【作者】 罗晓燕；

【导师】 梁鑫淼； 叶金星；

【作者基本信息】 华东理工大学 ， 制药工程与技术， 2011， 博士

【摘要】 Michael加成反应是一类应用非常广泛的重要的亲核加成反应,α,β-不饱和醛是一类用途广泛的Michael受体,通过与各种亲核试剂进行不对称Michael加成反应,可得到手性β-功能化的醛类衍生物,这些衍生物中有许多是具有多种用途的重要手性中间体或合成用的手性砌块,有些本身就是具有生物活性的物质。本论文第一部分研究了甘氨酸席夫碱镍络合物与α,“p-不饱和醛的不对称有机催化Michael加成反应。通过对反应的催化剂、辅助催化剂、溶剂的优化筛选确定反应的最优条件,最后按此优化条件进行底物拓展。在二氯甲烷与甲醇的混合溶剂中,室温下使用10 mo1%的J(?)rgensen-Hayashi催化剂以及20 mo1%的苯甲酸锂,能高效、高对映选择性地催化甘氨酸席夫碱镍络合物与α,β-不饱和醛的不对称Michael加成反应。加成反应后直接用硼氢化钠进行还原,反应产物收率最高可达98%,dr值高达49：1,ee值基本上均大于90%,最高达99%。加成还原产物进一步反应可得到两个手性中心六元内酯杂环。该模版法为制备各种手性a-取代氨基酸以及手性六元杂环提供了一种新的合成方法。本论文第二部分研究呋喃酮与α,β-不饱和醛的不对称Michael加成反应,为制备呋喃酮衍生物提供了一种新的合成方法。通过对反应条件的优化实验,确定了反应的最优条件。利用10 mo1%的J(?)rgensen-Hayashi催化剂以及20 mmo1%的醋酸锂,成功实现了呋喃酮与α,p-不饱和醛的不对称Michael加成反应。反应产物收率最高可达94%,dr值高达2.8：1,反应对映选择性高,产物的ee值基本上均大于95%,最高可达99%。本论文第三部分研究了二苯氧膦与α,β-不饱和醛的直接不对称有机催化Michael加成反应,解决了反应的区域选择性和立体选择性问题,从而为有效构建不对称C—P键提供一种新的有效合成方法。在二氯甲烷溶剂中,-20℃下,使用20 mo1%的J(?)rgensen-Hayashi催化剂,首次成功实现了二苯氧膦与α,β-不饱和醛的直接不对称Michael加成反应。反应的对映选择性高,ee值基本上均大于90%,最高可达99%,反应产物收率最高可达98%。更多还原

【Abstract】 Michael addition reaction is an important nucleophilic reaction.α,β-Unsaturated aldehyde is a valuable Michael acceptor, which reacts with various electron donors to affordβ-functionalization aldehyde derivatives. These derivatives are key chiral intermediates, building blocks or biologic active substances.In the first part, we studied the asymmetric organocatalytic Michael addition reactions of Ni (Ⅱ) complexes of glycine Schiff base toα,β-unsaturated aldehydes. After condition screening, the optimal reaction condition was obtained and applied to different enals. The reaction was carried out efficiently in the mixed solvent of MeOH and CH2Cl2 using 10 mol% of J(?)rgensen-Hayashi catalyst and 20 mol% of PhCOOLi, followed by reduction using NaBH4. The desired products were produced in up to 98% yield and 49:1 dr value. The enantioselectivity was up to 99% and all the ee values were>90%. The product was further treated to give a six-member lactone heterocycle with two adjacent chiral centers. This study offered an alternative approach to chiralα-amino acid derivatives and six-member heterocycles.Next, the asymmetric vinylogous Michael reactions ofα,β-unsaturated aldehydes withγ-butenolide was explored, which served as a powerful tool for the synthetically chiralγ-butenolide skeleton. The reaction of 2(5H)-furan to differentα,β-unsaturated aldehydes were proceeded successfully in MeOH by 10 mol% of J(?)rgensen-Hayashi catalyst and 20 mol% of LiOAc, in up to 94% yield and 2.8:1 dr value. The enantioselectivity was excellent (up to 99%), and all the ee values were>94%.Finally, the enantioselective organocatalytic phospha-Michael reaction ofα,β-unsaturated aldehydes with diaryl phosphine oxides was investigated, which provides a new and easy method to construct chiral P-C bond and chiral phosphine oxide derivitives with excellent chemo- and enantioselectivity. The reaction of diaryl phosphine oxides and differentα,β-unsaturated aldehydes was firstly conducted efficiently catalyzed by 20 mol% of J(?)rgensen-Hayashi catalyst at -20℃in CH2Cl2 with excellent enantioselectivity. Most of the ee values were>90%. The desired products were produced in up to 98% yield.更多还原