SYNTHETIC METHODOLOGY TOWARDS THE PREPARATION OF ANSAMYCIN ANTIBIOTICS

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The development of an enantioselective methodology for the total synthesis of the ansamycin antibiotics rifamycin S and streptovaricin D, and the hygrolide antibiotics bafilomycin A1 and elaiophylin is the long term goal of this proposal. These polypropionate natural products exhibit a broad range of biological activity. In recent years a great interest in their study and utilization (and that of some semisynthetic derivatives) as therapeutic agents has been evidenced by the extensive scientific literature being generated in this area. More specifically, we are proposing a formal total synthesis of rifamycin S, and the elaboration of the polypropionate units of streptovaricin D, bafilomycin A1 and elaiophylin, based on the utilization of oxirane chemistry. The selection of these target molecules is based on their notable biological activity, the great interest in their synthesis shown by other research groups, and the challenge that represents the elaboration of the different configurations found in their polypropionate units by the same methodology. The reported synthetic approaches to these targets, as for many other polypropionate systems, have been usually based on aldol and related chemistry. We believed that the utilization of epoxide chemistry as a general approach to these systems will be well received by the synthetic community. Our approach is a reiterative one and is based on the stereoselective epoxidation of homoallylic alcohols by means of iodocylisation reactions followed their cleavage via organoaluminium chemistry. With this methodology we can control the configuration of the methyl and hydroxyl groups which characterize the polypropionate units. Not only the desired chemical transformations proposed in this extensive study will be accomplished. The scope, limitations, stereochemistry and mechanistic implications of the key reactions included in this study will be examined. Although our methodology will be applied to these specific targets in principle its should be applicable to many other polypropionate systems.