The New Catalytic System Of Asymmetric Henry Reaction And Application Of Synthesis Of (R)-Aegeline

(R)-Aegeline is a nature occurringα-hydroxyamide with antihyperglycemic and antidyslipedemic activity, which was isolated from Aegel marmolos. Several approaches for the enantioselective synthesis of (R)-Aegeline have been reported in recent years, including asymmetric reduction of prochiral ketones, asymmetric cyanosilylation of p-methoxybenzaldehyde and asymmetric dihydroxylation of p-methoxystyrene. However, some of these methods need expensive chiral reagents and others require complicated multi-step synthesis. Henry reaction is a carbon-carbon bond forming reaction between carbonyl compounds and nitroalkanes, and its asymmetric version provides one of the most effective way for the preparation of chiralβ-nitroalcohols, which can be transformed into chiralβ-aminoalcohols by reduction of nitro group. Therefore, we chose asymmetric henry reaction to prepare the key intermediate for (R)-Aegeline, namely (R)-2-amino-1-(4-methoxy phenyl) ethanol. This work mainly involves the following three parts:1. A novel bifunctional organocatalyst (S)-1-(3, 5-bis(trifluoromethyl)phenyl)-3- (1-ethylpyrrolidin-2-ylmethyl)thiourea was synthesized from cost-effective (S)-2- aminomethyl-1-ethylpyrrolidine. It was apllied to the asymmetrc henry reaction of p-methoxybenzaldehyde with nitromethane, and the influence of temperature, solvents and catalyst load on the catalytic activity and enantioselectivity were examined. When the reaction was carried out in THF under 0~5℃, 71% yield and 84%ee were obtained with 10mol% catalyst load.2. A copper(II) complex with (-)-sparteine was prepared according to a reported procedure. Respective combination of this complex with seven tertiary amines were used as double catalytic activation systems for the asymmetrc henry reaction of p-methoxybenzaldehyde with nitromethane. The carbonyl group of p-methoxy- benzaldehyde was activated by the copper complex while nitromethane was activated by the tertiary amine. When the reaction was carried out in methanol under 0℃with (-)-sparteine-copper(II) complex and triethylamine as the double catalytic activation system, best catalytic activity and enantioselectivity were achieved, but the required catalyst load was up to 20mol%. Quinine, cinchonine and other bulky tertiary amine delivered much lower catalytic activity and enantioselectivity.3. Upon comprehensive comparasion, the bifunctional thiourea organocatalyst was chosen to catalyze the asymmetric henry reation of p-methoxybenzaldehyde with nitromethane to prepare (R)-1-(4-methoxyphenyl)-2-nitroethanol, which was transformed into (R)-2-amino-1-(4-methoxyphenyl)-ethanol upon Pd/C catalyzed hydrogenation. Finally, (R)-2-amino-1-(4-methoxyphenyl)-ethanol was treated with E-cinnamoyl chloride or E-cinnamic acid N-hydroxysuucinamide active ester to give (R)-aegeline. When E-cinnamoyl chloride was used as acylating agent, significant amount of N, O-diacylated byproduct was formed. When E-cinnamic acid N-hydroxysuucinamide active ester was used as acylating agent, little such byproduct was observed.