Totalsynthesis of Pentamycin

Abstract

The polyene macrolide pentamycin, first isolated from Streptomyces penticus in 1958, displays impressive biological activities against various pathogens, including Trichomonas vaginalis or Candida albicans, and can be used clinically to treat vaginal candidiasis, trichomoniasis, and other mixed infections. Its powerful biological properties combined with its unique 3D structure have attracted considerable interest from the synthetic community. However, a total synthesis has remained elusive, mainly due to the notorious instability caused by the pentaene fragment. <br /> In this work, the first total synthesis of pentamycin was accomplished by a modular strategy in 25 steps (longest linear sequence) in an overall yield of 1.5%. The key step was a final Stille-type ring closure that circumvented any stability problems during the synthesis, which proved essential for the realization of this total synthesis. This linchpin insertion of a protective group free bis-vinyl iodide and a trienyl-bis-stannane concomitantly closed the macrocycle and installed the sensitive pentaene fragment in the very last step. Presumably, a linear hydrogen bonding network of the polyol substrate, enabled by the 1,3-syn polyol moiety between C1* and C13, facilitates ring closure. <br /> The total synthesis unequivocally confirms the full relative and absolute stereochemistry of this polyketide, including the previously uncertain hydroxyl bearing center at C14. Furthermore, it represents one of the first examples of an extended hydrogen bond network being designed as a conformational template for complex macrocyclization and documents the importance of conformational design in total synthesis of complex natural products.