【作者】 王伟；

【导师】 王瑶；

【作者基本信息】 山东大学 ， 有机化学， 2020， 博士

【摘要】 S…O之间的弱相互作用是一种自然进化的力量,被自然界广泛用来调节蛋白质构象和维持酶的特异性活性。这种弱的相互作用已经被应用到晶体构建、药物设计和材料科学领域。同时,理论科学家也对这种弱相互作用力进行了研究。但是,这种S…O和Se…O弱相互作用力还无法用于催化化学反应,原因是这种非共价键作用力强度普遍偏低。因此,在本论文中发展了一类高活性硫键催化剂并对其弱相互作用机制进行了阐述,通过该类硫键催化剂和底物形成的S…O和Se…O作用,首次提出并成功实践了硫属元素互相作用的催化模式。我们进一步提出并发展了双硫键弱相互作用催化的策略,并用该策略实现了传统方法无法实现的化学转化。第一部分:高效硫键催化剂的发展及其催化的环化反应研究在很多晶体结构中观察到了S…O弱相互作用,后期这种令人困惑的作用力被理论化学家归属于二价硫族化合物的σ-hole作用,这意味着二价硫族化合物具有一定路易斯酸的性质,因此它能够和一些电子供体发生相互作用。鉴于大量理论研究的结果表明,S…O及Se…O之间的作用力很弱,我们通过在S原子或Se原子上键连一个阳离子,大幅度提高了二价硫族化合物的σ-hole的深度。基于这一理念我们扩充X+-Se-R和X+-S-R的催化剂库,通过催化剂的单晶结构和核磁实验,证实了 S…O、Se…O、Se…C1和Se…Se弱相互作用的存在。该类硫键催化剂可以通过形成S…O或Se…O作用去活化β酮醛衍生物,我们用多亲核位点的3位取代吲哚去捕获被活化的β酮醛衍生物,该反应可以简单高效的构建一种吲哚氮杂七元环骨架。除此之外,该类催化剂可以在中性条件下使非活化酮进行烯醇化,通过分子内Michael加成反应构建了一个桥环化合物骨架。众所周知,非共价键作用力很难将非活化酮转化为烯醇式,以上硫键催化剂的新应用无疑扩充了非共价键作用力的能力范畴。通过一系列控制实验的研究证实反应是Se…O作用驱动的。第二部分:双硫键弱相互作用协同催化策略的提出及其在环化反应中的应用硫键弱相互作用催化如何代替传统的催化途径并实现传统方法无法完成的反应是进一步研究的重要目标。基于此,我们提出并发展了双硫键弱相互作用催化的策略,即催化剂通过硫属元素之间的相互作用力同时与两个路易斯碱作用,进而产生催化活性促进化学反应。这种催化模式把原来分子间的反应转变为类似于分子内的反应模式,进而提高反应活性,这个催化策略为解决有机合成中的问题提供了新思路。为了验证这一策略的有效性与潜力,我们选择了 Rauhut-Currier类型的反应为研究对象。传统上,Rauhut-Currier类型反应需要使用强路易斯碱,例如三烷基磷类化合物作为促进剂/催化剂。通过实践双硫键催化的策略,以Se…O之间的相互作用力作为驱动力,醇作为促进剂即可实现Rauhut-Currier类型的反应。通过催化剂和不饱和酮以及醇相互作用的13C,77Se以及31P核磁实验研究,证实了催化剂和底物以及催化剂和醇之间的作用力为Se…O相互作用力。我们设计了系列实验来证明双硫键弱相互作用的催化机制。对于双催化机制,只有醇和烯酮比例适当时才能催化该反应,任意一个反应物过量都会抑制该反应进行。在醇作为促进剂的情况下,催化剂可以连续和烯酮形成Se…O作用,来构建一个并环化合物骨架。双硫键协同催化策略可以使α-位有取代基的低活性底物以及特殊取代基的底物顺利发生反应,然而,传统的路易斯碱催化策略却无法实现。除此之外,双硫键协同催化策略甚至可以区分甲基和乙基进而产生中等的区域选择性。这些研究结果展示了双硫键协同催化的潜力,有望为解决其它有机合成中的问题提供思路。更多还原

【Abstract】 Noncovalent S…O bonding interaction,is an evolutionary force that has been exploited by nature to regulate protein conformation and maintain specific enzyme activity.This weak interaction has been applied to the fields of crystal engineering,drug design,materials science.In addition,this type of weak interaction has been extensively investigated by theoretical scientists.However;such S…O interaction and analogous Se…0 interaction have not been applied to the field of organocatalysis so far.The reason is that such noncovalent force is comparatively weak.Therefore,in this thesis,we designed and synthesized a class of highly efficient chalcogen bonding catalysts and the weak interaction mode of these catalysts was elucidated.We developed the concept of "Chalcogen-Chalcogen Bonding Catalysis"(S…0 and Se…O)as well as the strategy of "Dual Chalcogen-Chalcogen Bonding Catalysis" to drive chemical reactions.Notably,the new strategy shows its advantage as it not only enables less reactive substrates working efficiently but tolerates inaccessible substrates using conventional methods.Part 1.The development of a class of highly efficient chalcogen bonding catalysts and their application of cyclization reactionThe S…O interaction has been observed in many crystal structures.This noncovalent force has been explained as the a-hole interaction by theoretical chemists.Considering the force between S…O or Se…O is very weak as demonstrated by theoretical and experimental results,we have significantly increased the depth ofσ-hole of divalent chalcogen by bonding a cation to the S atom or Se atom.As a result,we have developed a class of extraordinary catalysts featuring the structures of X+-Se-R and X+-S-R.The S…O,Se…O,Se…Cl and Se…Se interactions were observed from the single crystal structures of these catalysts.β-Ketoaldehyde derivatives can be activated by this type of chalcogen bonding catalyst by forming S…O or Se…O interaction.The reaction enables the assembly of discrete small molecules to construct N-heterocycles in a highly efficient manner.In addition,this type of catalyst can generate enols from non-activated ketones under neutral conditions.We discovered that Se…O activation of methyl ketone could generate enol which adds to the double bond to give bridged N-heterocycles in moderate yields.It is well-known that merely weak noncovalent forces are extremely difficult to generate enol from linear unactivated ketones.This finding undoubtedly expands the capacity of noncovalent forces.A series of control experiments demonstrate that Se…O bonding interaction is the driving force of these reactions.Part 2.The development of dual chalcogen-chalcogen bonding cooperative catalysis strategy and its application in catalytic cyclization reactionsIt remains an important goal how to realize traditional catalysis approaches through chalcogen bonding catalysis and in particular,to achieve challenging reactions that are unsuccessful by traditional methods.To this end,we have developed"dual chalcogen-chalcogen bonding cooperative catalysis" strategy that the distinct chalcogen atoms simultaneously interact with two chalcogen-based electron donors to give rise to the catalytic activity,thus facilitating chemical reactions.This catalytic mode enables shifting the intermolecular reantion to an ’intramolecular’ manner,which opens up a new door for driving chemical reactions.To demonstrate the advantage and potential of this strategy,the Rauhut-Currier type reaction was investigated.Conventional approaches to the Rauhut-Currier-type reactions require the use of strongly nucleophilic Lewis bases as essential promoters.The implementation of this dual chalcogen-chalcogen bonding catalysis strategy allows the simultaneous Se…O bonding interaction between chalcogen-bonding donors and an enone and an alcohol,enabling the realization of the Rauhut-Currier-type reactions in a distinct way.The 13C,77Se and 31P NMR experiments confirmed that the interaction between the catalyst,the substrate and the alcohol is the Se…O bonding interaction.We implemented a series of insightful experiments to prove the mechanism of dual chalcogen bonding catalysis.For a dual chalcogen bonding catalysis approach,the reaction can only be preceded when a proper ratio of alcohol/enone was used.The further implementation of a consecutive dual Se…O bonding catalysis approach enables the achievement of an initial Rauhut-Currier-type reaction to give an enone product which further undergoes an alcohol addition induced cyclization reaction.This work demonstrates that the nearly linear chalcogen-bonding interaction can differentiate similar alkyl groups to give rise to regioselectivity.Moreover,this dual chalcogen bonding catalysis strategy can make less reactive substrates and specific substrates react smoothly,which otherwise are failed using the traditional Lewis base catalysis approach.This research highlights the potential of this strategy and we envision that this dual catalysis strategy would find more applications and provide a solution to other synthetic problems in the future.更多还原