A polypropionate unit consists of an aliphatic chain with alternating methyl and hydroxy groups with a specific configuration at each carbon. This structural moiety is found in many polyketide natural products that exhibit a broad range of biological activities. Among the number of polypropionate examples in nature, the ansamycin family has been well studied as newer family members continue to be discovered, now also from marine origin. This renewed interest encompasses their synthesis, biosynthesis and therapeutic potential. Our contribution to this area has been the development of a alternative non-aldol oxirane-based methodology for the stereoselective construction of polypropionates. This approach combines the diastereoselective epoxidation of homoallylic alcohols and the regioselective cleavage of the resulting 3,4-epoxy alcohol as key steps in a reiterative fashion. This approach has successfully been applied to the synthesis of several polypropionate moieties. To further demonstrate the synthetic utility of our methodology, we engaged on the synthesis of the C5-C15 polypropionate chain of streptovaricin D, including the incorporation of a C10 hydroxymethyl group as a precursor the C10 carbomethoxy moiety. Interestingly, these polypropionate chains are common to other streptovaricin related compounds such as damavaricin, awamycin. Similarly, our methodology was applied in the elaboration of the C28-C20 fragment of the rifamycin S polypropionate chain. Again, this polypropionate chains is common to other recently discovered ansamycin compounds such as the chaxamycins and salinisporamycin.

Second generation oxirane-based approach for polypropionate construction: Application to the synthesis of ansamycins

253rd National Meeting (2017)

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