Synthetic chemistry study demonstrates deconstructive preparation of rifamycin analogues, indicating a viable pathway to engineer active antibiotics with modified core linkages.
A practical synthetic strategy for the preparation of rifamycin analogues has been developed, enabling access to the first compound modified at the critical enol ether–ketal linkage with demonstrated antimicrobial activity. Leveraging a deconstruction strategy, the rifamycin ansa chain can be isolated and selectively modified to reveal a hydroxyl group at O6, providing a handle for structural diversification. In parallel, a synthesis of the naphthoquinone core, highlighted by a biomimetic oxidative cyclization of a polypropionate precursor, furnished the complete C1–C13 fragment. Reunion of these fragments provided a new rifamycin analog, denoted rifalene M, in which the synthetically challenging enol ether motif is replaced with a simple allylic linkage and retains antimicrobial activity.
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Mahoney et al. (2026) studied this question.
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