An approach to the total synthesis of aplysiatoxin

Robert E. Ireland, Suvit Thaisrivongs, Patrick H. Dussault

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81 Scopus citations

Abstract

An approach to the synthesis of the polyacetate tumor promoter aplysiatoxin is described. The spiroketal framework was convergently constructed in a heteroatom Diels-Alder reaction between an enol ether and a vinyl ketone. The desired spirocenter stereochemistry was obtained by acid-catalyzed isomerization to the less sterically encumbered spiroketal. Subsequent manipulation provided diastereomeric 9-hydroxy derivatives (aplysiatoxin numbering) epimeric at C-15. These spiroketal alcohols were envisaged as key intermediates for attempted introduction of the C-3 lactol, as well as for appendage of the 12-membered bis(lactone). Attempted transannular remote oxidation using the derived C-9 alkoxy radical failed, however, to introduce the lactol. The 9-hydroxy derivatives were efficiently converted into bis(acetones), utilizing the photodeprotection of a nitrobenzyl ether as a key step. Bromination and deprotection afforded both possible C-15 epimers of 3-desoxyaplysiatoxin-20-O methyl ether. Circular dichroism spectra of synthetic intermediates provided a means of distinguishing the diastereomer with the natural C-15 stereochemistry. Nuclear Overhauser effect difference spectra on the bis(lactones) showed signal enhancement within the rigid spiroketal framework consistent with those reported for derivatives of the natural product.

Original languageEnglish (US)
Pages (from-to)5768-5779
Number of pages12
JournalJournal of the American Chemical Society
Volume110
Issue number17
DOIs
StatePublished - Aug 1988

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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