39 Huperzine Aの全合成(口頭発表の部)

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(-)-Huperzine A (1), a Lycopodium alkaloid isolated from Chinese folk medicine Huperzia serrata, has attracted a great deal of interests as a new drug for the treatment of Alzheimer's disease (AD) due to its potent, reversible and selective inhibitory activity against acetylcholinesterase (AChE). Because of the interesting biological activity coupled with the unique structural features, a bicyclo[3.3.1] skeleton and pyridone moiety, we initiated our efforts on the total synthesis of this fascinating molecule. Herein, we describe a total synthesis of huperzine A (1) featuring a unique cation-olefin cyclization. Our synthesis commenced with a construction of the bicyclo[3.3.1] core skeleton. Diels-Alder reaction between furan and maleic anhydride provided anhydride 9. Reduction of the anhydride followed by acidic work-up gave the lactone, which was subjected to hydrogenation to furnish lactone 6. The chemo-, regio-, and stereoselective alkylation of 6 was accomplished by treatment with two equivalents of KHMDS to generate dianion 10, which was alkylated with methallyl bromide to give homoallyl alcohol 5. A vanadium-catalyzed epoxidation of 5 gave epoxyalcohol 11, which was converted into α, β-unsaturated ketone 4 by means of Swern oxidation. Upon treatment with TBSOTf in the presence of base, 4 underwent unexpected cyclization to give silyl enol ether with bicyclo[3.3.1] skeleton, which was desilylated to provide ketone 13. More conveniently, ketone 13 was obtained by treatment of 4 with a catalytic amount of TIPSOTf in one step. We next focused on introduction of the amino functionality. After protection of the secondary alcohol with a MOM group, the lactone in 14 was opened by treatment with 1 equivalent of PhSK. The resulting carboxylic acid 15 was converted to methyl carbamate 17 via Curtius rearrangement. Subsequent treatment with mCPBA followed by β-elimination of sulfoxide provided the desired α, β-unsaturated ketone 19. Construction of the pyridone moiety was performed via a pyrone. After Michael reaction of sulfinyl amide to 19, ketoamide 22 was converted to pyrone 23 in refluxing toluene. Treatment of 23 with aqueous NH_3 under reflux gave pyridone 24 which was protected as its 2-methoxypyridine 25. Toward a total synthesis of huperzine A (1), we investigated the introduction of the ethylidene moiety. After cleavage of the MOM group, the resulting alcohol was oxidized by Swern oxidation. Since Wittig reaction is known to give the wrong stereochemistry, ketone 26 was converted into allyl chloride 28 via a two-step procedure including addition of vinyllithium and treatment with SOCl_2. Reduction of allylic chloride with LiBHEt_3, followed by demethylation with TMSI afforded huperzine A (1). Optically active lactone 6 could be obtained via an asymmetric opening of anhydride 9 using quinine according to the Bolm's procedure. Synthesis of (-)-huperzine A (1) is currently under way.
天然有機化合物討論会の論文
2008-09-01

39 Huperzine Aの全合成(口頭発表の部)

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