Second-generation organocatalysts for the highly enantioselective dynamic kinetic resolution of azlactones

Bifunctional organocatalysts of the thiourea-tert-amine type, carrying two "matched" elements of chirality, effect the alcoholytic dynamic kinetic resolution of a variety of azlactones with up to 95% ee.     

Metal complexes-catalyzed hydrolysis and alcoholysis of organic substrates and their application to kinetic resolution

Metal complexes-catalyzed hydrolysis and alcoholysis of organic substrates such as alkenyl esters, alkenyl ethers, and azlactones (oxazol-5(4H)-ones) are described. These reactions were applied for kinetic resolution of chiral compounds and high selectivities were achieved with vinyl ethers of 2-substituted cyclohexanols, 1,1′-bi-2-naphthols, 1,1′-bi-2-phenols, and 4,4-disubstituted azlactones. Oxidative carbon–carbon bond cleavage reactions, which were found in the course of the study of asymmetric hydrolysis were also described.     

Structural optimization of thiourea-based bifunctional organocatalysts for the highly enantioselective dynamic kinetic resolution of azlactones

This article describes the synthesis of a library of structurally diverse bifunctional organocatalysts bearing both a quasi-Lewis acidic (thio)urea moiety and a Br?nsted basic tertiary amine group. Sequential modification of the modular catalyst structure and subsequent screening of the compounds in the alcoholytic dynamic kinetic resolution (DKR) of azlactones revealed valuable structure-activity relationships. In particular, a "hit-structure" was identified which provides e.g.N-benzoyl-tert-leucine allyl ester in an excellent enantiomeric excess of 95%.     

Acid zeolites as alcohol racemization catalysts: screening and application in biphasic dynamic kinetic resolution

Acid zeolites were screened as heterogeneous catalysts for racemization of benzylic alcohols. The most promising zeolites appeared to be H-Beta zeolites, for which the optimal reaction conditions were studied in further detail. The zeolite performance was compared to that of homogeneous acids and acid resins under similar reaction conditions. In a second part of the research, H-Beta zeolites were applied in dynamic kinetic resolution (DKR) of 1-phenylethanol, which was conducted by means of a two-phase approach and which resulted in yields smoothly crossing the 50% border up to 90%, with an enantiomeric excess of >99%. To explore the applicability of this biphasic methodology, several other substrates were examined in the standard racemization reaction and in the biphasic dynamic kinetic resolution.     

Bifunctional polymeric organocatalysts and their application in the cooperative catalysis of Morita-Baylis-Hillman reactions

A series of soluble, non-cross-linked polystyrene-supported triphenylphosphane and 4-dimethylaminopyridine reagents were prepared. Some of these polymeric reagents contained either alkyl alcohol or phenol groups on the polymer backbone. The use of these materials as organocatalysts in a range of Morita-Baylis-Hillman reactions indicated that hydroxyl groups could participate in the reactions and accelerate product formation. In the cases examined, phenol groups were more effective than alkyl alcohol groups for catalyzing the reactions. This article is one of the first reports of the synthesis and use of non-natural, bifunctional polymeric reagents for use in organic synthesis in which both functional groups can cooperatively participate in the catalysis of reactions.     

Synthesis of new ionic-liquid-tagged organocatalysts and their application in stereoselective direct aldol reactions

New amino acid—1,2,3-triazolium conjugates were synthesized by establishing a 1,2,3-triazolium unit to the amino acid through Cu-catalyzed alkyne-azide cycloaddition and subsequent N-methylation. These products were applied as ionic-liquid-tagged organocatalysts in asymmetric direct aldol reactions. Remarkably, a lysine-derived conjugate performed better than proline derivatives. Evidence was found that IL-tagging improved the catalytic performance. Recycling of the organocatalyst was easily possible by extraction of products.     

Enzymatic kinetic resolution and chemoenzymatic dynamic kinetic resolution of delta-hydroxy esters. An efficient route to chiral delta-lactones

A successful kinetic resolution of a racemic mixture of delta-hydroxy esters 1 was obtained via lipase-catalyzed transesterification (E value up to 360). The combination of the enzymatic kinetic resolution with a ruthenium-catalyzed alcohol racemization led to an efficient dynamic kinetic resolution (ee up to 99% and conversion up to 92%). The synthetic utility of this procedure was illustrated by the practical syntheses of delta-lactones (R)-6-methyl- and (R)-6-ethyl-tetrahydropyran-2-one and (S)-5-(tert-butyldimethylsiloxy)heptanal. The former are important building blocks in the synthesis of natural products and biologically active compounds, and the latter is a key intermediate in the synthesis of widely used commercial insecticide Spinosyn A.     

Synthesis of substituted chiral chromans via organocatalytic kinetic resolution of racemic 3-nitro-2-aryl-2H-chromenes with ketones catalyzed by pyrrolidinyl-camphor-derived organocatalysts

Efficient kinetic resolution of racemic 2-aryl-3-nitro-2H-chromenes (1a–l) has been explored with the pyrrolidinyl-camphor derivative 2b as a bifunctional organocatalyst under neat conditions in the presence of AcOH at 0 °C. In general, the organocatalytic asymmetric Michael addition of ketones proceeded smoothly to give the functionalized Michael adducts (3a–n) with good-to-high diastereo- and enantioselectivities (up to 92:8 dr, 93% ee, and 47% yield). The less reactive chromenes (S)-1a–h, k, l and (R)-1i–j were recovered in high chemical yields and moderate optical purity (up to 42% chemical yield and 72% ee).     

Development of axially chiral bis(arylthiourea)-based organocatalysts and their application in the enantioselective Henry reaction

Axially chiral bis(arylthiourea)-based organocatalyst 6b, prepared from (R)-(+)-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-binaphthyl-2,2′-diamine, was found to be an effective chiral organocatalyst for the enantioselective Henry reaction of arylaldehydes with nitromethane to give the corresponding adducts in moderate enantioselectivities and good yields.     

(S)-selective kinetic resolution and chemoenzymatic dynamic kinetic resolution of secondary alcohols

(S)-Selective kinetic resolution was achieved through the use of a commercially available protease, which was activated with a combination of two different surfactants. The kinetic resolution (KR) process was optimized with respect to activation of the protease and to the acyl donor. The KR proved to be compatible with a range of functionalized sec-alcohols, giving good to high enantiomeric ratio values (up to >200). The enzymatic resolution was combined with a ruthenium-catalyzed racemization to give an (S)-selective dynamic kinetic resolution (DKR) of sec-alcohols. The DKR process works under very mild reaction conditions to give the corresponding esters in high yields and with excellent enantioselectivities.     

Dynamic kinetic and kinetic resolution of N-Boc-2-lithiopiperidine

Asymmetric substitution of 2-lithiopiperidines can be achieved by dynamic resolution; the organolithium is formed as a racemic mixture by proton abstraction (or tin-lithium exchange) and is resolved in the presence of a chiral ligand.     

Syntheses of 2-chloro-4-nitrophenyl beta-D-maltopentaosides with bulky modification and their application to the differential assay of human alpha-amylases.

Four novel maltopentaosides, 2-chloro-4-nitrophenyl O-(6-O-p-toluenesulfonyl-alpha-D-glucopyranosyl)-(1-->4)-tris[O- alpha-D-glucopyranosyl-(1-->4)]-beta-D-glucopyranoside (4), 2-chloro-4-nitrophenyl O-[6-O-(tert-butyldimethyl)silyl-alpha-D- glucopyranosyl]-(1-->4)-tris[O-alpha-D-glucopyranosyl-(1-->4)]-beta-D- glucopyranoside (5), 2-chloro-4-nitrophenyl O-[6-deoxy-6-(phenyl)sulfonyl-alpha-D- glucopyranosyl]-(1-->4)-tris[O-alpha-D-glucopyranosyl-(1-->4)]-beta-D- glucopyranoside (10), and 2-chloro-4-nitrophenyl O-(6-deoxy-6-phthalimido-alpha-D-glucopyranosyl)- (1-->4)-tris[O-alpha-D-glucopyranosyl-(1-->4)]-beta-D-glucopyranoside (11) were synthesized. Substrates 4, 5, 10, and 11 were hydrolyzed by human pancreatic alpha-amylase (HPA) from 1.1 to 2.9-fold faster than by human salivary alpha-amylase (HSA). Taking advantage of the difference in the hydrolytic rate of 5 (2.9-fold faster), we developed a new method for the differential assay of these two human alpha-amylases.     

Dispersive kinetic models for isothermal solid-state conversions and their application to the thermal decomposition of oxacillin

The authors recently published works in which the use of two novel equations for modeling the dispersive kinetics observed in various solid-state conversions are described. These equations are based on the assumptions of a ‘Maxwell-Boltzmann (M-B)-like’ distribution of activation energies and a first-order rate law. In the present work, it is shown that it may be possible to expand the approach to include mechanisms other than first-order, i.e. some of those commonly encountered in the field of thermal analysis, thus obtaining ‘dispersive versions’ of these kinetic models. The application of these dispersive kinetic models to the slightly sigmoidal, isothermal conversion-time (x-t) data of Rodante and co-workers for the degradation of the antibiotic, oxacillin, is described. This is done in an effort to test the limitations of the proposed dispersive models in describing kinetic data which is not clearly sigmoidal (i.e. as shown in previous works). Finally, it is demonstrated that, using graphical analysis, the typically sigmoidal x-t plots of first-order dispersive processes are the direct result of (asymmetric) activation energy distributions that are either ‘∩-shaped’ (for heterogeneous conversions) or ‘∪-shaped’ (for homogeneous conversions) in appearance, i.e. when the activation energy is plotted as a function of conversion. This finding lends support to the founding hypothesis of the authors’ approach for modeling dispersive kinetic processes: the existence of ‘M-B-like’ distributions of activation energies.     

A practical concept for the kinetic resolution of a chiral secondary alcohol based on a polymeric silane

The paper describes our preliminary studies on the use of PMHS as a functionalizable polymer and hydride source for the kinetic resolution of secondary alcohols via chiral Cu(I)-catalyzed dehydrogenative silylating process. The chiral phosphine that chelates the Cu metal center has little influence on the selectivity factor of the kinetic resolution. The use of a stereogenic silane appears to be a key requirement to reach enantiodifferentiation in such a process.     

Synthesis of novel carbohydrate-based valine-derived formamide organocatalysts by CuAAC click chemistry and their application in asymmetric reduction of imines with trichlorosilane

Novel organocatalysts combining carbohydrate and N-formyl-l-valine derivatives were prepared by Cu^II-catalyzed diazo transfer and Cu^I-catalyzed azide–alkyne 1,3-dipolar cycloaddition CuAAC click chemistry. It was found that the carbohydrate-based valine-derived formamide organocatalyst had high catalytic activity for the asymmetric reduction of imines with trichlorosilane. The reduction can proceed at room temperature in toluene in high yield (up to 98%) and with excellent enantioselectivity (up to 94%). ‘CuAAC’ click chemistry is a bridge to link N-formyl-l-valine derived organocatalysts with carbohydrates.     

Highly efficient asymmetric reduction of arylpropionic aldehydes by horse liver alcohol dehydrogenase through dynamic kinetic resolution

The enantioselective synthesis of (2S)-2-phenylpropanol and (2S)-2-(4-iso-butylphenyl)propanol ((S)-Ibuprofenol) has been achieved by means of Horse Liver Alcohol Dehydrogenase (HLADH) in buffered aqueous solution or buffered organic solvent mixtures; under the reaction conditions, a dynamic kinetic resolution (DKR) process was realized with good reaction yields and enantiomeric ratios.