Total Synthesis of Huperzine

Progress in synthesis of 3,4-fused indole alkaloids 13CJ01144. Progresses in the total synthesis of huperzine A (a sesquiterpene alkaloid, (1 il,9S, 13 )-l -amino-13-ethylidene-11 -methyl-6-azatricyclo [7.3.1.0 ] trideca-2(7),3,10-trien-5-one used for the treatment of Alzheimer s disease) 13CJ02261. 

For the formal total synthesis of huperzine A (152), an acetylcholinesterase inhibitor and potential drug for Alzheimer s disease, several substrates with different substitution patterns... 

Pharmacology of Huperzine A (1) Total Synthesis of Huperzine A (1) SAR Studies of Huperzine A (1) Conclusions... 

Total synthesis of racemic huperzine was achieved by Kozikowski utilizing bis-allylation of the p-k to ester 253 with 2-methylenepropanediol diacetate (252) to give 254 [92], and the enantioselective synthesis of (-)-huperzine has been carried out by Terashima [93] and Bai [94] using BPPFA-type ligands. The derivative 255 of (R)-(5 )-BPPFA (XI-12) was found to be the most effective chiral ligand among several known chiral ones (82 % yield, 90 % ee). 

The first organocatalyzed domino Michael/aldol reaction was used in the total synthesis of the natural product (—)-huperzine A [12]. This process was catalyzed by (—)-cinchonidine to convert a P-keto ester and methacrolein to a 5,9-methanocycloocta[h]pyridine tricyclic core. Two excellent reviews dealing with these processes have been recently published [8, 11], and in the field of natural products several total syntheses utilize a domino process involving a Michael reaction step [12-24]. This chapter will mainly cover the recent work in the development of novel domino reactions containing a Michael reaction published since the beginning of 2006, as the many such domino reactions were collated prior to this date by Tietze et al. in a comprehensive book [25]. 

The structure of huperzine A was confirmed by total synthesis. There are several reports on total synthesis [27]. The following described was recently accomplished by Kozikowski s group [28,29]. The monoprotected diketone, 1,4-cyclohexanedione monoethylene ketal 5-4 was used as starting material. The pyrrolidine enamine of 5-5 was heated with acrylamide followed by hydrolysis to provide an 85 15 mixture of the lactam 5-6 and 5-7. After protection of the lactam nitrogen by benzylation, dehydrogenation of the latter mixtures afforded pyridone 5-8, then hydrogenolysis of its N-benzyl group, followed by O-methylation with methyl iodide and silver carbonate which yielded methoxypyridine 5-... 

This review describes the recent studies on Lycopodium alkaloids isolated from the genus Lycopodium and Huperzia, the proposed biogenetic pathway, and the syntheses of Lycopodium alkaloids based on these biogenetic proposals. In section II, all of the Lycopodium alkaloids isolated so far, and including our recent work, are surveyed, while sections III and IV mainly deal with the biogenetic pathways and the total syntheses of the Lycopodium alkaloids, respectively. In sections V, VI, and VII, pharmacology, total synthesis, and SAR studies, respectively of huperzine A (I) are briefly surveyed. 

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