The severity of the cognitive and functional symptoms of various neurodegenerative diseases, including Alzheimer’s disease (AD), are strongly correlated to decreased levels of the neurotransmitter acetylcholine (ACh). Consequently, inhibition of acetylcholine esterase (AChE) is an established strategy to alleviate these symptoms, and several AChE inhibitors are currently in clinical use. (–)-Huperzine A (6) is a potent and reversible AChE inhibitor that is well-tolerated in humans. Natural (–)-huperzine A (6) has been employed for over a decade to treatment mild-to-moderate AD in China. In addition to relieving the symptoms associated with acetylcholinesterase deficiencies, there is evidence that huperzine may modify the progression of AD. Furthermore, a large body of evidence also suggests that (–)-huperzine A (6) may be useful as a prophylaxis against organophosphate-based nerve agents. Although several syntheses of huperzine have been reported, a practical and scalable route to the target has not been described, to our knowledge.
Our laboratory has recently developed an efficient and scalable synthesis of (–)-huperzine A (6). Our pathway to the target proceeds in eight operations from the known compound (R)-4-methyl-cyclohex-2-ene-1-one [1, itself available in three steps and 45% yield from the inexpensive reagent (+)-pulegone]. Our route proceeds in 35–45% overall yield, is optimized to maximize material throughput, and has already provided gram quantities of (–)-huperzine A (6). Collaborations are in place to scale our synthetic route and to evaluate the clinical potential of huperzine for a number of indications.
Maung Kyaw Moe Tun, Daniel-Joachim Wüstmann, and Seth B. Herzon Chem. Sci. 2011, 2, 2251.
Maung Kyaw Moe Tun and Seth B. Herzon J. Exp. Pharmacol. 2012, 4, 113.
Maung Kyaw Moe Tun and Seth B. Herzon J. Org. Chem. 2012, 77, 9422.