Abstract
Huperzine A and B are potent acetylcholinesterase inhibitors and promising against Alzheimer's disease. Completed and formal total syntheses of these medically relevant alkaloids are presented and discussed.
Highlights
Huperzine A and B are potent acetylcholinesterase inhibitors and promising against Alzheimer's disease
The exocyclic double bond was installed by a Wittig olefination which produced an E/Z-mixture in favor of the the undesired (Z) isomer
Huperzine A was obtained from acid 8 through subsequent Curtius rearrangement, O-demethylation and hydrolysis
Summary
Huperzine A (1) presents a fascinating bicyclo[3.3.1]nonane unit fused to a 2-pyridone moiety. Kozikowski disclosed a second generation synthesis of huperzine A in which he exploited a palladium catalyzed annulation of β-keto ester with 2-methylenepropane-1,3-diol diacetate (Scheme 2).[28,18] The exocyclic double bond in the product was isomerized with triflic acid to obtain olefin 15. After successive Pd-catalyzed bicycloannulation, Wittig olefination, E/Z isomerization and exo/endo isomerization of the olefinic double bond, the chiral handle was detached by LAH reduction This route can be regarded as a formal synthesis of unnatural (+)-huperzine as the resulting primary alcohol 23 was an intermediate in Kozikowskys asymmetric synthesis.[25]. A one pot sequence comprising the treatment of with SOCl2 followed by exposure to aqueous HBr led to the formation of (–)-huperzine A through demethylation, double bond transposition and Boc-removal This ten step route provided the natural product in 17% overall yield.
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