L-脯氨酰胺在不对称Aldol反应中催化应用研究进展

Aldol反应是构建C-C键最有效的有机合成方法之一,不对称Aldol反应产物是合成多种复杂有机化合物的重要原料或关键中间体。L-脯氨酰胺是催化不对称Aldol反应的重要手性催化剂之一,具有结构多样、合成简洁、立体选择性高等优点,近年来被广泛地研究。对近年来L-脯氨酰胺类手性催化剂在不对称Aldol反应中的催化应用进行综述。     

Chymopapain‐Catalyzed Direct Asymmetric Aldol Reaction

Chymopapain, a cysteine proteinase isolated from the latex of the unripe fruits of Carica papaya, displays a promiscuous activity to catalyze the direct asymmetric aldol reactions of aromatic and heteroaromatic aldehydes with cyclic and acyclic ketones in acetonitrile in the presence of a phosphate buffer. The excellent enantioselectivities of up to 96% ee and high diastereoselectivities of up to >99:1 (anti/syn) were achieved. The novel catalytic promiscuity of chymopapain widens the applicability of this biocatalyst in organic synthesis.     

Proline‐Catalyzed Asymmetric Aldol Reaction in Guanidine‐ Derived Ionic Liquids

A remarkable improvement of both the chemical yield (from 6% to 82%) and the enantiomeric excess (up to >99%), of (S)‐proline catalyzed direct aldol reactions of a wide range of aldehydes with acetone was found when hexasubstituted or pentasubstituted guanidinium salts were added as ionic liquids. Effects of temperature, amount of proline and the type of guandidinium salts on the outcome of the reaction were investigated.     

双功能磺酰胺的合成及不对称催化羟醛缩合反应研究

合成了一系列单磺酰化手性二胺,并用于催化丙酮与对硝基苯甲醛的不对称羟醛缩合反应。研究了手性二胺以及磺酰基结构对反应的影响,也研究了添加剂对反应的影响。对催化剂进行筛选,发现对硝基苯磺酰基取代的(1 S,2 S)-1,2-二苯基乙二胺为最佳催化剂,采用苯甲酸作为添加剂,反应可取得中等收率与对映选择性。     

Advances in Immobilized Organocatalysts for the Heterogeneous Asymmetric Direct Aldol Reactions

The aim of this article is to collect the results published from the beginning (2000) on asymmetric direct aldol reactions taking place in the presence of immobilized chiral organocatalysts. The seven groups of organocatalysts discussed are: asymmetric direct aldol reactions catalyzed by: (1) covalently bonded immobilized hydroxyproline organocatalysts; (2) covalently bonded immobilized prolinamide organocatalysts; (3) covalently bonded immobilized peptide organocatalysts; (4) other covalently bonded immobilized chiral organocatalysts; (5) chiral organocatalysts bonded by ionic groups; (6) chiral organocatalysts with adsorptive bonding; and (7) other types of immobilized chiral organocatalysts. The main objective of this article based on results obtained by using about 360 immobilized organocatalysts, to bring to the focus of catalyst systems in which the aldol reactions yield beta-hydroxyketones of maximal optical purity, while keeping catalyst concentrations and reaction times as low and as short as possible. Trends recognized in data obtained in this field of investigation may mark out further tasks for the purpose of practical application.     

Direct Asymmetric Aldol Reactions in Water Catalysed by a Highly Active C2‐Symmetrical Bisprolinamide Organocatalyst

A novel C₂‐symmetrical bisprolinamide organocatalyst was synthesised and used to facilitate asymmetric direct aldol reactions in a water emulsion. Reactions were performed at room temperature with very low catalyst loadings (1–2.5 mol%) without the required use of additives, co‐catalysts or extended reaction times (24 h). This catalyst system was then used with a variety of aldehyde substrates showing good reaction generality for benzaldehydes with cyclohexanone (dr range 77/23 to >99/1, anti/syn; ee range 33% to >99%) and moderate scope with cyclopentanone (dr range 45/55 to 76/24, anti/syn; ee range 14% to 68%). Ultra‐low catalysts loadings (0.1 and 0.05 mol%) were also investigated demonstrating catalyst turnover numbers in the order of 1000.     

Direct Catalytic Asymmetric Aldol Reactions Assisted by Zinc Complex in the Presence of Water

A combination of zinc triflate and chiral C₂‐symmetrical prolinamide ligand leads to high enantioselectivities in direct aldol reactions essentially assisted by water. The presence of 5 mol % of the catalyst affords an asymmetric intermolecular aldol reaction between unmodified ketones and aldehydes to give anti‐products with excellent enantioselectivities ranging from 86–98 % ee. The same bis(prolinamide) ligand is found to catalyze the direct aldol reactions in the presence of water (or in water) with excellent stereocontrol and furnish the corresponding aldols in up to 99 % ee. For the demonstrated catalytic systems organic solvent‐free conditions are applied.     

Asymmetric Mukaiyama‐Aldol Reaction in Aqueous Media Promoted by Zinc‐Based Chiral Lewis Acids

Asymmetric aldol reactions in aqueous media have been realized by using zinc‐based chiral Lewis acids. The aldol products have been obtained with high yield, diastereocontrol and a good level of enantioselectivity. The reactivity of both acetophenone and propiophenone enol ether surrogates was tested with a range of aldehydes.     

酸性离子液体催化aldol反应研究

以甲酰胺和氯丙酮等为原料合成了离子液体4-甲基-3-丁基噻唑硫酸氢盐。以aldol反应为探针,探究了离子液体催化苯甲醛与丙酮的缩合反应,并对催化剂用量、醛酮比、反应时间和催化剂重复利用等进行了考察。优化工艺条件为:n(苯甲醛)∶n(丙酮)=1.0∶1.8,催化剂用量3%(n/n),反应时间1.5 h,苄叉丙酮的收率达81.2%,催化剂重复使用5次仍可保持较高催化效果。     

Aqueous Asymmetric Mukaiyama Aldol Reaction Catalyzed by Chiral Gallium Lewis Acid with Trost‐Type Semi‐Crown Ligands

The combination of Ga(OTf)₃ with chiral semi‐crown ligands ( 1a – e ) generates highly effective chiral gallium Lewis acid catalysts for aqueous asymmetric aldol reactions of aromatic silyl enol ethers with aldehydes. A ligand‐acceleration effect was observed. Water is essential for obtaining high diastereoselectivity and enantioselectivity. The p‐phenyl substituent in aromatic silyl enol ether ( 2 h ) plays an important role and increases the enantioselectivity up to 95% ee. Although aliphatic silyl enol ethers provided low enantioselectivities and silylketene acetal is easily hydrolyzed in aqueous alcohol, the aldol reactions of silylketene thioacetal ( 12 ) with aldehydes in the presence of gallium‐Lewis acid catalysts give the β‐hydroxy thioester with reasonable yields and high diastereo‐ (up to 99 : 1) and enantioselectivities (up to 96% ee).     

Cinchona Alkaloid‐Catalyzed Enantioselective Direct Aldol Reaction of N‐Boc‐Oxindoles with Polymeric Ethyl Glyoxylate

The first enantioselective direct aldol addition of N‐Boc‐oxindoles to polymeric ethyl glyoxylate is presented. The reaction is performed by using as low as 0.1 mol% (DHQ)₂PHAL and gives access to α‐hydroxycarboxylate derivatives bearing adjacent secondary alcohol and quaternary stereocenters with high levels of diastereo‐ and enantiocontrol. The use of ethyl glyoxylate in its polymeric form represents an important advantage for synthetic applications and allows us to directly install a C₂ unit ready to be converted in useful building blocks. A further one‐pot protection/deprotection sequence catalyzed by Zn(ClO₄)₂⋅6 H₂O preserved the α‐hydroxycarboxylates from racemization by means of a parasitic alcohol‐catalyzed retroaldol reaction.     

Asymmetric Aldol Reaction Using Immobilized Proline on Mesoporous Support

The aldol reaction of hydroxyacetone with different aldehydes using immobilized proline on a mesoporous support, assisted by heat and microwaves, has been explored. It was found that heterogenized L ‐proline on MCM‐41 catalyzed aldol reactions in both hydrophilic and hydrophobic solvents, and provided stereoselectivities in some cases complementary to the homogeneous catalyst. The heterogeneous catalysts could be reused without significant lost of stereoselectivity.     

Highly Efficient Threonine‐Derived Organocatalysts for Direct Asymmetric Aldol Reactions in Water

The introduction of siloxy groups at the hydroxy function of natural threonine resulted in efficient hydrophobic organocatalysts, which could efficiently catalyze the direct aldol reactions of both cyclic and acyclic ketones with aromatic aldehydes in water with excellent enantiomeric excess.     

Catalytic Asymmetric Chlorinative Dearomatization Reaction of Benzofurans

A catalytic asymmetric chlorinative dearomatization reaction of benzofuran derivatives was achieved by using hydroquinidine 1,4‐phthalazinediyl diether [(DHQD)₂PHAL] as the catalyst and N‐chlorophthalimide (NCP) as the chlorinating reagent. A series of chlorinated spiro[benzofuran‐2,5′‐oxazole]s bearing two contiguous stereogenic centers was obtained in high yields (up to 99%) with excellent enantioselectivity (up to 99% ee).

     

Efficient Heterogeneous Asymmetric Catalysis of the Mukaiyama Aldol Reaction by Silica‐ and Ionic Liquid‐Supported Lewis Acid Copper(II) Complexes of Bis(oxazolines)

Lewis acid complexes based on copper(II) and an imidazolium‐tagged bis(oxazoline) have been used to catalyse the asymmetric Mukaiyama aldol reaction between methyl pyruvate and 1‐methoxy‐1‐trimethylsilyloxypropene under homogeneous and heterogeneous conditions. Although the ees obtained in ionic liquid were similar to those found in dichloromethane, there was a significant rate enhancement in the ionic liquid with reactions typically reaching completion within 2 min compared with only 55 % conversion after 60 min in dichloromethane. However, this rate enhancement was offset by lower chemoselectivity in ionic liquids due to the formation of 3‐hydroxy‐1,3‐diphenylbutan‐1‐one as a by‐product. Supporting the catalyst on silica or an imidazolium‐modified silica using the ionic liquid or in an ionic liquid‐diethyl ether system completely suppressed the formation of this by‐product without reducing the enantioselectivity. Although the heterogeneous systems were characterised by a drop in catalytic activity the system could be recycled up to five times without any loss in conversion or ee.     

An Organocatalytic Domino Thia‐Michael/Aldol Condensation Reaction: Highly Enantioselective Synthesis of Functionalized Dihydrothiophenes

An organocatalytic domino thia‐Michael/aldol condensation reaction of α, β‐unsaturated aldehydes with 1, 4‐dithiane‐2,5‐diol catalyzed by chiral diphenylprolinol TMS ether has been developed, which provides a new practical and direct route to chiral dihydrothiophenes with high yields (up to 90%) and excellent enantioselectivities (up to>99% ee). The catalytic mechanism of the domino reaction was further confirmed through the APCI‐MS detection of proposed reaction intermediates.     

Asymmetric Aldol Reaction of 3‐Acetyl‐2H‐chromen‐2‐ones and Isatins Catalyzed by a Bifunctional Quinidine Urea Catalyst

The asymmetric aldol reaction of 3‐acetyl‐2H‐chromen‐2‐ones and isatins has been realized by using a bifunctional quinidine‐derived urea as the catalyst. The corresponding 3‐hydroxyoxindole derivatives containing a 2H‐chromen‐2‐one moiety were obtained in good yields and high enantioselectivities. When (Z)‐ethyl 2‐benzylideneacetoacetate was used as the substrate, a mixture of two diastereomers (both Z and E) was obtained due to isomerization of the double bond under the reaction conditions.

     

氧化钙在催化Aldol反应中的应用

以市售氧化钙为催化剂催化苯乙酮和苯甲醛的aldol反应,对反应条件进行了优化.结果表明:在氧化钙用量为20％,反应温度为60℃条件下,苯乙酮与苯甲醛之间aldol反应的产率可达到80.8％;苯甲醛上取代基类型对反应的产率有较显著影响,强吸电子基导致反应速度过快,副产物多;较弱的吸电子基有助于提高产率;羟基对该反应有抑制...     

水介质中糖基胺-酸对直接Aldol反应的协同催化研究

以Brnsted酸为催化剂,糖基对甲苯磺酰肼为助催化剂(胺),研究了芳香醛与酮在水介质中的直接Aldol反应。以对硝基苯甲醛和环己酮合成2-[羟基-(4-硝基苯基)]甲基环己酮为模型反应,考察了不同的酸、不同的糖基对甲苯磺酰肼、酸的用量、糖基对甲苯磺酰肼的用量、底物用量比r对模型反应的影响。在最佳反应条件(40 mol%乙酸为催化剂,30mol%葡萄糖基对甲苯磺酰肼为助催化剂(胺),水为溶剂,r=1∶5,于室温反应12 h)下,2-[羟基-(4-硝基苯基)]甲基环己酮的产率为93%。对反应底物进行扩展,结果表明,具有表面活性剂性质的葡萄糖基对甲苯磺酰肼与乙酸配合,能在水介质中有效地催化芳醛与环状酮的直接Aldol反应。     

L‐Prolinethioamides – Efficient Organocatalysts for the Direct Asymmetric Aldol Reaction

A series of novel L ‐proline derived thioamides has been synthesised. They have been evaluated as organocatalysts in the direct asymmetric aldol reaction for the first time. Thioamides exhibit catalytic ability higher than proline itself and the model aldol reaction of 4‐cyanobenzaldehyde with acetone proceeds well in the presence of 5 mol % of catalyst (ee up to 100%). Other aromatic aldehydes gave aldol products with high ees and moderate yields. Small changes in the catalyst's structure [e.g., N‐Bn versus N‐CH(CH₃)Ph] as well as the addition of an acid have a profound effect on their activity. The unexpected formation of the catalyst‐derived cyclic adducts was observed and their reactivity was established giving valuable insight into the course of the reaction.