The further development of procedures for the synthesis of the ansamycin antibiotics rifamycin S, 1, and streptovacin V, 2, will be addressed in this work. This will be performed utilizing known stereoselective procedures coupled with the Lewis acid activation of hindered epoxides, methodology that we have been developing in the laboratory. The first approach involves the sequential coupling of fragments of the type 6 and 7 which can be synthesized economically from enantiomeric but otherwise identical precursors. This, the key step, has proven to be difficult if not impossible by previous methodologies. A solution to this problem then is expected to arise from the application of this Lewis acid methodology. This represents a synthesis of the ansa chain of rifamycin S. The second approach involves a reiterative route for the synthesis of the ansa chains for both 1 and 2 based on a modification of a sequence used for the synthesis of 1, 3-polyols.18 This involves the reaction of an organometallic reagent with a cis or trans- disubstituted epoxide, depending on the desired configuration of the methyl group in 3 followed by a stereoselective epoxidation based on the carbonate extension reaction.20 The procedure can be repeated and modified as needed until the desired carbon framework is obtained. Although it is intended for the synthesis of the ansa chains of 1 and 2 in principle it can be extended to the synthesis of other members of the family. In summary we would like to develop and improve methodologies for the synthesis of this important, biologically active, test targets as a contribution to this always expanding field.
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