Huperzine synthesis

The 1.3-allylic diacetate 135 can be used for the formation of the methy-lenecyclopentane 137 with the dianionic compound 136(86]. The cyclohexa-none-2-carboxylate 138 itself undergoes a similar annulation with the 1,3-allylic diacetate 135 to form the methylenecyclohexane derivative 139(90]. The reaction was applied as a key step in the synthesis of huperzin A[91]. On the other hand. C- and 0-allylations of simple J-dikctones or. 1-keto esters take place, yielding a dihydropyran 140(92]. 

In the synthesis of fluorinated analogs of the acetylcholinesterase inhibitor, huperzine A, it was necessary to accomplish reductive elimination of the diol 15-D to 15-E. Of the methods for diol reduction, which seems most compatible with the other functional groups in this compound ... 

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). 

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

A double alkylation reaction of a tetralone produced the key tricyclic intermediate for the synthesis of (-)-huperzine (Scheme 8E.38). A better enantioselectivity was obtained with the BPPFA-derived ligand 137b, possessing a more extended side arm (n = 3) [183-185]. 

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. 

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. 

Kaneko, S. Yoshino, T. Katoh, T. Terashima, S. A novel enantioselective synthesis of the key intermediate of (—)-huperzine A employing asymmetric palladium-catalyzed bicycloannulation. Tetrahedron-Asymmetry, 1997, 8(6) 829-832. 

He, X. C. Wang, B. Bai, D. L. Studies on asymmetric synthesis of huperzine A-1. Palladium-catalyzed asymmetric bicycloannulation of 5,6,7,8-tetrahydro-2-methoxy-6-oxo-5-quinolinecarboxylic esters. Tetrahedron Lett., 1998, 39(5-6) 411 14. 

Kozikowski, A. R Prakash, K. R. C. Saxena, A. Doctor, B. P. Synthesis and biological activity of an optically pure 10-spirocyclopropyl analog of huperzine A. Chem. Corn-mum., 1998, 12 1287-1288. 

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. 

Badia, A. Banos, J. E. Camps, R Contreras, J. Gorbig, D. M. Munoztorrero, D. Simon, M. Vivas, N. M. Synthesis and evaluation of tacrine-huperzine A hybrids as acetylcholinesterase inhibitors of potential interest for the treatment of Alzheimer s disease. Bioorg. Med. Chem., 1998, 6(4) 427-440. 

Rajendran, V. Saxena, A. Doctor, B. R Kozikowski, A. P. Synthesis of more potent analogues of the acetylcholinesterase inhibitor, huperzine B. Bioorg. Med. Chem. Lett., 2002, 12(11) 1521-1523. 

Camps, R Contreras, J. Font-Bardia, M. Morral, J. Munoz-Torrero, D. Solans, X. Enantioselective synthesis of tacrine-huperzine A hybrids. Rreparative chiral MRLC separation of their racemic mixtures and absolute configuration assignments by x-ray diffraction analysis. Tetrahedron-Asymmetry, 1998, 9(5) 835-849. 

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