Base-catalyzed Aldol Reaction Research Articles

A fast and efficient method for the analysis of α-dicarbonyl compounds in aqueous solutions: Development and application

Among the highly oxygenated species formed in situ in the atmosphere, α-dicarbonyl compounds are the most reactive species, thus contributing to the formation of secondary organic aerosols that affect both air quality and climate. They are ubiquitous in the atmosphere and are easily transferred to the atmospheric aqueous phase due to their high solubility. In addition, α-dicarbonyl compounds are toxic compounds found in food in biochemistry studies as they can be produced endogenously through various pathways and exogenously through the Maillard reaction. In this work, we take advantage of the high reactivity of α-dicarbonyl compounds in alkaline solutions (intramolecular Cannizzaro reaction) to develop an analytical method based on high performance ion chromatography. This fast and efficient method is suitable for glyoxal, methylglyoxal and phenylglyoxal which are detected as glycolate, lactate and mandelate anions respectively, with 100% conversion at pH > 12 and room temperature for exposure times to hydroxide ranging from 5 min to 4 h. Diacetyl is detected as 2,4-dihydroxy-2,4-dimethyl-5-oxohexanoate due to a base-catalysed aldol reaction that occurs before the Cannizzaro reaction. The analytical method is successfully applied to monitor glyoxal consumption during aqueous phase HO∙-oxidation, an atmospherically relevant reaction using concentrations that can be observed in fog and cloud water. The method also reveals potential analytical artifacts that can occur in the use of ion chromatography for α-hydroxy carboxylates measurements in complex matrices due to α-dicarbonyl conversion during the analysis time. An estimation of the artifact is given for each of the studied α-hydroxy carboxylates. Other polyfunctional and pH-sensitive compounds that are potentially present in environmental samples (such as nitrooxycarbonyls) can also be converted into α-hydroxy carboxylates and/or nitrite ions within the HPIC run. This shows the need for complementary analytical measurements when complex matrices are studied.

Chiral Lewis Base Catalyzed Aldol Reaction of Unprotected Carboxylic Acids

Chiral Lewis Base Catalyzed Aldol Reaction of Unprotected Carboxylic Acids

Diastereo- and enantioselective preparation of oxazolines via the base-catalysed aldol reaction of isocyanoacetates with aldehydes using cinchona alkaloids

A diastereo- and enantioselective base-catalysed aldol reaction of t-butyl isocyanoacetate with aldehydes under phase-transfer catalytic conditions yielded 19 4,5-disubstituted oxazolines, 16 of which are novel. Key to success was the use of a free 9-OH-containing cinchona alkaloid-based quaternary ammonium salt bearing bulky and electron-withdrawing aryl groups on the N-benzyl moiety. This process tolerates both aromatic and aliphatic aldehydes, affording the corresponding chiral oxazoline products in diastereoselectivities up to 20:1 and enantioselectivities up to 78% ee.

Design and synthesis of new inhibitors of p53–MDM2 interaction with a chalcone scaffold

The virtual screening of a library of chalcone derivatives led us to the identification of potential new MDM2 ligands. The chalcones with the best docking scores obeying the Lipinski rule of five were subsequently prepared by base-catalyzed aldol reactions. The activity of these compounds as inhibitors of p53–MDM2 interaction was investigated using a yeast-based screening assay. Using this approach two chalcones (3 and 4) were identified as putative small molecule inhibitors of p53–MDM2 interaction. The activity of both chalcones was further investigated in a panel of human tumor cells. Chalcones 3 and 4 revealed a pronounced tumor cell growth inhibitory effect on tumor cell lines. Additionally, chalcone 4 caused alterations in the cell cycle profile, induced apoptosis and increased the levels of p53, p21 and PUMA proteins in NCI-H460 cells. Computational docking studies allowed to predict that, like nutlin-3A (a well-known small-molecule inhibitor of p53–MDM2 interaction), chalcones 3 and 4 bind to the p53-binding site of MDM2. The results here presented will be valuable for the structure-based design of novel and potent p53–MDM2 inhibitors.

New polyhydroxylated flavon-3-ols and 3-hydroxy-2-styrylchromones: synthesis and ROS/RNS scavenging activities

New polyhydroxylated flavon-3-ols and 3-hydroxy-2-styrylchromones were prepared and assessed as reactive oxygen species (ROS) and reactive nitrogen species (RNS) scavengers. The synthetic strategy involved the preparation of 2′-hydroxychalcones and 2′-hydroxycinnamylidenoacetophenones from base-catalyzed aldol reaction of appropriate 2′-hydroxyacetophenones and benzaldehydes/cinnamaldehydes, followed by an Algar-Flynn-Oyamada (AFO) reaction to give the polyalkoxy(flavon-3-ols and 3-hydroxy-2-styrylchromones). The last step of this synthetic route consisted in the cleavage of the protecting groups affording the expected polyhydroxylated derivatives.The present work consisted in the study of the in vitro scavenging activities of the synthetized compounds against the most physiologically relevant ROS [superoxide radical (O2-), hydrogen peroxide (H2O2), hypochlorous acid (HOCl), singlet oxygen (1O2) and peroxyl radical (ROO)] and RNS [nitric oxide (NO) and peroxynitrite anion (ONOO−)]. Generally, all the tested new polyhydroxylated flavon-3-ols and 3-hydroxy-2-styrylchromones exhibited scavenging effects dependent on the concentration, and with IC50 values found within the micromolar range. This work allowed the establishment of new structure-activity relationships and brought the knowledge about the selective choice of a structure depending on the targeted reactive species.

1604079: Diastereo- and enantioselective preparation of oxazolines via the base-catalysed aldol reaction of isocyanoacetates with aldehydes using cinchona alkaloids - ESI

1604079: Diastereo- and enantioselective preparation of oxazolines via the base-catalysed aldol reaction of isocyanoacetates with aldehydes using cinchona alkaloids - ESI

Efficient Synthesis of Biologically Interesting Natural Pyranochalcones from Mallotus Philippensis and Their Unnatural Derivatives

This paper describes efficient synthetic approaches for isolating biologically interesting natural pyranochalcones and their unnatural derivatives from Mallotus Philippensis. The key strategies involve ethylenediamine diacetate-catalyzed benzopyran formation reactions and base-catalyzed aldol reactions.

ChemInform Abstract: Vasodilating and Antiarrhythmic Activity of Heteryl Lactones.

A new series of unsaturated γ- and δ-lactones with pyridyl, quinolyl and nitrophenyl substituents (9, 10) have been synthesized by the condensation of unsaturated methyl lactones with heteryl aldehyde or nitrobenzaldehyde in the base-catalysed aldol reaction. The antiarrhythmic, vasodilating and cardiotonic activities of the synthesized compounds have been studied in vivo and ex vivo. 3-Cyano-5,5-dimethyl-4-[4'-(4-pyridyl)-1',3'-butadienyl)]-2(5H)-furanone (9e) displayed a significant vasodilating activity. The antiarrhythmic activity of this compound was higher, but its toxicity lower than that of the procainamide reference drug. Five-membered lactones, particularly 3-cyano-4-(4-pyridylvinyl)-5,5-dimethyl-2(5H)-furanone (9c), exhibited a remarkable cardiotonic activity. The replacement of a pyridyl substituent by a nitrophenyl group in the pyranone derivative did not change the cardiovascular activity and toxicity.

Further Investigations on the Promoting Effect of Mesoporous Silica on Base-Catalyzed Aldol Reaction

Addition of an ordered mesoporous silica to a mixture of an aldol reaction, comprising 4-nitrobenzaldehyde with acetone catalyzed by organic amines, caused significant increase in the reaction rate to afford the β-hydroxyketone in high yield. A cooperative effect between the surface silanol and amine was considered to be the likely reason for the rate-enhancement, which was supported by FTIR spectroscopy.

Chiral Base-Catalyzed Reductive Aldol Reaction with Trichlorosilane

Chiral Base-Catalyzed Reductive Aldol Reaction with Trichlorosilane

Dimethoxyaurones: Potent inhibitors of ABCG2 (breast cancer resistance protein)

A series of 4,6-dimethoxyaurones were synthesized by reacting 4,6-dimethoxybenzofuran-3(2 H)-one with various benzaldehydes in a base-catalyzed aldol reaction. A Z configuration was assigned to the aurones based on spectroscopic and crystallographic data. The aurones were tested for their ability to modulate ABCG2 (breast cancer resistance protein)-mediated multidrug resistance in vitro. Several members (0.5 μM) increased the accumulation of mitoxantrone (MX) in human breast cancer cells (MDA-MB-231) transfected with ABCG2 and re-sensitized these cells to the cytotoxic effects of MX. In the re-sensitization assay, aurones at 0.5 μM reduced the resistance of the transfected cells to MX to just twice that of the parental cells, exceeding fumitremorgin C (FTC) tested at the same concentration. The aurones (10 μM) also increased calcein-AM accumulation in MDCKII/MDR1 cells that were transfected with ABCB1 (P-glycoprotein), at levels comparable to verapamil tested at the same concentration. Structure–activity analysis showed that substitution of the benzylidene ring B of the aurone template was less important for ABCG2 inhibition, with little variation in activity noted for compounds with an unsubstituted ring B or one that was substituted. In contrast, substitution of ring B gave rise to better inhibitors of ABCB1. A preference for the 3′ position of ring B was noted. There was also some indication from the data that aurones with good ABCG2 inhibitory activity were poor ABCB1 inhibitors and vice versa, but further confirmation would be required. Limited antiproliferative activity (>70% cell survival) was observed for many aurones on four different cell lines. Thus, functionalized 4,6-dimethoxyaurones are promising ABCG2 inhibitors that combine good activity at submicromolar concentrations with limited antiproliferative activity.

Concise Total Synthesis of Biologically Interesting Prenylated Chalcone Natural Products: 4'-O-Methylxanthohumol, Xanthohumol E, and Sericone

A new and efficient synthetic approach is reported for biologically interesting prenylated chalcones, 4'-Omethylxanthohumol (3), xanthohumol E (4), and sericone (5) from 2,4,6-trihydroxyacetophenone. The strategies involve the introduction of a prenyl group onto an aryl ring, benzopyran formation, and basecatalyzed aldol reactions.

Concise Total Synthesis of Biologically Interesting Mallotophilippens C and E

This paper describes a new and efficient synthetic approach for biologically interesting natural mallotophilippens C and E. The key strategies involved ethylenediamine diacetate-catalyzed benzopyran formation reactions and base-catalyzed aldol reactions.

Concise Total Synthesis of Biologically Interesting Pyranochalcone Natural Products: Citrunobin, Boesenbergin A, Boesenbergin B, Xanthohumol C, and Glabrachromene

New and efficient synthetic approaches to the biologically interesting natural products citrunobin, boesenbergins A and B, xanthohumol C, and glabrachromene are described. The key strategies involve ethylenediamine diacetate catalyzed benzopyran formation reactions and base-catalyzed aldol reactions.

Chiral base-catalyzed aldol reaction of trimethoxysilyl enol ethers: effect of water as an additive on stereoselectivities

An aldol reaction of trimethoxysilyl enol ether catalyzed by lithium binaphtholate is described. The aldol reaction of trimethoxysilyl enol ether derived from cyclohexanone under anhydrous conditions predominantly afforded the anti-aldol adduct with moderate enantioselectivity, whereas the reaction under aqueous conditions predominantly resulted in the syn-adduct and the enantioselectivity of the syn-adduct was considerably improved. The best enantioselectivity was obtained in the reaction of trimethoxysilyl enol ether derived from 1-indanone with cyclohexanecarboxaldehyde (97% ee ( syn)). This is the first example of an aldol reaction of trimethoxysilyl enol ether catalyzed by a chiral base.

Lithium Acetate-Catalyzed Aldol Reaction between Aldehyde and Trimethylsilyl Enolate in Anhydrous or Water-Containing N,N-Dimethylformamide

Abstract Lithium acetate (AcOLi)-catalyzed aldol reactions between trimethylsilyl enolates and aldehydes proceed smoothly in anhydrous DMF or pyridine to afford the corresponding aldols in good to high yields under weakly-basic conditions (Tables 1–5). This catalytic aldol reaction is performed smoothly also by using other metal carboxylates that are easily prepared in situ by treating carboxylic acids with lithium carbonate (Li2CO3) (Table 2, Scheme 5). In order to show the effect of mild and readily-available AcOLi catalyst, the aldol reaction in water-containing DMF was studied in detail. AcOLi and various metal carboxylates behaved as effective Lewis base catalysts in aldol reactions between trimethylsilyl enolate and aldehydes in DMF–H2O (50:1) (Tables 6, 7). One of the most characteristic points of the above reaction that took place in water-containing DMF is that the aldehydes having a free amide and a hydroxy or even a carboxyl group reacted smoothly and afforded the desired aldols 29–31 in moderate to high yields (Table 8, Entries 12–15). Trimethylsilyl enolates derived from carboxylic esters behaved similarly as excellent nucleophiles in the above reaction. This is the first example of Lewis base-catalyzed aldol reactions to afford the desired aldol adducts even when silyl enolates derived from carboxylic esters were used in a water-containing organic solvent.

Lewis Base Catalyzed Aldol Reaction of Trimethylsilyl Enolates with Aldehydes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Enhanced Effect of Mesoporous Silica on Base-Catalyzed Aldol Reaction

Abstract Aldol reaction of 4-nitrobenzaldehyde with acetone gives 4-(4-nitrophenyl)-4-hydroxy-2-butanone in high yield in the presence of both secondary amine and mesoporous silica, whereas the yield is low in the absence of the mesoporous silica.

Lewis Base Catalyzed Aldol Reaction of Trimethylsilyl Enolates with Aldehydes

AbstractA new Lewis base catalyzed aldol reaction of trimethylsilyl enolates with aldehydes is established in DMF or pyridine solvent by using a Lewis base such as lithium diphenylamide (Tables 4 and 5) or lithium 2‐pyrrolidone (Tables 6–8). The effect of solvent suggests that this reaction proceeds via the pentacoordinated hypervalent silicate generated by the coordination of the above Lewis base to a trimethylsilyl enolate. Successive coordination of the solvent to the thus‐formed pentacoordinated silicate leads to an active enolate intermediate having hexacoordinated silicate, which, in turn, attacks carbonyl compounds to form the desired aldols (Scheme 5).

Total Synthesis of the Pentacyclic Diterpenoid Tropone Hainanolidol

The total synthesis of the unusual diterpenoid tropone, hainanolidol (1), discovered in the bark of the yew species, Cephalotaxus hainanensis, has been completed in 26 steps from 3,5-dimethylanisole. The intramolecular cyclopropanation reaction of the aryl ring in (30) by means of the rhodium mandelate-catalysed reaction of the diazoacetyl function was used to assemble the 5/7 ring system of (31), at the same time elaborating a cycloheptatriene moiety that could be transformed subsequently to the tropone functionality in the target molecule. While removing the acetal protecting group from (31) an unexpected Mukaiyama–type aldol process was induced by ZnBr2, affording (32), the structure of which was determined by X-ray analysis. With greater care, the aldehyde (33) could be obtained and the desired carbocyclic ring system completed by means of a base-catalysed aldol reaction with the newly formed hydroxyl being employed subsequently in the formation of the σ-lactone function in (35). Desilylation, reduction of the C-10 carbonyl function and brief exposure to acid finally afforded (1). This last step took advantage of the stability of the tropylium ion (40) to provide a ‘thermodynamic sink’ for the reaction outcome. The synthesis of (1) also constitutes a formal synthesis of the troponoid ether, harringtonolide (2), since this compound had been obtained previously from (1) by means of a transannular oxidation process. Methodology for the assembly of the tropone moiety in (1) and (2) was modelled on the simpler bi- and tricyclic systems, (13) and (22), respectively.