An approach to modified heterocyclic analogues of huperzine A and isohuperzine A. Synthesis of the pyrimidone and pyrazole analogues, and their anticholinesterase activity

Alan P. Kozikowski, Giuseppe Campiani, Vito Nacci, Alessandro Sega, Ashima Saxena, Bhupendra P. Doctor

Research output: Contribution to journalArticle

Abstract

Synthetic approaches to the pyrimidone and the pyrazole analogues of the naturally occurring acetylcholinesterase (AChE) inhibitor huperzine A and its unnatural regioisomer, isohuperzine, are described. The pyrimidone analogues of huperzine A were obtained starting from cyclohexane-1,4-dione monoethylene ketal by first annealing to this monocycle a pyrimidine ring and then constructing the unsaturated three-carbon bridge using the previously described palladium-catalysed bicycloannulation methodology. A major problem in this synthetic undertaking proved to be introduction of the ethylidene appendage onto tricycle 10. While both Wittig and Takai olefination protocols proved unsuccessful, the ethylidene moiety was eventually introduced using the Danheiser methodology which involves a two step reaction sequence consisting of the intermediate construction of a β-lactone, which in turn undergoes a [2 + 2] cycloreversion leading to the desired olefin. This β-lactone synthesis, which has not previously been applied to β-keto esters, was found to proceed with excellent diastereoselectivity. In turn, the β-lactone underwent a stereospecific decarboxylation reaction to provide the E-olefin product as the sole isomer. Additionally, starting from the bicyclo[3.3.1]nonene intermediate 2 we describe a synthetic strategy for procuring modified heterocyclic analogues of isohuperzine A. This chemistry provides an attractive approach to the synthesis of heterocyclic analogues with unsaturation in the 6,7 position. While none of these new analogues was found to rival huperzine A in its ability to act as a reversible inhibitor of AChE, the data reported herein should prove useful to modeling efforts aimed at acquiring a better understanding of huperzine A's binding topography within AChE.

Original languageEnglish (US)
Pages (from-to)1287-1297
Number of pages11
JournalJournal of the Chemical Society, Perkin Transactions 1
Issue number11
StatePublished - Jun 7 1996
Externally publishedYes

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Pyrimidinones
Cholinesterase Inhibitors
Lactones
Alkenes
Palladium
Acetylcholinesterase
Isomers
Topography
Esters
Carbon
Annealing
pyrazole
huperzine A

ASJC Scopus subject areas

  • Organic Chemistry
  • Chemistry(all)

Cite this

An approach to modified heterocyclic analogues of huperzine A and isohuperzine A. Synthesis of the pyrimidone and pyrazole analogues, and their anticholinesterase activity. / Kozikowski, Alan P.; Campiani, Giuseppe; Nacci, Vito; Sega, Alessandro; Saxena, Ashima; Doctor, Bhupendra P.

In: Journal of the Chemical Society, Perkin Transactions 1, No. 11, 07.06.1996, p. 1287-1297.

Research output: Contribution to journalArticle

Kozikowski, Alan P. ; Campiani, Giuseppe ; Nacci, Vito ; Sega, Alessandro ; Saxena, Ashima ; Doctor, Bhupendra P. / An approach to modified heterocyclic analogues of huperzine A and isohuperzine A. Synthesis of the pyrimidone and pyrazole analogues, and their anticholinesterase activity. In: Journal of the Chemical Society, Perkin Transactions 1. 1996 ; No. 11. pp. 1287-1297.
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abstract = "Synthetic approaches to the pyrimidone and the pyrazole analogues of the naturally occurring acetylcholinesterase (AChE) inhibitor huperzine A and its unnatural regioisomer, isohuperzine, are described. The pyrimidone analogues of huperzine A were obtained starting from cyclohexane-1,4-dione monoethylene ketal by first annealing to this monocycle a pyrimidine ring and then constructing the unsaturated three-carbon bridge using the previously described palladium-catalysed bicycloannulation methodology. A major problem in this synthetic undertaking proved to be introduction of the ethylidene appendage onto tricycle 10. While both Wittig and Takai olefination protocols proved unsuccessful, the ethylidene moiety was eventually introduced using the Danheiser methodology which involves a two step reaction sequence consisting of the intermediate construction of a β-lactone, which in turn undergoes a [2 + 2] cycloreversion leading to the desired olefin. This β-lactone synthesis, which has not previously been applied to β-keto esters, was found to proceed with excellent diastereoselectivity. In turn, the β-lactone underwent a stereospecific decarboxylation reaction to provide the E-olefin product as the sole isomer. Additionally, starting from the bicyclo[3.3.1]nonene intermediate 2 we describe a synthetic strategy for procuring modified heterocyclic analogues of isohuperzine A. This chemistry provides an attractive approach to the synthesis of heterocyclic analogues with unsaturation in the 6,7 position. While none of these new analogues was found to rival huperzine A in its ability to act as a reversible inhibitor of AChE, the data reported herein should prove useful to modeling efforts aimed at acquiring a better understanding of huperzine A's binding topography within AChE.",
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