György Szőllősi

Reversal of the enantioselectivity in aldol addition over immobilized di- and tripeptides: studies under continuous flow conditions

Heterogeneous asymmetric direct aldol reactions between aldehydes (2-nitrobenzaldehyde, 2-methylpropanal) and acetone catalyzed by polystyrene resin (PS) supported di- and tripeptides H-Pro-Pro-, H-Pro-Pro-Pro-, H-Pro-Glu(OH)-, H-Pro-Pro-Glu(OH)-, H-Pro-Asp(OH)-, H-Pro-Pro-Asp(OH)-, H-Ser-Glu(OH)-, H-Ser-Ser-Glu(OH)-, H-Val-Glu(OH)-, H-Val-Val-Glu(OH)-MBHA-PS, were studied under identical experimental conditions at room temperature in a continuous-flow fixed-bed reactor (CFBR) system. In the asymmetric aldol reactions reversal of enantioselectivity was observed on H-Pro-Pro-Glu(OH)- and H-Pro-Pro-Asp(OH)-MBHA-PS-supported catalysts (ee 42–67% S) as compared to the H-Pro-Glu(OH)- and H-Pro-Asp(OH)-MBHA-PS-supported catalyst (ee 28–82% R). In the case of H-Pro-Pro- and H-Pro-Pro-Pro-MBHA-PS-supported catalysts reversed enantioselectivity was observed by using the benzoic acid additive (12% S) as compared to the H-Pro-MBHA-PS catalyst (25% R). The stability of the catalysts in the flow system was consistent with the heterogeneous character of the reaction, as was the linear behavior obtained using mixtures of L- and D-enantiomers of the supported H-Pro-MBHA-PS catalyst. The enamine character of the reaction intermediates was supported by ESI-MS measurements. Based on these and the computed structure of the peptides, the conformation of the intermediate adducts is held responsible for chiral induction, therefore for the enantioselectivity inversion observed in these reactions.

Three consecutive steps over the chirally modified Pt surface: asymmetric catalytic cascade reaction of 2-nitrophenylpyruvates

The influence of the reaction conditions on the asymmetric heterogeneous cascade reaction of 2-nitrophenylpyruvates over Pt catalysts modified with cinchonidine leading to (R)-3-hydroxy-3,4-dihydroquinolin-2(1H)-one derivatives has been studied. Results of studies on the amount of acetic acid or catalyst, nature of the Pt support, kinetic examinations, effect of H2 pressure, and modifier and substrate concentrations showed that all three steps of this catalytic cascade take place on the Pt surface, with the nitro group reduction immediately following the enantioselective hydrogenation of the keto group, whereas the final intramolecular amidation was preceded by desorption after complete reduction of the substrate and re-adsorption of the corresponding intermediate.

Reversal of Enantioselectivity in Aldol Reaction: New Data on Proline/γ-Alumina Organic–Inorganic Hybrid Catalysts

We report new results on the aldol reactions between aldehydes of three different types (aromatic, aliphatic and cycloaliphatic) and acetone/cycloalkanones as reaction partners, driven by organic–inorganic hybrid catalyst Pro/γ-Al2O3. In contrast to the homogeneous liquid-phase reaction, over Pro/γ-Al2O3 reversal of the enantioselection in up to 20–40xa0% ee depending on the structure of the aldehyde was observed in reactions of acetone. Reversal of the ee in the presence of γ-Al2O3 cannot be generalized, as it has only been observed for acetone among the ketones studied by us. It was proven using methods of a great variety such as ultrasonic irradiation, reuse measurements on used catalyst and the filtrate of the first reaction, measurements on the l-Pro-l-Pro(OH) dipeptide, studies using mixtures of l-Pro and d-Pro that the organic–inorganic hybrid catalyst Pro/γ-Al2O3 formed in situ is responsible for reversal of the ee. In the reactions of cycloalkanones there is presumably competition between the liquid-phase and the surface reaction over Pro/γ-Al2O3 with preference for the former. Based on these results a surface reaction pathway was proposed. Although, the ees obtained under heterogeneous catalytic conditions are low, further studies may lead to application of this unusual phenomenon for obtaining chiral heterogeneous catalysts suitable for the preparation of the desired enantiomer of a chiral compound using the same chiral source.Graphical Abstract

Heterogeneous Enantioselective Hydrogenation of Hydroxy-substituted ( E)-2,3-diphenylpropenoic Acids over Pd/Al2O3 Modified by Cinchonidine

The enantioselective hydrogenation of (E)-2,3-diphenylpropenoic acids substituted by hydroxyl group has been studied over Pd/Al2O3 catalyst modified by cinchonidine. The effect of the acidic hydroxyl substituents was compared with that of the methoxy group in the same position. The para-hydroxyl substituent on the 3-phenyl ring had similar effect on the enantioselectivity as the methoxy group, whereas the meta positioned decreased the optical purity of the saturated acid. This was explained by different origin of the increase in the enantioselectivity obtained in the presence of electron releasing substituents in these positions. Although, the para-hydroxyl group on the 2-phenyl ring had beneficial influence on the enantioselectivity of the hydrogenation of the mono-substituted acid, in the presence of fluorine or hydroxyl group on the 3-phenyl ring the effect of the two substituents was not additive. This study demonstrated that the cinchonidine-modified Pd catalyst is appropriate for the preparation of several hydroxy-substituted 2,3-diphenylpropionic acids in good optical purities, extending the scope of this catalytic system to new types of versatile chiral building blocks.Graphical AbstractHeterogeneous Enantioselective Hydrogenation of Hydroxy-substituted (E)-2,3-diphenylpropenoic Acids over Pd/Al2O3 Modified by Cinchonidine.

Asymmetric one-pot reactions using heterogeneous chemical catalysis: recent steps towards sustainable processes

The preparation of optically pure fine chemicals is among the most important and challenging tasks met by organic chemists. Recently, significant efforts have been focused on the development of green and sustainable procedures for the synthesis of these high value-added compounds. Asymmetric heterogeneous catalysis has provided efficient solutions to these challenges. The application of heterogeneous chiral catalysts in one-pot processes combines the advantages of use of these materials with time, material, and energy savings associated with cascade or sequential procedures. This review surveys these asymmetric one-pot reactions reported until July 2017, in which a heterogeneous chemical catalyst has been applied either as a single multifunctional catalyst or in combination with a second catalytically active material. These processes include one-pot procedures catalysed by carefully designed solids obtained by the immobilization of chiral metal complexes, by anchoring chiral organocatalysts, or by modifying catalytic surfaces with optically pure compounds, which may also incorporate uncatalyzed and homogeneously catalysed steps. Methods applying achiral heterogeneous catalysts in combination with soluble chiral chemical catalysts or biocatalysts are also presented. Sophisticated, finely tuned materials have been applied in most of these reactions, which have been discussed along with the main requirements necessary to perform these transformations in a one-pot manner.

Asymmetric Michael addition catalyzed by a cinchona alkaloid derivative non-covalently immobilized on layered inorganic supports

A study on the asymmetric Michael addition of a fluorine containing carbon nucleophile to β-nitrostyrene was carried out to find an easily obtainable cinchona alkaloid derivative, which provides high stereoselectivities, and may be conveniently immobilized over inorganic materials to obtain efficient chiral heterogeneous catalysts. It was shown that high enantioselectivities are reached in the addition of ethyl 2-fluoroacetoacetate catalyzed by β-isocupreidine accompanied by good diastereomeric ratios. This cinchona derivative prepared in one step from quinidine was immobilized by cation-exchange between the layers of an aluminum phyllosilicate, as evidenced by XRD measurements. However, due to the protonation of the tertiary amino group, the material lost its catalytic activity in the Michael addition. The immobilization of the deprotonated alkaloid over the particle surface of an anion exchanger layered double hydroxide resulted in an inorganic–organic hybrid material, with catalytic performance approaching that of the soluble organocatalyst. Upon reuse, gradual deactivation of this heterogeneous catalyst was observed due to the leaching of the organic material. However, using less polar media could increase the lifetime of the hybrid catalyst. The results of catalytic measurements indicated that the Michael addition might occur on the solid surface. Based on the catalytic behavior of the heterogeneous catalyst, bonding possibilities of the cinchona derivative to the surface of the layered hydroxide by electrostatic interactions and hydrogen bonding are suggested.

Pt-cinchonidine catalyzed asymmetric catalytic cascade reaction of 2-nitrophenylpyruvates in flow system

The asymmetric heterogeneous catalytic cascade reaction of ethyl 2-nitro-3-methylphenylpyruvate has been investigated over platinum modified by cinchonidine in continuous-flow system using a fixed-bed reactor. The high selectivities and enantioselectivities of the (R)-3-hydroxy-3,4-dihydro-8-methylquinolin-2(1H)-one obtained in previous studies in batch reactor were not reached. The catalyst was in situ prehydrogenated and premodified with cinchonidine, and the reaction conditions optimized for batch reactor were changed in order to increase the yield and enantioselectivity of the desired product under flow conditions. Results obtained in the flow apparatus contributed to the understanding of the reaction pathway through which the quinolone is formed. It was shown that, at low conversions, the intermediate aminohydroxyester desorbs preferentially and is further transformed by readsorption and cyclization to the quinolone derivative after complete disappearance of the 2-nitrophenylpyruvate. However, at high conversion, the formation of the quinolone may also occur instantaneously on the Pt surface following the two competitive reduction steps. The ratio of the product formed through these two pathways is determined by the reaction conditions and the system used.

Heterogeneous Asymmetric Hydrogenation of N-Heterocyclic Compounds: Hydrogenation of Tetrahydroisoquinoline Derivatives

The preparation and application of heterogeneous chiral catalysts are described. Heterogeneous Pd, Ir and Ru catalysts were tested in the enantioselective hydrogenations of N-heterocyclic compounds, namely 6,7-dimethoxy-3,4-dihydroisoquinoline and 1-methylene-2-ethoxycarbonyl-6,7-dimetoxy-3,4-dihydroisoquinoline in the presence of optically pure cinchonidine, (S,S)- and (R,R)-Ts-DPEN ligands. Cinchonidine-modified metal catalysts exhibited low ee, whereas catalysts stabilized by triphenylphosphane and modified by (S,S)-Ts-DPEN afforded promising ee values (70–80xa0%). Immobilized Ru(II)-aminophosphane complexes were found to be active in these hydrogenations producing the corresponding tetrahydroisoquinoline derivatives in high optical purities (up to 97xa0%). The latter catalysts were characterized by infrared spectroscopy, solid-state MAS NMR spectroscopy and elemental analysis. Recycling of these catalysts showed constant or increasing activities in racemic hydrogenation, whereas the presence of the chiral ligands led to leaching of the active species in the liquid phase.

Improved stereoselective synthesis of 3-methoxy- and 3-benzyloxy-16-hydroxymethyl-13α-estra-1,3,5(10)-trien-17-ol isomers by transfer hydrogenation using chiral Ru catalysts

The Noyori-type (1S,2S)- and (1R,2R)-N-(para-tosyl)-1,2-diphenylethylene-1,2-diamine ligands complexed with ruthenium have been found to be effective catalysts for the regiospecific transfer hydrogenation of 3-methoxy- and 3-benzyloxy-(Z)16-hydroxymethylidene-13α-estra-1,3,5(10)-trien-17-ones to 3-methoxy- and 3-benzyloxy-16-hydroxymethyl-13α-estra-1,3,5(10)-trien-17-one diastereomers. The ratio of the diastereomers depends on the catalyst used. Further reduction of the isolated products with NaBH4 in the presence of cerium(III) chloride (Luche reduction conditions) yielded the corresponding diols. In contrast to the previous preparation methods, this two-step simple hydrogenation/reduction protocol afforded all four possible isomers in almost equal amounts.

Design of Heterogeneous Organocatalyst for the Asymmetric Michael Addition of Aldehydes to Maleimides

Asymmetric Michael additions of isobutyraldehyde to maleimides catalyzed by optically pure diamines and their sulfonamides were investigated to develop heterogeneous chiral catalysts for these reactions. Encouraging results, i.u2009e. complete transformations and optically pure products, were obtained using para‐toluenesulfonamide or methanesulfonamide derivatives. Chiral solid materials were prepared by covalent bonding of the diamines on sulfonyl chloride functionalized supports. Immobilization of the amines was confirmed by FT‐IR spectroscopy. The heterogeneous catalyst prepared by bonding optically pure 1,2‐diphenylethane‐1,2‐diamine to polystyrene support was highly enantioselective, giving results approaching those obtained using soluble sulfonamide derivatives. The anchored catalyst was recyclable few times keeping its activity followed by gradual small decrease in conversion, however, still providing high, up to 97u2009%, enantiomeric excesses. These materials are among the first efficient recyclable catalysts used in the enantioselective Michael addition of aldehydes to maleimides.