategies.
