AN APPROACH TO MODIFIED HETEROCYCLIC-ANALOGS OF HUPERZINE-A AND ISOHUPERZINE-A - SYNTHESIS OF THE PYRIMIDONE AND PYRAZOLE ANALOGS, AND THEIR ANTICHOLINESTERASE ACTIVITY

Synthetic approaches to the pyrimidone and the pyrazole analogues of t he naturally occurring acetylcholinesterase (AChE) inhibitor huperzine A and its unnatural regioisomer, isohuperzine, are described, The pyr imidone analogues of huperzine A were obtained starting from cyclohexa ne-1,4-dione monoethylene ketal by first annealing to this monocycle a pyrimidine ring and then constructing the unsaturated three-carbon br idge using the previously described palladium-catalysed bicycloannulat ion 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 method ology which involves a two step reaction sequence consisting of the in termediate construction of a beta-lactone, which in turn undergoes a [ 2 + 2] cycloreversion leading to the desired olefin. This beta-lactone synthesis, which has not-previously been applied to beta-keto esters, was found to proceed with excellent diastereoselectivity. In turn, th e beta-lactone underwent a stereospecific decarboxylation reaction to provide the E-olefin product as the sole isomer. Additionally, startin g from the bicycle[3.3.1] nonene intermediate 2 we describe a syntheti c strategy for procuring modified heterocyclic analogues of isohuperzi ne 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 abi lity to act as a reversible inhibitor of AChE, the data reported herei n should prove useful to modeling efforts aimed at acquiring a better understanding of huperzine A's binding topography within AChE.