Approaches to the Marine-derived Polycyclic Ether Natural Products: First Total Syntheses of the Asbestinins and a Convergent Strategy for Brevetoxin A

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  • March 19, 2019
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  • Ellis, J. Michael
    • College of Arts and Sciences, Department of Chemistry
Abstract
  • Glycolate aldol reactions and glycolate alkylations, followed by ring-closing metatheses, are used to prepare medium ring ethers used as building blocks for polycyclic ether containing natural products. Using the glycolate aldol/ring-closing metathesis strategy, an approach to a previously unprepared subclass of the C2– C11 cyclized cembranoids known as the asbestinins is described. An oxonene is efficiently synthesized and utilized as a manifold for an intramolecular Diels–Alder cycloaddition to form a hydroisobenzofuran moiety characteristic of the asbestinins. This tricyclic adduct represents the bulk of the framework of the asbestinins. Ultimately, the tricycle was progressed to two different natural products, 11-acetoxy-4-deoxyasbestinin D and asbestinin-12, via a late-stage divergent route. The completion of these natural products represented the first instance of preparing an asbestinin using chemical synthesis, and served to confirm the absolute configuration of the subclass. Additionally, a glycolate alkylation/ring-closing metathesis strategy was used to prepare the B ring of brevetoxin A on multigram scale. Novel reactivity was discovered and exploited along this route. Namely, it was found that glycolate alkylation adducts can undergo direct Claisen condensation or reduction to the aldehyde to provide useful synthons. The B ring has been progressed to the BCDE tetracycle in a convergent fashion, and portions of this supply have been carried forward to provide possible coupling partners for the GHIJ fragment in hopes of completing brevetoxin A in a convergent manner.
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  • In Copyright
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  • Crimmins, Michael T.
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  • October 19, 2010

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