Enantioselective direct aldol reaction: the blossoming of modern organocatalysis

The use of simple (S)-proline as catalyst for the intermolecular direct aldol reaction at the beginning of this century became a true milestone in the growth of organocatalysis as a useful synthetic strategy. Since then, a plethora of new organocatalytic systems have been developed allowing to reach extraordinary levels of efficiencies, widening the scope of substrates used. Several modifications have been introduced to overcome some of the initial drawbacks, such as long reaction times, high catalyst loading, excess of reagents, etc., improving the expectations for their use in large scale synthesis. All these achievements would not be possible without a partial understanding of the involved mechanism. The acquired knowledge in this area has allowed the application of this strategy to be used in the synthesis of natural products. Within this review, a comprehensive look of all these aspects will be discussed.     

Ionic liquid/water as a recyclable medium for Tsuji-Trost reaction assisted by microwave

An efficient microwave protocol is described for allylic substitution with various carbon and heteronucleophiles catalyzed by Pd(OAc)₂/TPPTS in an [EMIm]BF₄/H₂O medium. The ionic liquid/water containing catalyst system can be recycled eight times without loss of activity.     

A recyclable non-immobilized siloxy serine organocatalyst for the asymmetric direct aldol reaction

A recyclable siloxy-l-serine organocatalyst has been developed to catalyze asymmetric direct aldol reactions in [bmim][BF₄], furnishing the β-hydroxy carbonyl scaffold in high enantio- and diastereoselectivities using a selection of aromatic aldehydes and cycloalkanes. The siloxy serine organocatalyst in the ionic liquid can be reused for up to four successive cycles with comparable enantioselectivities.     

Hammett correlation of nornicotine analogues in the aqueous aldol reaction: implications for green organocatalysis

[reaction: see text] A series of meta- and para-substituted 2-arylpyrrolidines were synthesized and examined for their ability to catalyze an aqueous aldol reaction under buffered conditions. Kinetic analysis of arylpyrrolidine-catalyzed reactions displayed a linear Hammett correlation with rho = 1.14 (R(2) = 0.996), indicating that the reaction is accelerated by electron-withdrawing aryl rings. These results show promise for the development of a synthetically viable aqueous organo-catalyst.     

Fluorogenic aldehydes bearing arylethynyl groups: turn-on aldol reaction sensors for evaluation of organocatalysis in DMSO

Fluorogenic aromatic aldehydes bearing arylethynyl groups were developed. They were used for monitoring the reaction progress of organocatalytic aldol reactions in DMSO through an increase in the fluorescence intensity based on the formation of the florescent aldol product. The ratios of the fluorescence intensities of the aldols to the aldehydes were more than 300. These results suggest that the fluorescence assay system using the aldehyde is useful for the rapid identification of superior aldol catalysts and reaction conditions.     

Ionic liquid-supported proline as catalyst in direct asymmetric aldol reaction

Ionic-liquid-supported proline derivative was synthesized starting from L-proline and was used to catalyze direct asymmetric aldol reaction of acetone with aldehydes. The yield and optical purity of the condensation products, the corresponding β-hydroxy carbonyl compounds were comparable with those obtained under homogeneous conditions. Moreover, the catalyst can be reused for at least four times. Published in Russian in Zhurnal Organicheskoi Khimii, 2008, Vol. 44, No. 12, pp. 1834–1837. The text was submitted by the authors in English.     

Polystyrene-supported hydroxyproline: an insoluble, recyclable organocatalyst for the asymmetric aldol reaction in water

4-Hhydroxyproline has been anchored to a polystyrene resin through click chemistry, and the resulting catalyst has been successfully applied to the direct aldol reaction in water. The high hydrophobicity of the resin and the presence of water are key to ensuring high stereoselectivity, whereas yield can be increased by using catalytic amounts of DiMePEG. This effect has been further demonstrated by the inefficiency of a homogeneous, more polar analogue.     

Enantioselective aldol reaction mediated by chiral lithium amide bases

Highly enantioselective aldol reaction mediated by chiral lithium amide bases was achieved between some methylketones and aldehydes     

Titanium mediated asymmetric aldol reaction with α-fluoropropionimide enolates

Aldol reaction utilising Evans N-(α-fluoropropyl)-2-oxazolidinones with TiCl₄ have been explored. Reactions of N-(α-fluoropropyl)-2-oxazolidinones with aliphatic aldehydes generated α-fluoro-β-hydroxy-aldol products with high diastereoselectivities. When (αR)- and (αS)-N-(α-fluoropropyl)-2-(4S)-oxazolidinones were explored as substrates they gave rise to identical aldol diastereoisomer products. Examination of the enolates formed in each case by ¹⁹F NMR, after treatment with TiCl₄, indicated that both preparations gave the same predominant enolate. This was assumed to be the E-enolate. The α-fluoro-β-hydroxy-aldol products were removed from the auxiliary either by alcoholysis or reduction and converted to the corresponding α,β-difluoro products by treatment with Deoxofluor™.     

A tandem enol silane formation-Mukaiyama aldol reaction mediated by TMSOTf

A slight excess of silyl trifluoromethanesulfonate mediates a tandem enol silane formation-Mukaiyama aldol reaction in the presence of Hunig’s base. Preformation of the enol silane is unnecessary for efficient reactions, which proceed in 75-97% yield for the addition of aryl methyl ketones and acetate esters to non-enolizable aldehydes. Mechanistic data suggests that free amine is crucial for full conversion.     

高效可循环离子型钯配合物催化羰化Sonogashira反应

炔酮类化合物作为一类具有生物活性的分子,是天然产物全合成中构建杂环类化合物的重要中间体.炔酮类化合物的传统合成方法是通过过渡金属催化金属有机炔烃和酰氯的交叉偶联,但存在酰氯本身稳定性和底物官能团耐受力较差的缺点.近年来,钯催化的羰化Sonogashira反应(末端炔烃和芳基卤化物与CO的偶联反应)成为合成炔酮类化合物更为直接和有效的方法,其中与钯中心原子配位的配体的电子效应和空间效应可显著调控钯配合物的催化性能.但均相钯催化的羰化Sonogashira反应体系存在催化剂流失、分离困难和难以循环使用的问题.我们以2-(1-咪唑基)噻唑为母体分子,合成了具有P,S,N杂合配体特征的配体L1,同时将配体L1通过与MeOTf的季铵化反应得到相应的离子型膦配体L2.在此基础上,利用L1和L2与过渡金属中心的配位作用合成相应的钯配合物1A和2A.由于L1和L2中含有多种不同配位能力的配体(P-配体,S-配体和/或N-配体),故通过N/S杂原子对Pd-中心原子的协同弱配位作用,可以调变相应钯配合物对羰化Sonogashira反应的催化性能.另外,2A中具有强吸电子效应的正电荷的存在,使其结构和催化性能也必然不同于中性配合物1A.实验结果表明,在温和的反应条件(90℃,lh,CO压强1.0 MPa)下,对于碘苯和苯乙炔的羰化Sonogashira偶联反应,1A体现出优于2A的催化性能,TOF值达到840 h-1;但反应温度提高到120℃时,1A的TOF高达3560 h-1,2A的TOF为2960 h-1.与L1的2JP-Se=744 Hz相比,L2的2JP-Se=768 Hz,说明L2中具有吸电子效应的正电荷的存在降低了相应P原子的σ给电子能力(2JP-Se数值越大,相应膦配体的6给电子能力越弱);同时,1A中具有弱配位能力的N配体的缺失削弱了配体对Pd活性中心的稳定作用.在底物普适性研究中发现,4-硝基溴苯在相同反应条件下几乎得不到羰化Sonogashira偶联产物.而将反应体系中的CO换为同样压强下的N2,却可以顺利实现Sonogashira偶联反应.我们推测,在CO氛围下形成的pd0-CO活性物种(与N2氛围下形成的Pd0活性物种相比)具有相对较低的对底物的氧化加成能力.离子型钯配合物2A的优势在于,当将其与室温离子液体[Bmim]PF6(溶剂)结合使用,在2A催化碘苯与苯乙炔的羰化Sonogashira偶联反应过程中,循环使用8次催化性能没有明显下降.     

Linear polystyrene anchored l-proline,new recyclable organocatalysts for the aldol reaction in the presence of water

Two l-proline-based linear polystyrene anchored catalysts 1a and 1b have been synthesized efficiently. The catalytic activities and stereoselectivity of these readily tunable and amphiphilic organocatalysts were evaluated in the direct asymmetric aldol reaction of various aromatic aldehydes and ketones. By using 5 mol % of the catalysts, the corresponding products of the aldol reaction were obtained in good yields (up to 94%) and with excellent anti diastereoselectivities (up to 96:4) and enantioselectivities (up to 96% ee) in DMF in the presence of water. The yields of these reactions in a ketone/water mixture were lower than those in wet DMF (up to 76%). However, the stereoselectivity was comparable (up to 93:7 anti/syn ratio and 95% ee, respectively). In addition, catalysts 1a and 1b could be recovered by a simple precipitation and filtration process. They could also be re-used for at least five times without obvious loss of catalytic efficiency.     

Ionic liquid mediated Cu-catalyzed cascade oxa-Michael-oxidation: efficient synthesis of flavones under mild reaction conditions

Flavonoids are a class of natural products, found in a wide range of vascular plants and dietary components. Their low toxicity and extensive biological activities, including anti-cancer and anti-bacterial, have made them attractive candidates to serve as therapeutic agents for many diseases. Herein, we disclose a highly efficient synthetic method of CuI-catalyzed cascade oxa-Michael-oxidation, using chalcones as substrates, mediated by the ionic liquid [bmim][NTf2] at a low temperature. This efficient synthetic method has demonstrated high synthetic utility and can afford flavones in good to high yields (up to 98%).     

Mimicking aldolases through organocatalysis: syn-selective aldol reactions with protected dihydroxyacetone

A practical organocatalytic strategy designed to mimic the l-rhamnulose 1-phosphate and D-fructose 1,6-diphosphate aldolases has been developed and shown to be effective in the preparation of carbohydrates and polyol derivatives. Threonine-based catalysts facilitated the aldol reaction of protected dihydroxyacetone or protected hydroxacetone with a variety of aldehydes to provide syn-aldol products with good yields and ee's up to 98%.     

Ionic liquid-phase organic synthesis (IoLiPOS) methodology applied to cross aldol reaction

Cross aldol reaction in task-specific ionic liquids was developed. Ionic liquid-phase bound aldehyde reacted with various ketones (acetone, cyclopentanone, and butan-2-one) with l-proline as catalyst to afford various ionic liquid-phase supported aldols in yields ranging from 81 to 99%. Detachment of the aldol in MeOH was realized by transesterification using 15% of MeONa. The structure of intermediates in each step was verified by spectroscopic analysis.     

Ionic liquid mediated four-component synthesis of novel phthalazinone based indole-pyran hybrids as cytotoxic agents

A robust design and synthesis of novel phthalazinone based indole-pyran hybrids as cytotoxic agents is described. A relatively safer ionic liquid medium ([BMIM]BF₄₎ was utilized to mediate a one-pot, four-component reaction to access the novel hybrids in short reaction time and good yields. The cytotoxic potential of the hybrids was investigated against selected cancer cell lines. The hybrids 5h and 5b displayed potent activity with IC₅₀ values in the range of 5.8–9.6 μM. The insilico docking demonstrated a pronounced affinity of hybrids 5h and 5b towards the human tankyrase-1 enzyme exhibiting binding energies values of ?11.2 and ?10.2 kcal/mole, respectively. Additional ADME and drug likeliness analyses revealed the potential of the active hybrids to be taken forward for advanced studies.     

Ionic liquid as a green catalytic reaction medium for esterifications

Esterifications of alcohols with carboxylic acids in the room temperature ionic liquid 1-butylpyridinium chloride–aluminium(III) chloride as green reaction medium in catalytic quantities have been investigated. Excellent conversion and selectivities were achieved, and the most of resultant esters could be easily recovered due to immiscibility with the ionic liquid.     

A tandem non-aldol aldol Mukaiyama aldol reaction

[reaction: see text] A new one-pot tandem aldol process is described in which a secondary epoxy silyl ether is converted into the 1,5-bis-silyloxy-3-alkanone in good yield. Thus, treatment of the epoxy silyl ether 8 with TBSOTf and base affords the silyl enol ether 9 via non-aldol aldol rearrangement and addition of benzaldehyde and TBSOTf gives the ketone 10 with 4:1 syn selectivity. The diastereoselectivity changes to an anti preference for most aldehydes. This anti selectivity overwhelms the normal Felkin-Ahn preference; namely, the 1,5-anti isomer predominates even when it is anti-Felkin-Ahn.     

Ionic liquid: An efficient and recyclable medium for the synthesis of fused six-membered oxygen heterocycles

The investigation for replacement of organic solvents in chemical synthesis is a growing area of interest due to increasing environmental issues. The use of ionic liquid salts as solvents and catalysts in organic reactions has gained extensive interest. Ionic liquids provided a new environmentally benign and improved alternative to traditional methods in modern synthetic chemistry. The aim of present review is to focus on the applications of ionic liquids for the synthesis of fused six-membered oxygen heterocycles.     

Ionic nucleophilic catalysis of chiral ammonium betaines for highly stereoselective aldol reaction from oxindole-derived vinylic carbonates

A new strategy for developing stereoselective bond-forming reactions is introduced; it takes advantage of the ionic nucleophilic catalysis of chiral ammonium betaines to utilize vinylic esters simultaneously as the enolate precursor and the acylating agent for coupling with electrophiles. Its synthetic utility is clearly demonstrated by the realization of a highly diastereo- and enantioselective aldol reaction from oxindole-derived vinylic carbonates.