Synthesis of Streptolydigin, a Potent Bacterial RNA Polymerase Inhibitor

Streptolydigin is a highly potent, broad-spectrum antibiotic produced by Streptomyces lydicus, which inhibits bacterial RNA polymerase. We describe the first synthesis of streptolydigin, which was assembled in a highly convergent and fully stereocontrolled fashion with a longest linear sequence of 24 steps starting from commercially available precursors. The assembly process entailed preparation of fully elaborated streptolic and ydiginic subunits of the natural product, followed by a highly efficient union in a three-step one-pot procedure, which included Dieckmann cyclization with a concomitant imide opening, Horner-Wadsworth-Emmons olefination, and desilylation.