DEVELOPMENT/PREPARATION OF ANSAMYCIN ANTIBIOTICS

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Description (Adapted from Application): The synthesis of macrolide and ionophore antibiotics continues to be regarded as a very active area of synthetic organic research. The attractiveness of these target molecules is related to their broad range of biological and medicinal activity together with their complex structure and array of stereogenic centers. The development of an enantioselective methodology for the synthesis of the ansamycin antibiotics, rifamycin S and streptovaricin D, and the hygrolide antibiotics, bafilomycin A1 and elaiophylin, is the main goal of this proposal. The selection of these target molecules is based on their extensive biological activity and the challenge that represents the elaboration of the different configurations found in their polypropionate units. In recent years, a great interest in their study and utilization (and that of some semi-synthetic derivatives) as therapeutic agents has been evidenced by the extensive and increasing scientific literature being generated in this area. The reported synthetic approaches to these targets, as for many other polypropionate systems, have been usually based on aldol and related chemistry. The applicants would like to demonstrate that epoxides are a viable alternative and that their use can be incorporated into a general, flexible, and stereoselective route to these very important target compounds. Their approach is a simple and reiterative one, and is based on the stereoselective epoxidation of homoallylic alcohols by means of iodocyclization reactions, following their cleavage via organoaluminum chemistry. With this methodology they can control the configuration of the methyl and hydroxyl groups that characterize the polypropionate units. Not only the desired chemical transformations proposed in this study will be accomplished. The scope, limitations, stereochemistry, and mechanistic implications of the key reactions will be examined. Although the methodology will be applied to these specific targets, in principle, its should be applicable to many other polypropionate systems and will open the door for the synthesis of analogues, which can present opportunities for increased or modified of biological activity and therapeutic potential.