【作者】 吴慧敏；

【导师】 王春江；

【作者基本信息】 武汉大学 ， 有机化学， 2021， 硕士

【摘要】 手性α-烷基化的半胱氨酸存在于多种生物活性分子和天然产物中。从天然的半胱氨酸出发合成手性α-烷基化的半胱氨酸衍生物,是最为简单的合成方法之一。但由于巯基易于氧化的性质以及硫原子对过渡金属催化剂潜在的毒化作用等,目前大多数已报道的方法是使用手性助剂辅助的不对称合成,仅有少数采用催化不对称策略直接制备α-烷基化半胱氨酸衍生物。近年来,我们课题组开发了高效的Pd/Cu和Cu/Ir双金属协同催化体系,用于亚甲胺叶立德的α-烯丙基化反应,以制备α,α-双取代烷基化的α-氨基酸。本论文主要研究了在Pd/Cu双金属协同催化作用下,以2-噻唑啉-4-羧酸酯作为亚甲胺叶立德前体,探索其与烯丙基碳酸酯发生区域选择性与立体选择性的烯丙基化反应,以中等至高的收率(45%-98%yield)和良好至优异的对映选择性(69%->99%ee)得到了重要的手性α-烷基化半胱氨酸衍生物,在该反应体系中铜催化剂与2-噻唑啉-4-羧酸酯配位生成刚性的环状亚甲胺叶立德中间体,同时协同的钯催化剂与烯丙基碳酸酯发生氧化加成得到π-烯丙基-钯中间体。亲核性的亚甲胺叶立德中间体以高对映选择性的方式进攻亲电性的π-烯丙基钯中间体可获得目标产物。该反应的底物简便易得,对于含有不同取代基的烯丙基碳酸酯有良好的适用性。而且,克级反应能以较高的对映选择性和收率得到手性α-烷基化的半胱氨酸衍生物(90%yield,97%ee),通过简单的化学转化将产物衍生为多种手性螺环类化合物,说明了该反应体系的潜在应用价值。另外,我们还实现了Ir催化的芳基亚氨基丙二酸酯与支链2-吲哚烯丙基醇的不对称串联烯丙基化/iso-Pictet-Spengler环化反应,以良好的收率,优异的对映选择性和非对映选择性得到了含多个手性中心和多官能化的手性四氢-γ-咔啉衍生物。更多还原

【Abstract】 Chiral α-alkylated cysteines are found in a variety of biologically active molecules and natural products,and the synthesis of chiral α-alkylated cysteines from natural cysteines is undoubtedly one of the simplest synthetic methods.However,due to the high oxidative potential of sulfhydryl groups and the notorious toxic effect of sulfur atoms on transition metal catalysts,chiral auxiliaries were used for asymmetric syntheses/construction in most of the reported methods,and only a few catalytic asymmetric strategies emerged to prepare α-alkylated cysteines directly.Recently,our group has developed efficient Pd/Cu and Cu/Ir bimetallic synergistic catalytic systems for the α-allylation reaction of azomethine ylides to prepare α,α-disubstituted alkylated α-amino acids.In this paper,2-thiazoline-4-carboxylic acid ester was used as a feasible precursor of azomethine ylide to react with allyl carbonate in the presence of Pd/Cu bimetallic catalyst,to obtain biologically and synthetically significant α-alkylated cysteine derivatives.Various α-alkylated cysteine derivatives were provided in moderate to high yields with good to excellent enantioselectivity(45%-98% yields69%->99% ee).By using nucleophilic metallized azomethine ylide to attack the electrophilic π-allyl palladium intermediate in a highly enantioselective manner,the enantiomerically enriched α-allyl cysteine derivatives were obtained with high yield and excellent enantioselectivity control.Meanwhile,the starting materials are easily accessible and have good applicability for allyl carbonates bearing different substituents.The results of derivatization experiments showed that the method enables access to spiro compounds from α-alkylated cysteines derivatives without loss of ee value,which exhibited the important utility of this methodology.In addition,we achieved the Ir-catalyzed asymmetric tandem allylation/isoPictet-Spengler cyclization of aryl arylidenaminomalonates with branched 2-indolyl allyl alcohols.The highly functionalized chiral tetrahydro-γ-carboline derivatives with multiple stereocenters were obtained with good yield and excellent diastereoselectivity and enantioselectivity.更多还原