【作者】 陆良秋；

【导师】 肖文精；

【作者基本信息】 华中师范大学 ， 有机化学， 2011， 博士

【摘要】 本文主要介绍我们在硫叶立德化学方面的研究工作——基于硫叶立德的串联反应、机理研究及其不对称过程：(一)、在研究硝基烯烃不对称转换的过程中,我们发现了酰基硫叶立德与该缺电子组分生成(?)唑啉酮的新反应。通过仔细地优化反应条件,我们以高达83%的收率得到了4-苯基-5-苯甲酰基嗯唑啉酮。此外,我们详细地研究了该反应的底物适用范围(芳基、烷基和酯基等,15-95%yields,≥91：9 dr),并从产物(?)唑啉酮出发合成了氨基二醇、a-羟基-β-氨基酸等其它重要的有机合成中间体。最后,通过同位素(氘和碳-13)标记、核磁跟踪反应以及中间体捕获等实验,我们研究了该反应的可能机理。结果表明,该反应在布朗斯特酸/碱有序催化下,经历了一个串联的[4+1]环化/开环重排/分子内加成-关环过程。(二)、基于上述反应的机理研究,我们发现硫叶立德与硝基烯烃的反应经过了中间体异嗯唑啉氮氧化物的阶段,这一环状中间体本质上是一个1,3-偶极子,能进行[3+2]环加成反应。因此,我们从廉价、易得的水杨醛及其衍生物出发,设计并合成了一类含有丙烯酸乙酯片段的硝基烯烃,成功实现了硫叶立德与该双缺电子组分的[4+1]/[3+2]串联环加成反应。该反应的特点是：1)无需使用任何催化剂；2)合成效率高。一步操作就可以同时高效构建三个新环、四个新的化学键和五个连续的立体中心(包括一个季碳中心)。通过该串联反应,我们高化学选择性、高立体选择性地合成了一系列结构新颖的稠杂环化合物(75-99% yields,≥95：5 dr)。这些产物经过简单的合成转换即可得到具有潜在生物活性的、含有羟基、氨基和酯基等多个官能团的吡咯烷并色满类杂环化合物。(三)、在前面的研究中,我们认识到底物的电子效应对反应的化学选择性有着十分重要的影响。因此,我们通过合理地调整不饱和亚胺的结构(包括改变电子和立体效应),成功实现了形式上是[4+1]环化而本质上是串联的Michael加成/分子内氮烷基化反应。重要的是,我们以BINOL衍生的轴手性硫醚为立体控制单元,我们成功实现了该串联反应的不对称过程,高化学选择性、高对映选择性地合成了一系列手性的吡咯啉羧酸酯(83-99% yields,up to 98% ee and>95：5 dr)。这些产物通过简单的合成转化还可以方便地得到多取代的脯氨酸酯等其它有意义的功能有机分子。此外,我们还通过X-单晶衍射和二维核磁技术研究了手性硫叶立德在溶液中的构象,并据此提出了准[4+2]加成模型来解释该串联反应中立体化学的诱导原理。(四)、轴手性诱导策略在不对称的[4+1]毗咯啉环化反应取得成功之后,我们进一步将该策略应用到更具挑战性的串联反应,即硝基烯烃和硫叶立德生成手性(?)唑啉酮的不对称[4+1]环化/重排串联反应。在最优的反应条件下,该串联反应普遍以中等到好的收率生成手性(?)唑啉酮(15-71%yields),对映选择性高达96%,非对映选择性全都大于95：5。另外,我们还通过DFT计算的方法研究了这一串联反应的立体化学诱导过程(第一阶段的[4+1]环化),发现第二步的分子内氧烷基化是决定整个反应速率和立体化学的关键步骤,而之前的Michael加成很有可能是个可逆的过程。最后,我们还研究了轴手性诱导的不对称[4+1]/[3+2]串联环加成反应,并取得了一定的成功(54-95% yields,up to 75% ee and 95：5 dr)。(五)、尽管我们已经利用轴手性诱导的方法实现了酰基硫叶立德和硝基烯烃的不对称串联反应,但是多步合成所造成的操作上的复杂性(手性硫叶立德)、底物的局限性以及普遍中等的反应收率促使我们发展新的策略来更加有效地实现这些新型串联反应的不对称过程。通过筛选大量的氢键催化剂和其他反应参数,我们发现了C2对称的手性多氢键催化剂能有效地促进酰基硫叶立德和双缺电子组分的不对称[4+1]/[3+2]串联环加成(63-99% yields,up to 80% ee and95：5 dr)。值得说明的是,这种简单、廉价且容易回收的手性脲催化剂高效地控制了五个连续手性中心(包括一个季碳中心)的构建,并且通过一次简单的重结晶操作就可以得到近乎光学纯的稠杂环产物。更有意义的是,我们还通过非线性效应、在线红外、Job方法、氢键滴定、DFT计算等方法详细地研究了氢键作用机制,建立了Lewis酸/碱协同催化的模型,并在最后完整地阐述了该串联反应立体化学的产生和传递过程。(六)、在本论文的最后部分,我们还将这种氢键不对称催化策略成功应用到硫叶立德和硝基烯烃生成手性(?)唑啉酮的不对称串联反应。在最优反应条件下,该串联反应以65-96%收率和高达94%的对映选择性、>95：5的非对映选择性生成了多种手性嗯唑啉酮产物。尤其重要的是,这种策略能有意义地将底物范围拓宽到烷基和烯基取代的硝基烯烃或稳定硫叶立德。天然产物的合成是检验有机合成方法学的重要平台。基于此,我们还将这一不对称催化的串联反应成功地应用到具有重要生理活性的类天然产物(+)-epi-Cytoxazone和天然产物Valinotin A的合成。通过在线红外和氢键滴定等实验,我们初步解释了这一反应比前面提及的[4+1]/[3+2]串联环加成反应具有更好对映选择性的原因。更多还原

【Abstract】 In this dissertation, we have highlighted recent advances on the chemistry of sulfur ylides and then described our works in this field. At first, we have disclosed the discovery of an unexpected tandem reaction and the rational design of novel cascade reactions on the basis of the mechanism investigation. Furthermore, we have developed two efficient strategies to achieve the asymmetric reactions of sulfur ylides and electron-deficient components. The key discoveries are listed below.1. An unprecedented reaction between sulfur ylides and nitroolefins has been disclosed to afford diverse and structurally complex oxazolidin-2-ones in 15-95% yields and≥95:5 dr. Significantly, many other useful synthetic building blocks such as vicinal amino diols and a-hydroxyl-β-amino acids are easily accessed from these oxazolidin-2-ones. More importantly, based on a series of experiments such as isotope-labeling experiments (D and 13C), intermediate capture and reaction tracking with NMR, we proposed a possible mechanism to account for this new reaction. The reaction was supposed to pass through mechanism-discriminative processes catalyzed by Br(?)nsted acid and base in sequence:Brensted acid-catalyzed formal [4+1] cycloadditions between sulfur ylides and nitroolefins, and Br(?)nsted base-catalyzed rearrangements of the corresponding cyclic nitronate intermediates.2. In the course of the mechanism investigation on the above-mentioned unprecedented transformation, we found the existence of a transiently generated cyclic nitronate. In principle, this cyclic nitronate is a 1,3-dipole which can react with electron-deficient components in situ. Accordingly, we proposed a novel reagent, alkene-tethered nitroolefins, and successfully developed the first inter-[4+1]/intra-[3+2] cycloaddition cascade of sulfur ylides. This novel and catalyst-free strategy allows rapid access to fused heterocyclic architectures in highly chemo-and diasteroselectivity (75-99% yields,≥95:5 dr), which could be further transformed to chromans bearing an attractive pyrroline ring and many other function groups such as amino, hydroxyl and ester. Note that only one manipulation in this tandem reaction could construct three new rings, four new chemical bonds and five consecutive stereocenters.3. By tuning the electronic effect ofα,β-unsaturated imines to stabilize the key zwitterionic intermediates generated from the Michael addition, we first accomplish the formal [4+1] cylcoaddition of sulfur ylides and unsaturated imines in high chemoselectivity. By means of the atropisomeric sulfide derived from S-or R-BINOL as the stereocontroller, the asymmetric version of this novel [4+1] annulation was performed to generate enantiomerically enriched structure-diverse pyrroline-2-carboxylates in high yields (83-99%) and excellent stereoselectivities (up to 98% ee, >95:5 dr.). Notably, these products could be readily converted into other useful functional molecules. More importantly, we established the configuration of chiral ylides in solution by X-ray analysis and 2D NMR spectroscopy, and then proposed a cisoid/quasi-[4+2] addition model to rationalize the stereoinduction of the asymmetric [4+1] annulation.4. Inspired by the success of an atropisomeric inducement strategy in the [4+1] pyrroline annulations, we continued to apply this strategy to the enantioselective tandem reactions between sulfur ylides and nitroolefins. Under the optimum reaction conditions, yields and stereoselectivities of chiral oxazolidinones are among the moderate to good level (15-71% yields, up to 96% ee and>95:5 dr). In addition, the asymmetric [4+1]/[3+2] cycloaddition cascade of sulfur ylides was also investigated with moderate results (54-95% yields, up to 75% ee and 95:5 dr). More importantly, we have studied the asymmetric course of these tandem reactions by DFT calculation. It was found that the intramolecular O-alkylation in the [4+1] annulation is the rate-and stereo-determined step. Furthermore, the first Michael addition in the cascade reaction was found to be a reversible process.5. In order to further improve the reaction efficiency, we have established an alternative method: catalytic asymmetric reaction of sulfur ylides with electron-deficient components. By rationally screening a series of H-bonding catalysts in details, a C2 symmetric chiral urea was found to be the best choice for the asymmetric [4+1]/[3+2] cascade cycloaddition. Under the optimal reaction conditions, the optically active fused heterocycles was delivered in good to excellent yields (63-99% yields) with greatly improved stereoselectivies (up to 80% ee and 95:5 dr). Remarkably, we have also investigated the stereocontrol course of the asymmetric [4+1]/[3+2] cycloaddition cascade and established a model of Lewis acid/base cooperative catalysis in virtue of non-linear effect experiment, in situ IR experiment, Job method, H-bonding titration and DFT calculation.6. We have significantly extended the success of H-bonding catalysis to asymmetric synthesis of chiral oxazolidinones. This reaction affords the desired products in moderate to excellent yields (65-96% yields) and good to excellent stereoselectivies (up to 94% ee and 95:5 dr). It was found that the good enantioselectivity was attributed to the stronger H-bonding strength between nitroolefins and H-bonding catalysts (compared with the above-mentioned [4+1]/[3+2] cascade reaction). Note that formidable alkyl- and alkenyl-substituted nitroolefins or sulfur ylides were well tolerated in this reaction (65-87% yields, up to 94% ee and 95:5 dr). Perhaps more significantly, we also successfully applied this methodology to the total synthesis of (+)-epi-Cytoxazone and (-)-Valinotin A with reduced synthetic steps compared with previous reports.更多还原