Huperzine alkaloids

Chemistry, pharmacology, and clinical efficacy of the Chinese nootropic agent huperzine A, alkaloid from Hupenia sermta with annulated 2-pyridone and l-amino-3-methyl-9-ethylidenebicyclo[3.3.l]nona-2,6-diene fragments 99ACR641. 

The group of Terashima [35] developed an asymmetric domino Michael/aldol process using the chinchona alkaloid (-)-cinchonidine (2-103), to prepare an intermediate for the synthesis of the natural product (-)-huperzine A (2-102) [36] (Scheme 2.22). 

Zangara A. (2003) The psychopharmacology of huperzine A An alkaloid with cognitive enhancing and neuroprotective properties of interest in the treatment of Alzheimer s disease. Pharmacol BiochemBehav 75 675-686. 

Complexed with the Nootropic Alkaloid Huperzine A. Nat. Struct. Biol. 1997, 4, 57-63. 

The intramolecular Heck reaction is a powerful method for the synthesis of constrained tertiary and quaternary carbon centers and has been applied as a key step in the synthesis of a number of pyridine alkaloids. Mann et al. have accessed the bicyclononane core structure of huperzine A 150 in moderate yield by intramolecular Heck reaction of bromopyridine 151 (Equation 117). Another notable application of this methodology is the intramolecular a-arylation of the amide enolate generated from 152 to give the carbon skeleton of cytosine <20040BC1825> (Equation 118). 

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. 

Raves, M. L., Harel, M., Pang, Y. P., Silman, I., Kozikowski, A. P., Sussman, J. L. Structure of Acetylcholinesterase Complexed with the Nootropic Alkaloid Huperzine A, Nature Struct. Biol. 1997,... 

Acetate is also a precursor of several groups of alkaloids in the form of a polyketide chain that interacts with an unknown nitrogen source (as in the terpene alkaloids). Examples of acetate-derived alkaloids are coniine—the toxic principle of Conium maculatum, pinidine—from several Pinus species, and the naphthy-lisoquinoline alkaloids (e.g., ancistrocladine)—showing antimalarial and anti-HIV activity. The latter alkaloids are apparently derived from the oxidative coupling of two pentaketide units. Huperzine A, currently in clinical trials for the treatment of Alzheimer s disease and isolated from the club moss (Serrata huperzia), is derived from a polyacetate precursor (Fig. 46). 

Huperzine-A (278), an alkaloid from Hu-perzia serrata Trev. (orLycopodium serratum Thunb.) is three times as potent as physostig-... 

A myriad of natural compounds have been tested for the past 20 years in a frenetic search for agents with potential effects against AD neuropathology. Some of these compounds include alkaloids from the calabar bean (Physostigma venenosum) huperzine A from Huperzia serrata-, galantamine from the snowdrop Galanthus woronowii cannabinoids (cannabidiol from Cannabis sativa) ... 

Huperzine A, a potent anticholinesterase alkaloid, and huperzine B were separated from a Chinese medicinal herb, Huperzia serrata (Thunb) Trev. Lycopodium serratum Thunb.), (Lycopodiaceae), by Liu et al [25]. The plant was used in Zhejiang Province of China for treatment of some mental disorders. 

Among the alkaloids in Lycopodium plants, huperzine A (2) was isolated from Lycopodium serratum Thunb. in 1986 and has been shown to have acetylcholine esterase (AChE) inhibitory activity and to improve memory disorders in Alzheimer s disease [13-15]. In addition to these unique activities, it was recently reported that some Lycopodium alkaloids possessing skeletons different from that of huperzine A (2) are able to enhance nerve growth factor (NFG) mRNA expression and production in human glial cells [16, 17]. Because of their useful biological activities, Lycopodium alkaloids are an attractive target in natural product chemistry, synthetic chemistry, and medicinal chemistry. 

Hemscheidt and Spenser conducted feeding experiments and found that Lycopodium alkaloids are secondary metabolites of lysine (3) [18] (Scheme 1). The decarboxylation of lysine (3) yields cadaverine (4), which consists of five carbons, and this, in turn, is converted into A -piperideine (5). The condensation of A -piperideine (5) with 3-oxoglutaric acid (6) produces 4-(2-piperidyl)acetoacetic acid (7) and this is converted into pelletierine (8) after a decarboxylation reaction. The biosynthetic process from this point to structurally complex Lycopodium alkaloids, such as lycopodine (1) and huperzine A (2), is deduced from the structures of the isolated alkaloids. The condensation of pelletierine (8) with 4-(2-piperidyl)... 

Michael/aldol reaction. The key step in a synthesis of the alkaloid huperzine A (3) involves a Michael/aldol reaction of the (3-keto ester 1 with methacrolein to provide the bridged ketol 2. The usual Michael reaction catalysts (NaOCHs, BU4NF, ZnCl2) are ineffective, but the desired reaction can be effected in 93% yield with tetramethylguanidine as catalyst. DBU can also catalyze this reaction. Conversion of 2 to 3 is effected by dehydration of the ketol (45% yield), Wittig reaction of the ketone... 

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