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.
ASJC Scopus subject areas
- Colloid and Surface Chemistry