Asymmetric acyloin condensation catalyzed by phenylpyruvate decarboxylase

Cells obtained from growth of Achromobacter eurydice, Pseudomonas aromatica and Pseudomonas putida on -phenylalanine containing medium catalyzed the enzymatic acyloin condensation of phenylpyruvic acid 1 and acetaldehyde 2 by phenylpyruvate decarboxylase to produce 3-hydroxy-1-phenyl-2-butanone 3. The acyloin condensation by Achromobacter eurydice and P. aromatica was stereoselective, providing the 3R enantiomer 3a with enantiomeric excess (ee) of 95% and 84%, respectively. A partially purified enzyme was prepared from the cell free extract of Achromobacter eurydice. The acyloin product 3a was obtained in 45% yield with an ee of 91% by using this partially purified preparation of phenylpyruvate decarboxylase.     

One-Pot Lipase-Catalyzed Aldol Reaction Combination of In Situ Formed Acetaldehyde

A facile tandem route to α,β-unsaturated aldehydes was developed by combining the two catalytic activities of the same enzyme in a one-pot strategy for the aldol reaction and in situ generation of acetaldehyde. Lipase from Mucor miehei was found to have conventional and promiscuous catalytic activities for the hydrolysis of vinyl acetate and aldol condensation with in situ formed acetaldehyde. The first reaction continuously provided material for the second reaction, which effectively reduced the volatilization loss, oxidation, and polymerization of acetaldehyde, as well as avoided a negative effect on the enzyme of excessive amounts of acetaldehyde. After optimizing the process, several substrates participated in the reaction and provided the target products in moderate to high yields using this single lipase-catalyzed one-pot biotransformation.

Concise and efficient synthesis of E-stereoisomers of exo-cyclic carbohydrate enones. Aldol condensation of dihydrolevoglucosenone with five-membered aromatic aldehydes Part 1

Stereoselective synthesis of exocyclic enones 10–17 via a base-catalyzed direct aldol condensation between dihydrolevoglucosenone 1 and heterocyclic aldehydes 2–9 is described. The reaction is performed under mild conditions and is applicable to variety of heterocyclic aldehydes. E-Steroisomers of exo-cyclic enones are the only products. They are very easy to isolate and were formed in good to excellent (72–88%) yield. ¹H NMR, ¹³C NMR analyses provide the structural assignment and absolute stereochemistry of the condensation products. Single-crystal X-ray diffraction of condensation product 12, additionally supports the structural assignment.     

Aldol Reactions of the trans-o-Hydroxybenzylidenepyruvate Hydratase-Aldolase (tHBP-HA) from Pseudomonas fluorescens N3

In this paper, a recombinant trans-o-hydroxybenzylidenepyruvate hydratase-aldolase (tHBP-HA) of Pseudomonas fluorescens N3 was used as a new catalyst for aldol condensation reactions. The reaction of some aldehydes with a different electronic activation catalyzed by tHBP-HA is presented and discussed together with some hints on the product structure. The enzyme is strictly pyruvate-dependent but uses different aldehydes as acceptors. The structure of the products is highly dependent on the electronic characteristics of the aldehyde. The results are interesting for both their synthetic importance and the mechanism of the formation of the products. Not only the products obtained and the recognition power are reported, but also some characteristics of its mechanism are analyzed. The results clearly show that the enzyme is efficiently prepared, purified, and stored, that it recognizes many different substrates, and that the products depend on the substrate electronic nature.     

Enantioselective alkynylation of aldehydes with chiral β-imino α-perfluoroalkylpropanol derivatives

Chiral β-imino α-perfluoroalkylpropanol derivatives 1 were prepared by condensation of (2S,3S)-2-amino-3-perfluorooctyl-1-phenylpropan-3-ol 2 and aldehydes. Among them, (2S,3S)-1d prepared from 2 and salicylaldehyde catalyzed the asymmetric alkynylation of aldehydes using alkynylzincs to afford the product in up to 81% ee.     

Asymmetric routes towards polyfunctionalized pyrrolidines: application to the synthesis of alkaloid analogues

The Mukaiyama aldol type condensation of t-butyldimethylsilyloxypyrrole 1b with methyl 2-formylbenzoate furnished the aldol adduct 9 with high yield and complete stereoselectivity. An erythro (anti) configuration was established (X-ray) in sharp contrast with the reaction of 1b with aliphatic aldehydes. Simple chemical transformations were used to transform 9 into original phthalidopyrrolidine compound analogous of bicuculline alkaloids.     

Stereoselective aldol condensations of organotin reagents with aldehydes

The reaction of the enolstannanes of cyclohexanone or propiophenone with various aldehydes under kinetic control (-78°) gave predominately the three aldols, diastereoselectivity as high as 95:5 being achieved. At higher temperatures (+45°) predominate erythro selectivity was observed. The enolstannane of propiophenone exists as an equilibrium mixture of O-Sn (probably the E-isomer) and C-Sn derivatives. Reaction at -78° takes place rapidly with the O-Sn enolate, further reaction requiring isomerization of the C-Sn to the O-Sn enolate. The Pd catalyzed condensation of cyanomethyltributyltin with reactive aldehydes, such as nitrobenzaldehydes, took place at ambient temperatures in polar solvents to give high yields of condensation products. No reaction occurred with aldehydes such as benzaldehyde. Only low stereoselectivity (10-34% ee) was observed when (-) DIOP or (-)BPPM were utilized as chiral phosphine ligands.     

The Knoevenagel reaction: analysis and recycling of the ionic liquid medium

A study involving the scope of substrate in the Knoevenagel reaction in an IL medium has been conducted. Reactivity trends favor formation of the condensation product using electron deficient aryl aldehydes. Use of electron rich aldehydes and ketones lead to lower levels of conversion and no measurable amounts of condensation products, respectively. A recycling study confirmed that the reaction medium could be used multiple times affording, with each run, the desired condensation product 1a in excess of 90% conversion. Post-run analyses of the IL documented that the IL medium was unaltered upon reuse.     

Direct asymmetric aldol reactions in brine with recyclable fluorous β-aminosulfonamide organocatalysts

Fluorous organocatalyst 3 promotes direct asymmetric aldol reactions of ketones with aldehydes in brine, leading to the synthesis of the corresponding anti-aldol products in high yields with up to 96% ee. Fluorous organocatalyst 3 is easily recovered by solid-phase extraction using fluorous silica gel and can be reused up to five times without purification.     

Unexpected formation of a chiral δ-lactone by reduction of the 1,3-dicarbonylic cyclopentanoid derivatives

We have described the synthesis of highly functionalized chiral cyclopentanoids, which are important building units for synthesis of biological active compounds. The (−)- or (+)-7,7-dimethoxy-1,4,5,6-tetrachlorobicyclo[2.2.1]hept-5-en-2-endo-yl acetate, obtained from the enzyme catalyzed transesterification of the racemate, was converted to α-diketone chiral. The α-diketone was treated with H₂O₂/NaOH and esterified with CH₂N₂ to furnish a mixture of the compounds (+)- or (−)-10 and (+)- or (−)-11. The reduction of the (+)- or (−)-10 and/or (+)- or (−)-11 with BH₃·THF furnished the lactone (+)- or (−)-13 with excellent yield. The α-diketone was reduced with indium metal in the presence of NH₄Cl furnishing the acyloin (+)-14 in 67% of yield. The treatment of acyloin (+)-14 with Pb(OAc)₄ furnished the aldehyde (+)-15 with 80% of yield. The reduction of the aldehyde (+)-15 with NaBH₄ has again produced the lactone (+)-13.     

Carboligation reactivity of benzaldehyde lyase (BAL,EC 4.1.2.38) covalently attached to magnetic nanoparticles

Epoxy-functionalized Fe₃O₄–SiO₂ core–shell magnetic nanoparticles (epoxy-M-support) were prepared by modification with glycidyloxypropyltrimethoxysilane (GPTMS) and characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), and fourier transform infrared spectroscopy (FTIR) methods. Pure histidine-tagged recombinant benzaldehydelyase (BAL, EC 4.1.2.38) was efficiently immobilized onto the epoxy-M-support with covalent binding. An immobilized BAL epoxy-M-support system was tested to catalyze the self and cross condensation reactions of aldehydes, and the kinetic resolution of racemic acyloins. The acyloin products were obtained in high yield and with high enantiomeric excesses (?98% ee). The carboligation reactivity of the immobilized enzyme was comparable to that of free enzyme-catalyzed reactions. The covalent immobilization offers high enzyme activity and stability (at least 5 repeats without losing its activity).     

Diastereoselective trimolecular condensation between indole,Meldrum’s acid and chiral sugar-derived aldehydes

The trimolecular condensation of indole, Meldrum’s acid and chiral, sugar-derived aldehydes took place in good yield and high diastereoselectivity. The absolute configuration of the α-carbon of the chiral aldehydes ensured a predictable diastereocontrol of the newly created stereogenic centre except for (3aR,5S,6S,6aR)-6-benzyloxy-2,2-dimethyl-tetrahydrofuro[3,2-d][1,3]dioxole-5-carbaldehyde 3i. In this case, the opposite stereochemistry may be explained by a less congested conformer of the Knoevenagel-adduct intermediate.     

Novel condensations of nitroacetic esters with aromatic aldehydes leading to 5-hydroxy-1,2-oxazin-6-ones

Contrary to the early literature [Dornow, A.; Wiehler, G. Justus Liebigs Ann. Chem. 1952, 578, 113–121], esters of 2,4-dinitro-3-arylglutaric acids 2 could not be obtained by double condensation of aryl aldehydes with alkyl nitroacetates. Instead, under these conditions, we observed formation of novel 4-aryl-5-hydroxy-1,2-oxazin-6-one-3-carboxylates 1. The roles of the solvent, the reaction conditions, and the nature of the reagents in this new condensation were investigated. The data obtained suggest that the heterocyclic products 1 originate from intramolecular oxidation (similar to the Nef reaction) of dinitro derivative 2, followed by nucleophilic attack of the oxime oxygen at the carboxylate group. The condensation presented provides a novel general synthetic route to these types of heterocycle.     

Synthesis and biological activity of some fluorinated arylhydrazotriazoles

Potential biologically active derivatives of arylhydrazotriazole (3a–l) were prepared by the condensation reaction of diazonium salts using various aromatic amines (1a–l) and 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl) ethanones (2). The synthesized products were obtained in 75–85% yield. All the synthesized products were having good-excellent antifungal activity as compared with standard (Fluconazole and Ketoconazole) drugs.     

Switching regioselectivity in crossed acyloin condensations between aromatic aldehydes and acetaldehyde by altering N-heterocyclic carbene catalysts

An unprecedented high level of regioselectivities (up to 96%) in the intermolecular crossed acyloin condensations of various aromatic aldehydes with acetaldehyde was realized by an appropriate choice of N-heterocyclic carbene catalysts.     

Syntheses of new thiazolium salt polymers and their catalytic activities

Thiazolium salt polymers were synthesized for the purpose of obtaining a more efficient catalyst for the acyloin condensation. A new thiazolium salt, N-methyl-4-vinylphenylthiazolium iodide was synthesized. However, this compound did not homopolymerize by radical initiator. Therefore, 4-vinylphenylthiazole was polymerized and the obtained polythiazole was quarternized by methyl iodide. Poly(N-methyl-4-vinylphenylthiazolium iodide) was examined as a polymer-catalyst for the acyloin condensation of several aldehydes. This polythiazolium salt had an excellent catalytic activity in organic solvents, even in nonpolar solvents. Moreover, it was observed that the catalytic activity increases with the decrease of quarternization.     

Two efficient methods for the synthesis of novel indole-based chalcone derivatives

Two powerful methods for the synthesis of indole-based chalcone derivatives, namely (E)-1-(2-chloro-1-(4-chlorobenzyl)-1H-indol-3-yl)-3-aryl(hetaryl)prop-2-en-1-ones (3a–l), are described, involving the ultrasound-assisted or solvent-free Claisen–Schmidt condensation reaction of 3-acetyl-2-chloro-1-(4-chlorobenzyl)indole (1) and various aromatic aldehydes (2a–l). The ultrasound-assisted Claisen–Schmidt condensation reaction was carried out using 1,4-dioxane as solvent and KOH as base at room temperature to give the corresponding products (3a–l) in yields ranging from 75 to 88 %. Alternatively, the Claisen–Schmidt condensation reaction could also be conducted under solvent-free conditions to obtain the products (3a–l) in comparable yields. The two procedures offer easy access to indole-based chalcone derivatives in short reaction times and good yields under mild conditions. Particularly, the advantageous aspect of the solvent-free method could avoid the use of environmentally hazardous and toxic solvents, and also reduced costs. The structures of all the newly synthesized indole-based chalcones 3a–l were confirmed by spectral data and elemental analyses.     

Umpolung catalysis: assessment of catalyst and substrate reactivities in acyloin type reactions

The umpolung of aldehydes and acylsilanes in acyloin type reactions is computationally studied by a sequence of model reactions (CPCM-THF B3LYP/6-31G(d)//B3LYP/6-31G(d)) with three different types of catalysts. Cyanide, a nucleophilic carbene and a phosphite form adducts, transition structures for [1,2]-H-shifts or [1,2]-SiMe₃-Brook rearrangements and generate the umpoled d¹-species. Aliphatic and aromatic aldehydes and acylsilanes (i.e., acetaldehyde, benzaldehyde, acylsilane, and benzoylsilane) show that π-conjugation slightly favors the umpolung. For aldehydes, the nucleophilic carbene, N-methylthiazol-2-ylidene, is by far the most reactive catalyst, while cyanide is slightly superior to the glycole based phosphite. For all catalysts, a dramatic decrease of activation barriers is apparent with the acylsilanes due to [1,2]-SiMe₃-Brook rearrangements, thermodynamically formations of d¹-species with strong Si-O bonds become highly favored.     

A lipase catalyzed condensation reaction with a tricyclic diketone: yet another example of biocatalytic promiscuity

Novozym 435 (a commercially available immobilized form of Candida antarctica lipase B) was found to catalyze a condensation reaction of 5-hydroxy-endo-tricyclo[5.2.1.0^2,6]deca-4,8-dien-3-one with acetaldehyde (enzymatically produced from vinyl acetate in situ) under low water conditions, in presence of 10% organic co-solvent (N,N-dimethyl formamide or pyridine), to form a bis-adduct. Even though the condensation reaction occurred with pyridine (acting as a base catalyst) in the presence of acetaldehyde and in the absence of enzyme, the reaction was very slow as compared to the enzymatic process. Thus, while the non-enzymatic process took 4 days to achieve 100% conversion; in presence of enzyme it was possible within 4 h.     

Purification and Characterization of the Glucoside 3-Dehydrogenase Produced by a Newly Isolated Sphingobacterium faecium ZJF-D6 CCTCC M 2013251

A soluble glucoside 3-dehydrogenase (G3DH) was purified from a newly isolated Sphingobacterium faecium ZJF-D6 CCTCC M 2013251. The enzyme was purified to 35.71-fold with a yield of 41.91 % and was estimated by sodium dodecyl sulphate–polyacrylamide gel electrophoresis with a molecular mass of 62 kDa. The sequences of two peptides of the enzyme were all contained in a GMC family oxidoreductase (EFK55866) by mass spectrometry analysis. The optimal pH of the enzyme was around 6.2. The enzyme was stable within a pH range of 5.0–6.6 and was sensitive to heat. G3DH from S. faecium exhibited extremely broad substrate specificity and well regioselectivity to validoxylamine A. The enzyme was completely inhibited by Hg₂Cl₂ and partly inhibited by Cu²⁺, Fe²⁺, Ca²⁺, and Cd²⁺. The apparent K _m values for D-glucose, sucrose, and validoxylamine were calculated to be 1.1, 1.7, and 2.1 mM, respectively. With this purified enzyme, 3-keto sucrose was prepared at pH 5.0, 30 °C for 10 h with a yield of 28.7 %.