Asymmetric Organocatalysis12

Organocatalysis – Catalysts andApplicationsOrganocatalysis is a relatively recent development in the field of organic chemistry. Unlike traditional catalysis, which relies on metals to facilitate reactions, organocatalysis utilizes small organic molecules as catalysts. The use of organic catalysts has many advantages, including high selectivity, lower toxicity, and cost-effectiveness. In this article, we will explore the various types of organocatalysts and their applications.Types of OrganocatalystsThere are numerous types of organocatalysts, each with its unique properties and capabilities. One of the most commonly used organocatalysts is the amine. Amines can be easily synthesized and have a high affinity for many organic substrates, making them an ideal catalyst for many reactions. Another popular catalyst is the imidazole, which is known for its ability to facilitate various types of reactions, including Michael additions and cycloadditions.Another type of organocatalyst is the thiol. Thiols are unique in that they are capable of activating the electrophilicity of other molecules, making them excellent catalysts for reactions that involve nucleophilic addition. A third category of organocatalysts includes the phosphines. These compounds are versatile and can be used to catalyze a wide range of reactions, including hydrogenation and reduction.Applications of OrganocatalysisOrganocatalysis has numerous applications in organic synthesis. One of the most common applications is in asymmetric synthesis. Organocatalysts can be used to induce chirality into non-chiral molecules, enabling the production of enantiomerically pure compounds. This is particularly important in the pharmaceutical industry, where the production of chirally pure compounds is critical.Organocatalysts are also used in the synthesis of natural products. Many natural products have complex structures that are difficult to synthesize using traditional methods. Organocatalysis offers an alternative approach that can facilitate the synthesis of complex natural products. Additionally, organocatalysis is increasingly being used in polymerization reactions, where it can enhance the selectivity and efficiency of the reaction.ConclusionOrganocatalysis has emerged as an important field of research in organic chemistry. The use of organic catalysts has significant benefits over traditional metal catalysts, including high selectivity, lower toxicity, and cost-effectiveness. Organocatalysts are capable of facilitating a wide range of reactions, including asymmetric synthesis, natural product synthesis, and polymerization reactions. As research in this field continues to evolve, we can expect to see even more applications and advances in organocatalysis.。

新型手性胺的设计、合成及其手性识别与不对称催化性能研究摘要本论文首先较全面地归纳和综述了有机不对称催化，特别是手性胺催化不对称Michael加成反应研究进展，在此基础上，对新型手性胺的设计、制备、表征及其手性设别和不对称催化Michael加成和Michae-aldol串联反应性能进行了较深入的研究。

设计合成了一类以氨基酸为原料，经还原、溴化、季铵化和离子交换反应得到的新型离子化手性胺。

该类离子化手性胺表现出离子液体的特性，具有较低的玻璃化温度和良好的热稳定性（T dec在210℃以上）。

其晶体结构表明质子化的手性胺通过形成氢键和离子键等形式构建成稳定的网状超分子结构。

核磁共振波谱研究表明：该新型离子化手性胺可提供有效的手性环境，具有明显的手性识别性能。

设计了一类新型手性胺－硫基咪唑类化合物，并通过氨基酸衍生物α-溴代脂肪胺氢溴酸盐与巯基咪唑进行硫醚化反应高收率高选择性地得到该类化合物，其结构通过NMR、IR、MS和X-射线单晶衍射分析确认。

在核磁共振波谱研究中发现：该类化合物对外消旋酸具有良好的手性识别性能。

ESI-MS分析发现：以设计的(S)-吡咯烷－硫基咪唑与质子酸形成的离子型手性胺可有效地被PEG－800包裹，形成类似超分子结构的稳定催化体系，在酮与硝基烯烃的不对称Michael加成反应中表现出优异的催化活性和立体选择性，在室温下反应12～48小时，得到收率高达97％的Michael产物，d/r比大于90：10，ee值高达99％。

该离子型手性胺－PEGs催化体系还具有良好的稳定性，可稳定重复使用7次以上。

聚乙二醇包裹阳离子和阴离子的有效游离是显现优异催化性能的主要原因。

设计的(S)-吡咯烷－硫基咪唑盐在烯醛与水杨醛的不对称Michael－aldol串联反应合成手性苯并吡喃衍生物中也具有良好的催化性能。

由于催化剂中的硫醚基团与底物水杨醛之间的静电相互作用，不对称诱导生成以S构型为主的苯并吡喃衍生物。

二胺 Michael 加成反应催化剂引言二胺 Michael 加成反应是一种重要的有机合成方法，可以将二胺与α，β-不饱和酮或醛反应，形成新的C-C键。

这一反应在药物合成、材料科学和天然产物合成等领域具有广泛的应用。

为了提高反应的效率和选择性，研究人员一直在寻找新的催化剂，以实现高效、经济和环境友好的合成方法。

二胺 Michael 加成反应概述二胺 Michael 加成反应是一种亲核加成反应，通过亲核试剂（二胺）与α，β-不饱和酮或醛发生反应，生成新的碳-碳键。

这一反应的机理通常包括亲核加成、质子转移和消除等步骤。

二胺 Michael 加成反应可以在无机催化剂或有机催化剂的催化下进行。

二胺 Michael 加成反应催化剂的研究进展1. 无机催化剂无机催化剂在二胺 Michael 加成反应中起到了重要的作用。

一些金属催化剂，如钯、铜和银等，被广泛应用于该反应中。

这些催化剂能够提供活性位点，促进亲核试剂与底物的反应。

此外，一些无机催化剂还可以通过调节反应条件来实现对反应的选择性控制。

2. 有机催化剂有机催化剂在二胺 Michael 加成反应中也具有重要的地位。

一些有机小分子，如胺类化合物和有机酸等，被广泛应用于该反应中。

这些催化剂通常能够提供亲核试剂和底物之间的氢键或离子键相互作用，从而促进反应的进行。

此外，一些有机催化剂还可以通过调节反应条件来实现对反应的选择性控制。

3. 新型催化剂的研究为了提高二胺 Michael 加成反应的效率和选择性，研究人员一直在寻找新的催化剂。

近年来，一些新型催化剂的研究取得了重要进展。

例如，金属有机框架材料（MOFs）和金属有机骨架材料（MOMs）等新型催化剂被发现具有较高的催化活性和选择性。

此外，一些手性催化剂也被成功地应用于二胺 Michael 加成反应中，实现了对产物手性的控制。

二胺 Michael 加成反应催化剂的设计原则1. 活性位点设计催化剂的活性位点设计是提高二胺 Michael 加成反应效率和选择性的关键。

L-脯氨酸衍生物催化的不对称Michael加成反应刘杰 （有机化学）摘要：有机小分子有着不含贵金属、温和、廉价、对环境友好等优点，其应用已成为催化领域的重要发展趋势。

有机小分子催化的不对称合成反应是目前研究最为活跃的领域之一。

Michael加成反应在有机合成中是一种非常重要的形成碳碳键的反应。

近来，许多手性小分子催化剂被用于催化不对称Michael加成反应。

脯氨酸作为一种结构简单而且含量丰富的手性小分子催化剂在多种不对称催化反应中表现出的非常好的催化性能。

本文的主要工作是从以下两个方面对脯氨酸衍生物催化的不对称Michael加成反应进行了研究：（1）设计并制备了四种Merrifield树脂负载的含脯氨酸单元的手性小分子催化剂，经过实验，发现其中一种在催化Michael加成反应时是非常有效的，当使用5 mol%的该催化剂来催化环己酮和取代硝基苯乙烯时，产率最高可以达到92 %，ee值最高可以达到98 %，d. r.值最高可以达到99:1。

另外该催化剂可以循环使用5次以上，产率上只有很小的减少，而ee值基本不发生改变。

（2）设计并制备了一种糖-四氢吡咯催化剂，通过“Click”反应将 D-glucose 骨架与四氢吡咯连接在一起，在催化 Michael 加成反应时取得了良好效果，仅需要10 mol%的催化剂，在无溶剂条件下室温下反应24小时，产率高达98 %，ee 值大于99 %，d. r.大于99:1。

以上结果与一些天然氨基酸催化的Michael加成反应相比，不仅提高了产率和立体选择性，而且扩大了底物的范围，增大了反应的广谱性。

另外，我们还对功能化离子液体系中发生的 Heck 反应进行了研究。

设计并制备了三种功能化离子液，其中一种在催化Heck反应时非常有效。

该离子液既可作为配体又可作为碱。

在优化条件下，产率较高，且循环六次产率基本没有发生改变。

关键词：有机小分子催化，不对称Michael加成反应，脯氨酸衍生物，Heck 反应，功能化离子液，Pd粉L-Proline’s derivatives Catalyzed AsymmetricMichael AdditionJie Liu(Organic Chemistry)Abstract:Organic catalysts without noble metals have played an important role in the development of the catalytic reaction, due to their moderate effect, cost efficiency, environment friendly and other advantages. Organocatalytic asymmetric reaction is an increasingly active area in oraganic sythesis.The Michael addition reaction is one of the most important carbon-carbon bond-forming reactions in organic synthesis. Asymmetric organocatalytic Michael addition has attracted intense interests in the recent few years due to its stability, cheapness and the generation of multiple chiral centers in a single step. Recently, quite a number of small chiral organic molecules have been developed as stereoselective catalysts for asymmetric Michael reactions. Proline has been gradually recognized as a simple, abundant and powerful chiral catalyst for many asymmetric reactions.In this context, Asymmetric Michael addition reaction is studied from two sides as following.(1) One of the four Merrifield resin-supported pyrrolidine-based chiral organocatalysts,through A3-coupling reaction linkage have been developed and found to be highly effective catalysts for the Michael addition reaction of ketones with nitrostyrenes. The reactions generated the corresponding products in good yields (up to 98 %), excellent enantioselectivies (up to 98 % ee) and high diastereoselectivities (up to 99:1 d.r.). In addition, the catalysts can be reused at least five times without a significant loss of catalytic activity and stereoselectivity.(2) A modular sugar-based pyrrolidine was prepared and was found to be a highly enantioselective and cooperative organocatalyst for asymmetric Michael addition of ketones to nitrostyrenes. In the presence of 10 mol% of the organocatalysts,a pyrrolidine unit anchored to a natural D-glucose backbone through click chemistry, the Michael additions of ketones to nitrostyrenes underwent smoothly to generate the corresponding adducts in good yields (up to 98 %), high enantioselectivities (up to >99 % ee) and excellent diastereoselectivities (up to >99:1 d.r.) under solvent-free reaction conditions.In contrast to the above catalysts, some natural amino acids catalyzed the Michael addition reactions in low yields and stereoselectivities, or the substrates are very limited.In addition, we made research on the study of Heck reaction in ionic liquids. A kind of amino-functionalized ionic liquids has been prepared and investigated as ligand and base for the Heck reactions between aryl iodides and bromides with olefins in the presence of a catalytic amount of Pd submicron powder in [Bmim]PF6. The reactions generated the corresponding products in excellent yields under mild reaction conditions. The generality of this catalytic system to the different substrates also gave the satisfactory results. The key feature of the reaction is that Pd species and ionic liquids were easily recovered and reused for six times with constant activity.Keywords: Organocatalysis, Asymmetric Michael addition reaction, proline’s derivates Heck reaction; functionalized ionic liquids; Pd submicron powder.目 录第一章研究背景 (2)1.1 不对称合成的意义 (2)1.2 不对称合成的方法 (3)1.3 手性催化法 (4)1.4 脯氨酸简介 (5)参考文献 (20)第二章 Merrifield树脂负载的脯氨酸衍生物催化的不对称Michael加成反应 (28)2.1 引言 (28)2.2 结果与讨论 (28)2.3 实验部分 (34)2.4 化合物的结构表征 (37)参考文献 (41)第三章糖-四氢吡咯催化不对称Michael加成反应的研究 (43)3.1 引言 (43)3.2 结果与讨论 (43)3.3 实验部分 (48)3.4 化合物的结构表征 (49)参考文献 (55)第四章功能化离子液体系中钯催化的Heck反应 (57)4.1 引言 (57)4.2 结果与讨论 (58)4.3 实验部分 (63)4.4 化合物的结构表征 (64)参考文献 (67)附I 部分化合物谱图 (70)附录II 硕士期间发表论文题录 (77)致 谢 (78)第一章 研究背景1.1 不对称合成的意义手性（chirality）一词源于希腊语，在多种学科中表示一种重要的对称特点。

5-Pyrrolidin-2-yltetrazole as an asymmetric organocatalyst for theaddition of ketones to nitro-olefinsAlexander J. A. Cobb, Deborah A. Longbottom, David M. Shaw and Steven V. Ley*Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK CB2 1EW.E-mail: svl1000@; Tel: +44 (0)1223 336398Received (in Cambridge, UK) 24th June 2004, Accepted 5th July 2004First published as an Advance Article on the web 26th July 2004The organocatalytic Michael addition of enamines derived fromketones to a range of nitro-olefins has been effected using theproline derived 5-pyrrolidin-2-yltetrazoleAsymmetric organocatalysis is becoming an increasingly well-investigated area of organic chemistry. This is primarily because ofthe obvious advantages it holds over its metal-mediated counter-part; there is no need for expensive and often toxic metals, andorganocatalysts are generally easier to make and more easilyrecoverable than standard catalytic reagents.We recently reported the first use of proline-derived organocata-lyst 12in an asymmetric Mannich-type reaction.use of a tetrazole in catalytic asymmetric organocatalysis had beenreported and subsequently the importance of this catalyst overScheme 1General pyrrolidine-mediated nitro-Michael additionCatalyst Solvent T/°CYield(%)a,bL-Proline DMSO20931DMSO2097L-Proline MeOH20371MeOH20611MeOH5042L-Proline DCM2001DCM2020L-Proline DCM Reflux01DCM Reflux981THF2033Based on isolated product. b All drs were >15 : 1 by spectroscopy. c Determined by chiral HPLC (Daicel Chiralpak AD-HC o m m u n.,2004,1808–1809However, this could be ascribed either to the difference in hydrogen-bonding strengths between the tetrazole and the car-boxylic acid functionality or to the increased size of the tetrazole In conclusion, several advances in the asymmetric addition of a RYield (%)a ,b p -MeO-C 6H 43832-Furanyl 459m -NO 2-C 6H 45922-Thiophene 674p -CF 3-C 6H 47582-Pyridinyl 847Based on isolated product. b All drs were >15 : 1 by spectroscopy. c Determined by chiral HPLC (Daicel Chiralpak AD-H Ketone Catalystt /h Yield (%)a Dr(syn : anti )b L -Proline244710 : 11246210 : 115246710 : 11241006 : 1124719 : 114872—17268>19 : 1Based on isolated product. b Determined by 1H NMR spectroscopy.Determined by chiral HPLC (Daicel Chiralpak AD-H column). HPLC showed that opposite enantiomer 14was formed. e * Indicates position of enamine formation.。

D. W. C. MacMillan (2005)Y. Hayashi (2009)K. C. Nicolaou (2009) Littoralisone, Oseltamivir(Tamiflu○R)，and Hirsutellone B7.1 IntroductionThe molecules featured in this chapter, namely littoralisone (1, Scheme 1), oseltamivir (Tamiflu○R, 2, Scheme 1), and hirsutellone B (3, Scheme 1), belong to three distinct structural classes and possess unrelated biological activities. They are grouped together because of the use of organocatalytic reactions in their total syntheses. Before we proceed with examining these synthetic campaigns, we shall provide a broad overview of the rapidly advancing field of asymmetric organocatalysis.本章中的分子，即littoralisone（1，方案1），奥司他韦（Tamiflu○R，2，方案1）和hirsutellone B（方案1），属于三个不同的结构类别并且具有无关的生物活性。

由于在它们的总合成中使用了有机催化反应，它们被归类在一起。

在我们开始研究这些合成活动之前，我们将提供一个关于不对称有机催化迅速发展的领域的广泛概述。

During the latter part of the twentieth century, the growing field of catalytic enantioselective synthesis was dominated by the use of transition metal complexes with chiral organic ligands. Many organic chemists envisioned a future in which organometallic catalysts would play an increasingly important role in the development of asymmetric reactions. Indeed, chiral transition metal catalysts now mediate a wide array of practical asymmetric transformations, and the scope of their capabilitiescontinues to be expanded. However, while their potential is enormous, transition metal catalysts are not without limitations and drawbacks. ln certain cases, organic catalysts offer potential advantages, and may play complementary roles in asymmetric synthesis alongside organometallic complexes. Many chiral organic catalysts are derived from inexpensive and readily available biological compounds, such as amino acids and carbohydrates. In contrast to some transition metal complexes, organic catalysts tend to be quite stable, rendering their reactions more tolerant of water and oxygen. Furthermore, they tend to be less toxic than heavy metal complexes. In view of these potential advantages, the development and use of small organic molecules as asymmetric catalysts is rather appealing.在二十世纪后期，催化对映选择性合成的增长领域主要是使用具有手性有机配体的过渡金属配合物。

有机⼩分⼦催化讲解引⾔⾃从2000年以来，在Benjamin. List，Carlos F. Barbas III和David W. C. MacMillan 等⼈推动之下，有机催化（Organocatalysis）开始了伟⼤的复兴。

也就是从那时候开始我对这⼀领域产⽣了浓厚的兴趣，阅读了不少⽂献。

从本贴开始，将以回复的形式介绍有机催化领域的经典⽂献。

希望能对chem8er有点帮助。

本贴是为chem8⽽写，转贴请注明出处。

⾸先，罗列⼀些⽂献。

以下⽂献都是review，不是原始⽂献。

要想对此领域有深⼊的了解还是要读原始⽂献⽐较好。

专著两本：a) A. Berkessel, H. GrQger, Asymmetric Organocatalysis: From Biomimetic Concepts to Applications in Asymmetric Synthesis, Wiley-VCH, Weinheim, 2005; b)Enantioselective Organocatalysis (Ed.: P. I. Dalko) Wiley-VCH, Weinheim, 2007。

这两本书书籍中⼼都有。

专刊两期：Acc. Chem. Res. 2004. 37, 487-621；Chem. Rev. 2007, 107, 5413-5883。

每期⼤概⼗篇⽂章，包括了organcatalyst的各个分⽀。

零散的review很多，简单罗列⼀下，不是很全。

特别是专门介绍某⼀分⽀的review 没有列出，否则太多了。

a) P. I. Dalko, L. Moisan, Angew. Chem. Int. Ed. 2001, 40, 3726-3748; b) E. R. Jarvo, S. J. Miller, Tetrahedron 2002, 58, 2481-2495; c) B. List, Tetrahedron 2002, 58, 5573-5590; d) P. I. Dalko, L. Moisan, Angew. Chem. Int. Ed. 2004, 43, 5138-5175; e) J. Seayad, B. List, Org. Biomol. Chem. 2005, 3, 719-724; f) B. List, Chem. Commun. 2006, 819-824; g) M. Marigo, K. A. J?rgensen, Chem. Commun. 2006, 2001-2011; h) F. Cozzi, Adv. Synth. Catal. 2006, 348, 1367-1390; i) M. J. Gaunt, C. C. C.Johansson, A. McNally, N. T. V o, Drug Discovery Today 2007, 12, 8-27; j) R. M. de Figueiredo, M. Christmann, Eur. J. Org. Chem. 2007, 2575-2600; k) D. Enders, C. Grondal, M. R. M. HRttl, Angew. Chem. Int. Ed. 2007, 46, 1570-1581; l) A. Ting, S.E. Schaus, Eur. J. Org. Chem. 2007, 5797-5815;m) S. B. Tsogoeva, Eur. J. Org. Chem. 2007, 1701-1716; n) A. G. Doyle, E. N. Jacobsen, Chem. Rev. 2007, 107, 5713-5743; o) C.F. Barbas III, Angew. Chem. Int. Ed. 2008, 47, 42-47; p) A. Dondoni, A. Massi, Angew.Chem. Int. Ed. 2008, 47, 4638-4660。