@article{91e1e27ce2f1463cad8b0a0af227deb2,
title = "Synthesis of the benzenoid analogue of the chinese nootropic agent huperzine a",
abstract = "A short synthesis of the benzene isostere of huperzine A, an anticholinesterase of potential use in the treatment of Alzheimer's disease, is described starting from β-tetralone.",
author = "Yan Xia and Reddy, {E. Rajarathnam} and Kozikowski, {Alan P.}",
note = "Funding Information: The synthesis was begun using commercially available p-tetralone (Scheme I). This compound was a-carbomethoxylated6. and the resulting P-keto ester 3 then reacted with methacrolein in the presence of 1,1,3,3-tetramethylguanidine( TMG) as catalyst to afford 4. TMG was found to be the most effective catalyst for carrying out this tandem Michael addition/aldol condensation reaction. I The stereoisomeric mixture of products 4 was then converted to its mesylate and a solvolytic elimination reaction brought about using sodium acetate in acetic acid.8 The olefin 5 was isolated in 42% yield along with unreacted trans. diequatorial mesylate 6. The Wittig reaction of 5 with ethylidenetriphenylphosphoranc was carried out next to afford the olefin mixture 7 (E/Z = 10:90)9. This olefin mixture was readily isomerized with thiophenol in the presence of AIBN to provide olefin mixture 8 (E/Z = 80:20).1 0 The carbomethoxy group of 8 was hydrolyzed by a solution of 20% NaOH in THF and MeOH to provide the acid 9. Under these reaction conditions, only the ester of E-olefin stereochemistry underwent saponification, while the ester of Z-olefin stereochemistry was recovered and could be recycled through the olefin isomerization step. Lastly, the carboxyl group of 9 was transformed to an amino group through a sequence of steps involving acid chloride formation, Curtius rearrangement, and carbamate hydrolysis.1 191 2 This short sequence of chemical operations provides an efficient route to racemic 2, a close structural analogue of huperzine A. The discovery that TMG is able to efficiently catalyze the direct conversion of 3 to 4 provides the main simplifying feature of the synthetic scheme. The synthetic strategy detailed herein is being applied to the preparation of huperzine A.3b While the anticholinesterase activity of 2 and related analogues will be reported fully elsewhere, preliminary studies indicate that 2 is approximately 1000 fold less potent than natural huperzine A.13 Acknowledeements. We are indebted to the National Institute on Aging (Grant No. lROlAG07591) for their generous support of our cognition program. Y. Xia thanks the University of Pittsburgh for an Andrew Mellon predoctoral fellowship (1986-1988).",
year = "1989",
doi = "10.1016/S0040-4039(00)99224-4",
language = "English (US)",
volume = "30",
pages = "3291--3294",
journal = "Tetrahedron Letters",
issn = "0040-4039",
publisher = "Elsevier Limited",
number = "25",
}