【作者】 陈万锁；

【导师】 戎顺熙； 陈志荣；

【作者基本信息】 浙江大学 ， 化学工程及技术， 2005， 博士

【摘要】 本文介绍了醛的不对称烯丙基化反应,以光学纯酒石酸为原料,研究了不同构型手性配体在醛的烯丙基化反应中的立体选择性,全文共分三部分十个章节: 第一部分(一～二章)对当前手性药物和手性技术进行了概述,并由此展开了本文的研究背景和任务; 第二部分(三～六章)为有机合成部分,对醛的不对称烯丙基化反应进行了深入探讨,以苯甲醛为原料对反应条件进行优化,在优化的反应条件下对制备的七种可回收手性酰胺配体(N-苄基酒石酸二酰胺、N-对甲苯基酒石酸二酰胺、N-邻甲苯基酒石酸二酰胺、N-邻氯苯基酒石酸二酰胺、N-a-萘基酒石酸二酰胺、N-环己基酒石酸二酰胺和N-苯基酒石酸二酰胺)进行筛选,优化配体回收实验条件,最终确定出N-苄基酒石酸二酰胺在苯甲醛的不对称烯丙基化反应中具有较大优越性,结晶回收的手性配体光学纯度保持不变。然后,将上述几种配体用于3-溴丙醛(由丙烯醛与溴化氢气体加成得到)的烯丙基化反应,发现N-苄基酒石酸二酰胺同样具有较高的立体选择性(94.1%e.e.),产物经氧化和碘加成内酯化反应得到阿伐他汀中间体(3R,5S)-3-羟基-5-碘甲基戊内酯(10);将N-苄基酒石酸二酰胺用于邻氯苯甲醛的不对称烯丙基化反应以较高光学收率得(R)-甲基烯丙基-2-氯苯基-甲基醇(87.7%e.e.),产物经S_N2反应得瑞格列萘中间体(S)-甲基烯丙基-2-氯苯基-叠氮甲烷(17);同时,将筛选出的新型手性配体N-苄基酒石酸二酰胺用于其他几种醛(正丁醛,异戊醛和环己醛)的不对称烯丙基化反应,并与广泛应用的Roush配体(22)和Brown配体(27)相比较,发现其立体选择性优于Roush配体,并接近Brown配体,但明显具有可回收利用的优势。 第三部分(七～十章)为计算化学部分,运用密度泛函理论B3LYP方法在Gaussian03软件上对已经报道的几种手性配体参与的醛不对称烯丙基化反应过程进行模拟计算,基于相对反应速率理论找出两种构型过渡态间活化能的差异与产物光学收率之间的关系;并以此为基础,用AM1和MNDO方法对上述合成的几种配体控制的反应过程进行量化计算,从而在理论上证实了N-苄基酒石酸二酰胺配体在醛的不对称烯丙基化反应中具有较高的立体选择性。更多还原

【Abstract】 This work, concentrated on the asymmetric allylation of aldehydes controlled by different chiral auxiliaries prepared from rotational pure tartaric acid, can be divided into three parts.The first part aims to review the developments of chiral drugs and asymmetric synthesis, from which derived the present research topic backgrounds and works.Synthesis and applications of allylation from aldehydes are the second part of the thesis. By optimizing the reaction conditions, such as solvents, temperature, time and chiral auxiliaries like N,N’-dibenzyl tartamide, N,N’-p-dimethylphenyl tartamide, N,N’-o-dimethylphenyl tartamide, N,N’-o-dichlorophenyl tartamide, N,N’-a-dinaphyl tartamide, N,N’-dicyclohexyl tartamide and N,N’-diphenyl tartamide, ideal experimenttal conditions are obtained according to HPLC monitoring, as well as the auxiliaries’ recoveries experiments. Starting from benzaldehyde and 3-bromopropaldehyde, N,N’-dibenzyl tartamide is considered the best auxiliary in this reaction. The homoallylic alcohol product, (4R)-4-hydroxy-6-bromo-1-hexylene, can be easily synthesized into (3R,5S)-3-hydroxy-5-iodomethyl-d-valerolactone, a very important intermediate of Atorvastatin, in excellent enantiomeric excess (94.1%e.e.). In a similar way, using N,N’-dibenzyl tartamide as auxiliary, (S)-(2-methyl)allyl-2-chloro-phenyl-methyl azide, a vital intermediate of Repaglinide, can be prepared via asymmetric allylation of o-chlorobenzaldehyde in 87.7%e.e. The auxiliary can be recovered in high yield (81%) only by filtering and recrystallization. Besides, some other aldehydes have been chosen to test the enantioselectivity of N,N’-dibenzyl tartamide, in comparison with two other allylaborates reagents developed previously by Roush and Brown, respectively. The results show that %e.e. of homoallylic alcohol is superior to that of the former, and approaches the Brown reagent.The third part of this thesis is reactive simulating calculation In this section, some well-known auxiliaries are selected to compute in density functional theory B3LYP on Gaussian 03, from which the relationship between reaction active energies of transition states and enantiomeric excess of chiral products homoallylic alcohols isobtained based on relative reactive ratio theory. Using this relationship, calculations on the reaction of more than eight auxiliaries with four other aldehydes are carried out in AMI and MNDO, proving that N,N’-dibenzyl tartamide has higher enantioselectivity than others in this reaction.更多还原