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在有机合成中,季碳中心的构建始终是一项充满挑战的课题.含手性季碳中心的胺基膦酸化合物以其多样的生物活性,如酶抑制剂、抗真菌剂、抗菌剂和抗病毒剂等,受到了科研工作者的广泛关注.目前已有许多合成策略报道,其中亲核试剂与α-酮亚胺膦酸酯的不对称加成策略为含手性季碳中心胺基膦酸衍生物的合成提供了一条简洁有效的路径,但是却鲜有报道,已有的报道也仅局限于乙酰氰、丙酮、硝基甲烷和芳基硼酸作亲核试剂.为满足多样的手性胺基膦酸衍生物的合成需求,新的合成策略和亲核源仍有待进一步发展.值得一提的是,不对称傅-克反应是一种非常有效的构建碳-碳键的合成方法,并已有广泛报道.基于吲哚与亚胺底物的傅-克反应经验,我们研究组发展了一种有机催化吲哚与环状酮亚胺膦酸酯傅-克反应合成含手性季碳胺基膦酸衍生物的方法,使用的有机催化剂是手性磷酸.通过对溶剂、催化剂和温度的筛选发现,使用在3,3′-位引入吸电子的3,5-二三氟甲基苯基取代的H8-BINOL衍生的手性磷酸作催化剂,反应温度为30℃,溶剂为均三甲苯时,最高能以98%对映选择性得到含手性季碳胺基膦酸酯化合物.该反应操作简单,条件温和,不仅适用于吲哚衍生物,对吡咯也能取得较好结果.总之,该方法提供了一条简洁有效的合成手性胺基膦酸衍生物的途径.
In the organic synthesis, the construction of quaternary carbon center has always been a challenging topic.Aminophosphonic acid compounds containing chiral quaternary carbon center with its diverse biological activity, such as enzyme inhibitors, antifungal agents, antibacterial agents and Antiviral agents, etc., have drawn wide attention of researchers.At present, there are many synthetic strategies reported, in which the asymmetric addition strategy of nucleophile and α-ketimine phosphonate is a chiral quaternary carbon-containing amine group The synthesis of phosphonic acid derivatives provides a concise and effective route but few reports have been reported on the use of acetyl cyanide, acetone, nitromethane and arylboronic acid as nucleophiles. The demand for synthesis of the amine derivatives of aminophosphonic acids, new synthesis strategies and nucleophilic nuclei still need further development.It is worth mentioning that the asymmetric Friedel-Crafts reaction is a very effective method for the synthesis of carbon-carbon bonds, And has been widely reported.According to the experience of Friedel-Crafts reaction of indole and imine substrates, our group developed an organic-catalyzed Friedel-Crafts reaction of indole and cyclic ketimine phosphonate with chiral Methods of using the carbamido phosphonic acid derivative are as follows The catalyst was chiral phosphoric acid.Selection of solvent, catalyst and temperature was found to be found using H8-BINOL-derived chiral phosphoric acid substituted with 3,3,5-electron-withdrawing 3,5-ditrifluoromethylphenyl As the catalyst, the reaction temperature is 30 ℃, the solvent is mesitylene, the highest 98% can be enantioselective enantioselective quaternary ammonium carbonates containing phosphonates. The reaction is simple, mild conditions, not only for the indole The results showed that pyrrole can give better results.In summary, this method provides a simple and effective way to synthesize chiral amino phosphonic acid derivatives.