Total Synthesis of (-)-Aplysin and (-)-Debromoaplysin

Article abstract of DOI:10.1021/jo01299a037

The total synthesis of optically active (-)-aplysin (1) and (-)-debromoaplysin (2) employing novel (isopinocampheyloxy)methyl ethers for phenolic hydroxyl protection and diastereomeric resolution is described.A key transformation is the unusual cyclization of the diastereomeric chlorohydrins 12 and 13 in methanolic base to form the enantiomeric tricyclic alcohols (-)-16 and (+)-16 with cleavage of the acetal-linked (isopinocampheyloxy)methyl resolving/protecting group.This transformation was followed by substitution of the tertiary hydroxyl via the derived chloride with a methyl group by Grignard coupling with methylmagnesium bromide.The methyl insertion occurred with retention of configuration and resulted in formation of the natural aplysin system from 12 in just three steps.The conversion of the methylated tricyclic ether 20 to (-)-debromoaplysin (2) was accomplished in two steps by double bond isomerization and selective reduction.Bromination of (-)-2 afforded (-)-aplysin (1).