A fully synthetic route to the neurotrophic illicinones: Syntheses of tricycloillicinone and bicycloillicinone aldehyde

Tricycloillicinone (1) and bicycloillicinone asaronacetal (2) were both iso lated from extracts of the wood of Illicium tashiroi. These compounds were found to enhance the action of choline acetyltransferase, which catalyzes t he synthesis of acetylcholine from its precursor. Since one of the characte ristic symptoms of Alzheimer's disease involves degeneration of cholinergic neurons, resulting in markedly reduced levels of acetylcholine, compounds with the properties of 1 or 2 could well serve as agents in the treatment o f such disorders. In this paper, we report the total synthesis of 1 and the construction of the core structure 3 of 2. The tricycloillicinone synthesi s employed a novel strategy to control the regiochemistry of two ortho Clai sen rearrangements. A sulfonyl group introduced at C-2 of an allyl group ef fectively suppressed its unwanted rearrangement to the para position (23 -- > 24). Subsequently, ortho Claisen rearrangement was conducted using a reve rse O-prenylated derivative 31 to furnish the desired 32, selectively. 32 w as used as a common precursor for the syntheses of both 1 and 3. The applic ation of Corey-Snider oxidative cyclization and the Barton-McCombie deoxyge nation provided a direct route to 1. For bicycloillicinone aldehyde 3, a ne w tandem reaction using the Et2AlCN to construct the cage structure (39 --> 41) was employed. Flexible syntheses of the polycyclic illicinones should provide access to analogous structures for future biological and SAR studie s.