One-step synthesis of Lycopodium alkaloid (-)-huperzine W via Suzuki-Miyaura coupling

The first total synthesis of (−)-huperzine W (1) has been achieved. Key element of the synthesis is a highly convergent assemblage for the two rings system of target molecule utilizing an efficient Suzuki-Miyaura coupling reaction between chiral iodide 2 and 2-allylpyrrolidinone 4. Evaluation of the AchE inhibition of synthetic huperzine W was also carried out.


Introduction
The Lycopodium alkaloids 1 are a diverse group of structurally complex natural products. Owing both to their appealing, synthetically challenging polycyclic systems with dense stereochemical array and wide-ranging biological activities, a wealth of total synthesis of Lycopodium alkaloids have been reported. 2 In the context of our ongoing synthetic endeavor on a complex polycyclic Lycopodium alkaloid, 3 huperzine W, an unusual structure-simplified natural Lycopodium alkaloid attracted our attention. Huperzine W, isolated in 2002 along with alopecuridine by Zhu 4 and co-workers from the plant of Huperzia serrata, is a novel 14 carbons Lycopodium alkaloid whose structure consists of a chiral cyclohexenone unit and a 2-pyrrolidinone moiety, linked by three carbon atoms. We were attracted to a synthesis of huperzine W not only because it has not yet to be synthesized, albeit architecturally rather simple, but also due to our interesting observation that the unique backbone of huperzine W is embedded delicately in the more intriguing polycyclic systems of other Lycopodium alkaloids (see Figure 1), such as 8-deoxyserratinine, 3b,3c,5 serratinine 6 and serratezomine A. 7 In principle, a stepeconomical and ideal synthesis of huperzine W, no doubt, will facilitate the total synthesis of the above complex alkaloids. Besides, we have a question about the biological activity of huperzine W, because its congener huperzine A is a wellknown potent inhibitor of the enzyme acetylcholinesterase (AchE) used for the treatment of Alzheimer's disease. 8

Results and Discussion
Our retrosynthetic analysis of huperzine W (1) is outlined in Scheme 1. We conjectured that an intermolecular Suzuki-Miyaura cross-coupling 9 of 2-allylpyrrolidinone 4 with iodide 2 would directly furnish the target molecule with just one single step. Both iodide 2 and 2-allylpyrrolidinone 4 are known compounds. 10 Iodide 2 was envisioned to arise from the optical cyclohexenone 3 and 2-allylpyrrolidinone 4 was prepared from pyrrolidinone 5 by N-alkylation. Our synthesis commenced with the preparation of the two fragments. As shown in scheme 2, upon treatment with iodide and pyridine, the starting material enone 3, prepared in multigram quantities according to the Caine's method, 11 smoothly yielded the -iodo enone 2. On the other hand, 2-allylpyrrolidinone 4 can be prepared quantitatively through N-alkylation of pyrrolidinone 5 (NaH, allyl bromide). *To whom correspondence should be addressed. E-mail: yangyurong@mail.kib.ac.cn Hydroboration of the 2-allylpyrrolidinone 4 with 9-BBN, then the in situ generated trialkylborane intermediate (not shown) was reacted with -iodo enone 2 under the standard Suzuki-Miyaura coupling conditions gave (-)-huperzine W (1) in 75% yield. All spectroscopic data matched those reported for the natural material. Our synthetic huperzine W (1) shows [α] 25 D -33 (c 1.28, CHCl 3 ), while the [α] D value of the natural huperzine W is unavailable for comparison.
Since the biological activity of huperzine W has not been documented in the isolation paper, we still wondered whether huperzine W might be active in inhibition of acetylcholinesterase (AChE), hoping to associate it with the potent huperzine A; and then evaluation of the AchE inhibition of synthetic huperzine W was performed. Unfortunately, this structural simplified Lycopodium alkaloid entirely lacks any activity in inhibition of AChE (see Table 1), 12 suggesting the unique chemical structure of huperzine A is not replaceable and essential for its pronounced bioactivity.
In summary, the one-step and first asymmetric total synthesis of huperzine W was realized by a highly convergent route using an efficient Suzuki-Miyaura coupling reaction between chiral iodide 2 and 2-allylpyrrolidinone 4. This stepeconomical synthesis is potentially beneficial to the synthesis of other relevant complex Lycopodium alkaloids.

Experimental Section
General Experimental Procedures. All reactions were performed with dry solvents under anhydrous conditions, unless otherwise noted. Dry tetrahydrofuran (THF) were distilled over sodium-potassium alloy. Dichloromethane and dimethylformamide (DMF) were distilled over calcium hydride. Yields refer to chromatographically and spectroscopically homogeneous materials, unless otherwise noted. Reagents were used as received without further purification, unless otherwise stated. Silica gel (200-300 mesh, Qingdao Marine Chemical Ltd., China), light petroleum ether (bp 60-90 ºC), ethyl acetate and methanol were used for product purification by flash column chromatography. NMR spectra were recorded in CDCl 3 solution on Bruker AV-400 instrument with tetramethylsilane (TMS) as an internal reference. IR spectra were recorded with KBr pellets on a Bruker Tensor 27 FT-IR spectrometer. Optical rotations were determined on a Jasco P-1020 digital polarimeter. Highresolution mass spectral analysis (HRMS) data were recorded via electron impact mass spectrometry using a time of flight analyzer.

Electronic Supplementary Material
Supplementary material is available in the online version of this article at http://dx.doi.org/ 10.1007/s13659-012-0084-2 and is accessible for authorized users.