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New methodology for the synthesis of peroxides: Total synthesis of plakinic acids
The number of peroxide-containing natural products has increased in recent years as an array of cyclic peroxides has been isolated from marine invertebrates. We became interested in the plakinic acids, a burgeoning new class of 5-membered ring peroxides which possesses anticancer, antibiotic, and antifungal activity. The majority of this thesis describes new methodology for peroxide synthesis, culminating in the asymmetric total synthesis of a plakinic acid. ^ One of the major limitations to the synthesis of peroxide natural products is the lack of available methods for the synthesis of chiral peroxides. A major goal of this research was to develop of a general asymmetric approach applicable to all of the plakinic acids. As an initial approach we chose to investigate the ability of chiral auxiliaries to control the stereochemistry of additions to peroxycarbenium ions. In the course of this work, we synthesized a new chiral thioacetate silyl ketene acetal. The new chiral nucleophile showed good reactivity but no stereoselection in addition to peroxycarbenium ions. ^ Our second attempt towards the asymmetric synthesis of 1,2-dioxolanes was based on accessing chiral 1,3-peroxyalcohols from the opening of enantiomerically enriched oxetanes with H2O2. Chiral oxetanes were obtained in high yields from the closure of chiral 1,3-diols. Perhydrolysis of oxetanes using ethereal H2O2 and catalytic Yb(OTf)3 led to good yields of chiral nonracemic 1,3-hydroperoxy alcohols. Peroxide opening was found to proceed with inversion. A methodology study demonstrated that oxetane perhydrolysis is successful with different methyl substitution patterns on the oxetane ring. The application of this new methodology to the asymmetric total synthesis of a plakinic acid will be discussed. ^ Finally, incorporation of a peroxide group into a peptide-like framework was explored as the basis for a new enzyme inhibition strategy. ^
Trullinger, Tony Kent, "New methodology for the synthesis of peroxides: Total synthesis of plakinic acids" (2002). ETD collection for University of Nebraska - Lincoln. AAI3074107.