A palladium-catalyzed route to huperzine A and its analogs and their anticholinesterase activity

Abstract

Huperzine A is an alkaloid isolated from Huperzia serrata (Thunb.) Trev., a Chinese club moss the extracts of which have been used in Chinese folklore medicine to treat a variety of maladies including memory disorders. Recently, this molecule has attracted widespread attention because of its possible use in the treatment of Alzheimer's disease (AD). We describe herein a palladium-catalyzed bicycloannulation route to this molecule which makes huperzine A available in 40% overall yield. The application of this methodology to seven other huperzine A analogues together with their biological activity in the inhibition of rat cortex acetylcholinesterase (AChE) is detailed herein. None of these new compounds was more potent than the parent structure as AChE inhibitors

Development of huperzine A and B for treatment of Alzheimer's disease

“…In order to avoid the low-yielding step of elimination of the aldol product, the palladium-catalyzed bicycloannulation of β-keto ester 3 was reported by Kozikowski's group [25] using tetramethylguanidine as base and 2-methylene-1,3-propanediol diacetate as bis-electrophile in the presence of tetrakis (triphenylphosphine)-palladium(0). The resulting methylene-bridged compound 7 was in 92 % yield.…”

“…Since the double-bond migration could be performed in the last step, an isomer 8 was obtained. The overall yield of HupA was 40 % from β-keto ester 3 (Scheme 3) [25]. Based on the same stratagy, the stereoselective synthesis of HupA was tested by using different chiral ligands instead of triphenylphosphine.…”

Synthetic approaches towards huperzine A and B

“…Kozikowski disclosed a second generation synthesis of huperzine A in which he exploited a palladium catalyzed annulation of β-keto ester 13 with 2-methylenepropane-1,3-diol diacetate (Scheme 2). 28,18 The exocyclic double bond in the product 14 was isomerized with triflic acid to obtain olefin 15. Huperzine A was obtained from 15 by the same sequence as in his racemic route.…”

“…17 Interestingly, its pharmacological profile is found to be superior to that of tetrahydroaminoacridine (Tacrine), an FDA-approved drug for the treatment of AD. 18 Its superiority over other drugs can be partly attributed to its lower toxicity. 18 Huperzine B possesses an even higher therapeutic index than huperzine A which is in agreement with its longer duration of action.…”

“…18 Its superiority over other drugs can be partly attributed to its lower toxicity. 18 Huperzine B possesses an even higher therapeutic index than huperzine A which is in agreement with its longer duration of action. 19 Both huperzine A and huperzine B were isolated from the Chinese club moss Huperzia serrata 20 which has a long history of use as Chinese folk medicine against various ailments like contusions, strains, swellings, and schizophrenia.…”