A Fully Synthetic Route to the Neurotrophic Illicinones: Syntheses of Tricycloillicinone and Bicycloillicinone Aldehyde

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Abstract

Tricycloillicinone (1) and bicycloillicinone asaronacetal (2) were both isolated from extracts of the wood of Illicium tashiroi. These compounds were found to enhance the action of choline acetyltransferase, which catalyzes the synthesis of acetylcholine from its precursor. Since one of the characteristic 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 of such disorders. In this paper, we report the total synthesis of 1 and the construction of the core structure 3 of 2. The tricycloillicinone synthesis employed a novel strategy to control the regiochemistry of two ortho Claisen rearrangements. A sulfonyl group introduced at C2 of an allyl group effectively suppressed its unwanted rearrangement to the para position (23 → 24). Subsequently, ortho Claisen rearrangement was conducted using a reverse O-prenylated derivative 31 to furnish the desired 32, selectively. 32 was used as a common precursor for the syntheses of both 1 and 3. The application of Corey−Snider oxidative cyclization and the Barton−McCombie deoxygenation provided a direct route to 1. For bicycloillicinone aldehyde 3, a new 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 studies.

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