金鸡纳碱衍生物催化的β-二羰基化合物不对称α-羟基化

发布时间：2018-02-01 03:23

  本文关键词： 不对称催化 金鸡纳碱 β-二羰基化合物 α-羟基化 光致氧化 分子氧　出处：《大连理工大学》2016年博士论文　论文类型：学位论文

【摘要】：手性是自然界的基本属性之一,与化学、生物、医药、工程等学科密切相关,产业界对手性化合物的巨大需求推动了手性科学的迅速发展。具有光学活性的α-羟基-β-二羰基化合物是一类非常重要的结构单元,催化β-二羰基化合物的不对称α-羟基化是获得该类结构简单、直接和高效的方法。首先,本文以金鸡纳碱奎宁及奎尼丁为先导有机催化剂,重点对金鸡纳碱C-2'和C-6'位进行结构修饰,制备并筛选了21种金鸡纳碱催化剂。以有机催化5-氯茚酮甲酸甲酯不对称α-羟基化为模型反应,考察催化剂结构与模型反应的构效关系。奎尼丁衍生C-2'位溴代、C-9和C-6'为羟基的QD-3催化该反应具有92%ee和98%收率;反应放大至克级仍有91%ee和96%收率。在该反应体系中,使用过氧化氢异丙苯为氧化剂,得到S构型的产物,对映选择性80%-98%ee,收率87%-99%；使用30%双氧水为氧化剂,得到R构型的产物,对映选择性36%-87%ee,收率35%-96%。该催化体系同时可实现β-酮酰胺类底物的不对称α-羟基化,产物具有38%-92%ee和51%-94%收率。本文还对反应机制进行了探讨,认为催化剂、底物、氧化剂之间的氢键作用是反应高效进行的主要原因。其次,以二氢奎宁为催化剂,实现了肼活化分子氧制备手性α-羟基-β-酮酸酯的方法,获得了55%-85%ee和67%-95%收率的a-羟基化产物。分子氧活化过程是肼在碱的作用下形成自由基正离子,与氧分子反应生成过氧化氢,最后氧化底物实现α-羟基化。最后,通过光致氧化策略,实现分子氧参与的有机-光催化β-二羰基化合物不对称a-羟基化,具有100%的原子经济性。通过对金鸡纳碱相转移催化剂的设计、合成与筛选,发现辛可宁衍生C-2'带有取代苯基的催化剂PTC 3I能够催化30种β-酮酸酯以及β-酮酰胺底物不对称α-羟基化,最高90%ee和99%收率。此外,发现N-氧化辛可宁衍生物相转移催化剂PTC-Cn-7具有易回收重复使用的性质,催化β-二羰基化合物不对称α-羟基化具有最高83%ee和99%收率。催化剂循环使用6次,产物仍有78%ee以及91%收率。本文还对光致氧化可能的机理进行了阐述,推测氧化反应经历了单线态氧过程,以及过氧化物中间体氧化过程。
[Abstract]:Chirality is one of the basic attributes of nature, which is closely related to chemistry, biology, medicine, engineering and so on. The rapid development of chiral science is driven by the huge demand of chiral compounds in industry. The optically active 伪-hydroxyl-尾-dicarbonyl compounds are very important structural units. Catalytic asymmetric 伪 -hydroxylation of 尾 -dicarbonyl compounds is a simple, direct and efficient method for obtaining this kind of compounds. Firstly, quinine and quinidine are used as lead organic catalysts. The structural modification of the C-2 'and C-6' sites of cinchonabine was emphasized, and 21 kinds of cinchona base catalysts were prepared and screened. The asymmetric 伪 -hydroxylation of methyl 5-chlorindenone formate was modeled by organic catalysis. The structure-activity relationship between the catalyst structure and the model reaction was investigated. The yields of quinidine derived C-2'brominated C-9 and C-6 '-hydroxyl QD-3 were 92 and 98% respectively. In this system, isopropylbenzene hydrogen peroxide was used as oxidant to obtain the product of S configuration. The enantioselectivity of the product was 80-98. The yield is 87-99; The product of R configuration was obtained by using 30% hydrogen peroxide as oxidant, and the enantioselectivity was 36-87. The catalytic system can realize asymmetric 伪 -hydroxylation of 尾 -ketoamides at the same time. The yield of the product was 38-92 and 51- 94% respectively. The reaction mechanism was also discussed and the catalyst and substrate were considered. The hydrogen bond between oxidants is the main reason for the high efficiency of the reaction. Secondly, using dihydroquinine as catalyst, the method of preparing chiral 伪 -hydroxy- 尾 -ketoate by activating molecular oxygen with hydrazine was realized. The a-hydroxylation products in 55- 85 and 67-95% yields were obtained. The process of molecular oxygen activation was that hydrazine formed free radical positive ions under the action of alkali and reacted with oxygen molecules to form hydrogen peroxide. Finally, 伪 -hydroxylation of the oxidized substrate was achieved. Finally, the asymmetric a-hydroxylation of 尾 -dicarbonyl compounds with the participation of molecular oxygen was realized by photooxidation strategy. It has atomic economy of 100%. Through the design, synthesis and screening of Jinchona alkaloid phase transfer catalyst. It was found that C-2'substituted phenyl catalyst PTC 3i could catalyze 30 尾 -ketoacid esters and asymmetric 伪 -hydroxylation of 尾 -ketoamide substrates. The highest yields of 90 and 99% were obtained. In addition, it was found that the phase transfer catalyst PTC-Cn-7 was easy to be recycled and reused. The asymmetric 伪 -hydroxylation of 尾 -dicarbonyl compounds has the highest yields of 83 and 99%, and the catalyst is recycled for 6 times. The yield of the product is still 78 and 91%. The possible mechanism of photo-induced oxidation is also discussed. The oxidation reaction has undergone a singlet oxygen process and an intermediate peroxide oxidation process.
【学位授予单位】：大连理工大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R914
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本文编号：1480798