【作者】 杨柳；

【导师】 毕锡和；

【作者基本信息】 东北师范大学 ， 有机化学， 2022， 硕士

【摘要】 醚类化合物广泛存在于功能材料、天然产物、农药和药物分子中,是廉价易得的化学合成原料。在醚α位引入取代基团有助于提高活性化合物的代谢稳定性,延长活性化合物在体内的作用时间,成为现代新药研发的重要手段之一。因此,通过醚α-C–H键官能化构建α-多取代醚引起了人们的持续关注。其中,卡宾对醚α-C–H键的选择性插入已经成为构建C–C键的有力工具,可以合成其它方法难以合成的位阻较大的α-多取代醚类化合物。供体/受体和受体卡宾对醚α-C–H键插入反应得到了广泛地研究,并成功应用于复杂天然产物的合成。但是,这类反应仍存在着一定的缺陷:1)需要使用有毒且具有潜在爆炸性的α-羰基重氮化合物,而且重氮化合物大多需要提前制备并用注射泵缓慢滴加,这将不利于大量合成反应;2)分子间卡宾插入反应底物主要局限于具有环张力的环状醚、活化的苄基和烯丙基醚;3)迄今为止,分子间的供体卡宾对醚α-C–H键插入反应仍然没有实现。因此,亟需发展各种醚,尤其是非环状醚α-C–H键的供体卡宾插入反应。N-邻三氟甲基苯磺酰腙具有廉价易得,稳定,操作安全等优点,可以在温和条件下缓慢释放出不稳定的供体重氮化合物。本论文以N-邻三氟甲基苯磺酰腙作为卡宾前体,在银催化下,首次实现了分子间供体卡宾对醚α-C-H键的插入反应,为从简单的醚出发合成药物学重要的大位阻α-苄基取代醚提供了新方法。同时,该方法也适用于分子内反应,可以快速合成各种5-8元的氧杂环。本文发展的方法成功用于克级制备α-苄基取代醚,证明了该方法的稳定性和可放大性。通过数个天然产物分子全合成的例子证明了该方法的简便与高效。此外,本文研究了不同类型的银卡宾与不同C(sp~3)-H键插入反应的相对反应活性。通过对照实验和DFT计算研究了反应机理与反应区域选择性产生的根源。更多还原

【Abstract】 Ether compounds widely exist in functional materials,natural products,pesticides and drug molecules.They are cheap and easily available raw materials for chemical synthesis.The introduction of a substituent group at theαposition of the ether helps to improve the metabolic stability of the active compound and prolong its action time in the body,which has become one of the important means of modern new drug research and development.Therefore,the construction ofα-polysubstituted ethers by functionalization of etherα-C–H bonds has attracted continuous attention.Among them,the selective insertion of carbene into etherα-C–H bond has become a powerful tool to construct C–C bond,which can synthesizeα-polysubstituted ether compounds with large steric hindrance that are difficult to synthesize by other methods.Donor/acceptor and acceptor carbene insertion reactions to etherα-C–H bonds have been extensively studied and successfully applied to the synthesis of complex natural products.However,there are still some defects in this kind of reaction:1)It is necessary to use toxic and potentially explosiveα-diazo carbonyl compounds,and most of the diazo compounds need to be prepared before use,and are slowly dripped with a syringe pump,which is not conducive to large-scale synthesis and preparation;2)The substrates of intermolecular carbene insertion reaction are mainly limited to cyclic ethers with cyclic tension,activated benzyl and allyl ethers;3)So far,intermolecular donor carbene insertion reactions to etherα-C–H bonds have not been realized.Therefore,it is urgent to develop various ethers,especially donor carbene insertion reaction of acyclic ethersα-C–H bond.N-triftosylhydrazones has the advantages of low cost,easy availability,stability,safe operation,and can slowly release unstable donor diazo compounds under mild conditions.In this paper,N-triftosylhydrazones was used as the carbene precursor,and under the catalysis of silver,the insertion reaction of the intermolecular donor carbene to the etherα-C-H bond was realized for the first time.It provides a new method for the synthesis ofα-benzyl ether with high steric hindrance from simple ethers.At the same time,this method is also suitable for intramolecular reactions,which can rapidly synthesize various5-8 membered oxygen heterocycles.The method developed in this paper was successfully used to prepareα-benzyl-substituted ethers at multi-gram scale,demonstrating the stability and scalability of the method.The simplicity and efficiency of this method are demonstrated by several examples of total synthesis of natural product molecules.In addition,the relative reactivity of different types of silver carbenes with different C(sp~3)-H bond insertion reactions was investigated.The reaction mechanism and the origin of the reaction regioselectivity were investigated through control experiments and DFT calculations.更多还原