Total Synthesis of the Unique Pederin Family Member Psymberin & Chemical Studies Toward Saliniketal Family Members: Saliniketal a, Salinisporamycin and Rifsaliniketal




Feng, Yu

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This manuscript consists of six chapters. The first four chapters involve the psymberin/irciniastatin A project. Psymberin was isolated from a psammoncinal sponge possessing an unprecedented differential cytotoxicity profile, whereas irciniasatin A was isolated from the marine sponge Ircinia ramose showing potent growth-inhibitory properties against solid human tumor cell lines. The first chapter provides the background information, i.e. isolations, biosynthesis and preliminary biological activities of psymberin/irciniastatin A. The second chapter reviews all the total syntheses and formal syntheses from the chemistry community. In the third chapter, we detail our chemical studies toward the unique pederin family member psymberin. The De Brabander laboratory had previously demonstrated that psymberin and irciniastatin A are identical. Subsequently, a highly convergent second generation of psymberin was finished, and the synthetic highlights were including the Iridium-catalyzed bis-allylation of 2,2-imethylpropane-1,3-diol, and a stepwise Sonogashira coupling/cycloisomerization/reduction sequence to construct the dihydroisocoumarin unit. The total synthesis of psymberin and its analogs would provide sufficient material for mode-of-action and SAR studies. The fourth chapter describes the biological studies toward psymberin. Structural modifications of psymberin helped to elucidate that protein translation can be uncoupled from cytotoxicity, suggesting that psymberin has more than one bioactivity. The Roth laboratory developed a forward genetic screen in C. elegans to identify the molecular target(s) of psymberin. Finally, our analogs aided in demonstrating the blistering activity associated with pederin and other members of the family is not due to their protein synthesis inhibiting activity. Unlike pederin and mycalamide, psymberin does not display irritant or blistering activity. The last two chapters involve the saliniketal family members: saliniketal A, salinisporamycin and rifsaliniketal. Saliniketal A, salinisporamycin and rifsaliniketal are three novel secondary metabolites from the marine actinomycete Salinispora arenicola. The fifth chapter reveals the isolation of the molecules, biological activities and their biorelationship with rifamycin. In the final chapter, we review the previous synthetic efforts toward saliniketals, followed by our studies including the synthesis of the three members via a highly convergent route. These studies were aimed at enabling future structure-function and mode of action studies. The synthetic highlights for saliniketal A includes: Pt(II)-catalyzed cycloisomerization to construct the dioxabicyclo[3.2.1] ring system, a highly diastereoselective aldol coupling whose stereochemical outcome was influenced by the γ-stereogenic methyl group and an unique dihydropyranone fragmentation/amidation sequence. For salinisporamycin and rifsaliniketal, the 1,4-naphthoquinone skeleton was assembled via Diels-Alder cycloaddition or benzyne cycloaddition. A peptide coupling or Buchwald C-N bond coupling at a late stage between saliniketal A and the 1,4-naphtholene fragments followed by radical oxidation afforded salinisporamycin and rifsaliniketal, respectively.

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