Synthesis of Sultams and Related Sulfur Heterocycles Using the Ring-Closing Metathesis Reaction

Abstract

The use of ring-closing metathesis (RCM) for the construction of small, medium and large rings has become a powerful tool in organic chemistry. The application of this reaction for the construction of sulfur heterocycles (S-heterocycles) as potential pharmacological targets has become a major focus in our laboratories. The goal of this dissertation is to demonstrate the application of RCM for the construction of a variety of sulfur heterocycles including sultams, cyclic sulfamides, cyclic sulfamoyl carbamates and cyclic sulfamoyl ureas with the ultimate goal of biological screening. The successful synthesis of 6- to 11-membered ring S-heterocycles using this method will be discussed. The first project described in this dissertation involves the use of RCM for the construction of 6-membered ring sultams with multiple handles for further functionalization and library development. The utility of these sultams as versatile scaffolds for a variety of diversification reactions using solution-phase chemistry will be explained. Also, the successful application of ROMP-derived reagents developed in our laboratories as facilitated protocols for diversification strategies and subsequent library development will be discussed. The second project describes the use of RCM for the facile construction of sulfamide analogs of the HIV protease inhibitor DMP 323. The accomplishment of both symmetric and unsymmetric cyclic sulfamides will be discussed. Also, efforts towards the synthesis of N-hydroxy cyclic sulfamides will be presented. The third project describes the use of RCM for the construction of 9-membered ring sulfamoyl ureas and 9- to 11-membered ring sulfamoyl carbamates.