92(P08) 光学活性(-)-フペルジンAおよびその含フッ素類縁体の合成研究(ポスター発表の部)
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Huperzine A (1) is an alkaloid isolated from Huperzia serrata (Thunb.) Trev. The gross structure of 1 was determined by Liu et al. in 1986 (Figure 1). This natural product exhibits a potent inhibitory activity against acetylcholinesterase (AChE). Consequently, it is expected that 1 serves as a therapeutic agent for the treatment of Alzheimer's desease. The total synthesis of racemic 1 was achieved by Qian et al. in 1989 and by Kozikowski et al. in 1989 and in 1993, independently. The asymmetric synthesis of (-)- 1 was also reported by Kozikowski et al. in 1991. We wish to present here the synthesis and in vitro AChE inhibitory activity of optically active (-)-huperzine A (1) and its fluorinated analogues. The asymmetric synthesis of (-)-1 was achieved by employing two novel methods. Thus, one is Michael addition of 2 with acrolein in the presence of chiral base (Scheme 1). The good optical yield (64% ee) of the adduct was obtained by employing (-)-cinchonidine (5) as a chiral base. The other one is asymmetric allylation of 2 employing a π-allylpalladium complex (Scheme 2). The use of ferrocenyl derivative 7 as a chiral ligand gave the best enantioselectivity (49% ee). Optically pure (+)-4 obtained by recrystallization was converted to (-)-1 by Kozikowski's procedure (Scheme 3). Next, we designed and synthesized some fluorinated huperzine A analogues (Figure 2) so far not reported. The trifluoromethyl-substituted compounds 11-13 were efficiently synthesized by a method featuring addition of trifluoromethyltrimethylsilane promoted by fluorine anion and Corey-Winter's olefin formation reaction as key steps (Scheme 4-6). Additionally, the synthesis of the mono-fluorinated compound 26 was accomplished by a method which employs fluorination of a hydroxy group (Scheme 7). With completion of the synthesis of (-)-1, 11-13, 26, in vitro AChE inhibitory activity was next assessed (Table 1). All these fluorinated analogues were found to still retain AChE inhibitory activity. Taking into account their racemic forms, analogues 11 and 26 were estimated to be 40- and 20-fold less potent than 1, respectively. These studies on the structure-activity relationships should hold promise for designing novel analogues of 1 which may exhibit characteristic profiles.
- 天然有機化合物討論会の論文
- 1996-09-02
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