Total synthesis of pentamycin by a conformationally biased double stille ring closure with a trienyl-bis-stannane Alexander Babczyk , Dirk Menche University of Bonn, Germany The polyene macrolide pentamycin, first isolated from Streptomyces penticus in 1958, 1 displays impressive biological activities against a range of various pathogens including Trichomonas vaginalis or Candida albicans and can be used clinically to treat vaginal candidiasis, trichomoniasis, and other mixed infections. 2 The powerful biological properties in combination with its unique 3D structure has attracted considerable interest from the synthetic community. However, a total synthesis has remained elusive, partly due to the notorious instability caused by the pentaene fragment. The first total synthesis of this potent polyene macrolide antibiotic will be presented. It was accomplished by a modular strategy in 25 steps (longest linear sequence) in an overall yield of 1.5%. Key step was an ultimate Stille- type ring closure, circumventing any stability issues during the synthesis which proved essential for realization of this sequence. This adventurous double Stille cross coupling with a trienyl-bis-stannane closed the macrolactone and installed the sensitive pentaene fragment in a joint fashion. Presumably, this remarkable linchpin insertion is enhanced by the linear hydrogen bonding skeleton of the polyol substrate. Further key features include a tailored Rychnovsky alkylation of cyanohydrin acetonides and elaborate Krische couplings to set the characteristic hydroxyl and hydroxymethyl bearing centers with excellent selectivity and yield. The total synthesis unequivocally confirms the full relative and absolute stereochemistry of this polyketide, including a previously uncertain hydroxyl bearing center. Furthermore, it represents one of the first examples where an extended hydrogen bonding network was designed as a conformational template for a complex macrocyclization. It also documents the importance of conformational design in elaborate total synthesis.
References 1. Umezawa, S.; Tanaka, Y. J. Antibiot. 1958 , 26−29. 2. Zhou, S.; Song, L.; Masschelein, J.; Sumang, F. A. M.; Papa, I. A.; Zulaybar, T. O.; Custodio, A. B.; Zabala, D.; Alcantara, E. P.; de los Santos, E. L. C.; Challis, G. L. ACS Chem. Biol. 2019 , 14 , 1305−1309.
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