Huperzine analogues

It is interesting that, in addition to its AChE inhibitory eflfects, huperzine A is reported to inhibit NMDA receptor binding and this is also of use in treating AD/ Recently, three compounds, huprine X (42) and its F and Br analogues, huprine Y and huprine Z have been synthesized. These compounds combine the carbobicyclic structural feature of huperzine A (40) with the 4-aminoquinoline skeleton of tacrine (28). All three compounds showed a very strong selectivity for AChE over BuChE and also for human as opposed to bovine AChE and this was demonstrated in vivo as well as in vitro. 

Zhou GC, Zhu DY, Synthesis of 5-substituted analogues of huperzine A, Bioorg... 

Recently, analogues of nucleosides [60], natural products Huperzine-A [61] and Hydroartemisinin [62], and inhibitors of metallo-/ -lactamases have been synthesised [63]. With acylsilane electrophiles, the initial adducts undergo Brook rearrangement which is interrupted by -Si bond fission with loss of fluoride anion (Eq. 16), leading to the formation of extremely useful difluoro-enol silanes [64]. Of the various fluoride sources employed, the tetrabutylam-monium triphenyldifluorostannate described by Gingras appears to be particularly effective. The numerous other methods for trifluoromethylation formed the subject of an exhaustive review [65]. More recently, the Olah group described a chlorodifluoromethyl trimethylsilane which is expected to have a rich chemistry [66]. 

The Stork s aza-annulation method with acrylamide180,181 has been used frequently for the synthesis of six-membered nitrogen-containing heterocycles. Recently, this reaction was applied to the synthesis of 315 and 316 from protected enamine 314 (equation 68)182. Compound 315 is a key intermediate in the synthesis of the alkaloid Huperzine A and its analogues. 

Camps, R Contreras, J. Fontbardia, M. Solans, X. Improved synthesis of methyl 7,7-ethylenedioxy-3-methyl-9-oxobicyclo[3.3.1]non-3-ene-l-carboxylate intermediate for the synthesis of huperzine A analogues. Synthetic Commun., 1996, 26(1) 9-18. 

Camps, R Contreras, J. El Achab, R. Mortal, J. Munoz-Torrero, D. Font-Bardia, M. Solans, X. Badia, A. Vivas, N. M. New syntheses of rac-huperzine A and its rac-1-ethyl-derivative. Evaluation of several huperzine A analogues as acetylcholinesterase inhibitors. Tetrahedron, 2000, 56(26) 4541-4553. 

Campiani, G. Kozikowski, A. R Wang, S. Ming, L. Nacci, V. Saxena, A. Doctor, B. P. Synthesis and anticholinesterase activity of huperzine A analogues containing phenol and catechol replacements for the pyridone ring. Bioorg. Med. Chem. Lett., 1998, 8(11) 1413-1418. 

Kozikowski, A. R Campiani, G., Nacci, V., Sega, A., Saxena, A., Doctor, B. P. An approach to modified heterocyclic analogues of huperzine A and isohuperzine A. Synthesis of the pyrimidone and pyrazole analogues, and their anticholinesterase activity. J. Chem. Soc. Perkin Trans. 1, 1996, 11 1287-1297. 

Kaneko, S. Nakajima, N. Shikano, M. Katoh, T. Terashima, S. Synthesis and acetylcholinesterase inhibitory activity of fluorinated analogues of huperzine A. Bioorg. Med. Chem. Lett., 1996, 6 1927-1930. 

Camps, R Munoztorrero, D. Simon, M. Easy access to 4-substituted ( )-huperzine A analogues. Synthetic Commun., 2001, 31(22) 3507-3516. 

An organobase including guanidine is often used as co-catalyst (or base) in palladium coupling reactions [84]. The 2-methylenepropane-l,3-diol diacetate reacts with 7,8-dihydroquinoline derivative in the presence of palladium acetate [Pd(OAc)2], TMG (1) and triphenylphosphine (PPhs) to give the methylene bridged compound in 92% yield, which can be converted to a diamino analogue of huperzine A, an inhibitor of acetylcholine esterase [84a](Scheme 4.32). 

Kaneko S, Yoshino T, Katoh T, Terashima S (1998) Synthetic Studies of Huperzine A and its Fluorinated Analogues. 1. Novel Asymmetric Syntheses of an Enantiomeric Pair of Huperzine A. Tetrahedron 54 5471... 

Kaneko S, Nakajuna N, Shikano M, Katoh T, Terashima S (1998) Synthetic studies of huperzine A and its fluorinated analogues.2. Synthesis and acetylcholinesterase inhibitory activity of novel fluorinated huperzine A analogues. Tetrahedron 54 5485... 

Natural (—)-huperzine A (1) inhibits acetylcholinesterase (AChE) 30 times more potently than its enantiomer (+)-huperzine A, and the racemic form is about two times less potent than the natural form (127,128). In the past ten years, major efforts have been devoted to the preparation of both structurally simplified analogues and derivatives with the tricychc skeleton of huperzine A (1) as a promising lead compound (Fig. 23). 

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