Enhancement Of Enantioselectivity Research Articles

Backbone Effect of MAP Ligands on Their Coordination Patterns with Palladium(II)

The allylpalladium complexes (R)-4 and (R)-5 of chiral P, N auxiliaries (R)-1 and (R)-3 have been prepared. The X-ray structures of the complexes have been determined, and the results clearly show that two different chelating modes (P, N vs P, Cσ) are involved. The coordination patterns of donating atoms were dependent on the binaphthyl backbone of the chiral ligands. The isodesymmetrization revealed that the reaction occurs without regiochemical memory effect, which demonstrates a full dynamic equilibrium has been attained before nucleophilic attack. These results, combined with the solution behaviors of the complexes revealed by NMR studies, provided a further understanding of their asymmetric induction in allylic substitution of 1,3-diphenylprop-2-en-1-yl acetate with dimethyl malonate. The dramatic enhancement of enantioselectivity with (R)-3 as a chiral inducer can be related to the different chelating mode of catalyst (R)-5 from that of (R)-4. The change of bite angles of the two donors with palladium in the complexes (R)-4 and (R)-5 was considered as a direct reason for their dramatically different enanatioselectivities in the catalysis.

Copper‐Catalyzed Enantioselective Conjugate Addition of Diethylzinc to Acyclic Enones in the Presence of Planar‐Chiral Phosphaferrocene‐Oxazoline Ligands.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Enhancement of Enantioselectivity by THF in Asymmetric Mo‐Catalyzed Olefin Metathesis. Catalytic Enantioselective Synthesis of Cyclic Tertiary Ethers and Spirocycles.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Chemical modification of lipases with various hydrophobic groups improves their enantioselectivity in hydrolytic reactions.

Semi-purified lipases from Candida rugosa, Pseudomonas cepacia and Alcaligenes sp. were chemically modified with a wide range of hydrophobic groups such as benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, t-butoxycarbonyl, lauroyl and acetyl moieties. The Candida rugosa lipase MY modified with the benzyloxycarbonyl group (modification ratio = 84%) brought about a 15-fold increase in enantioselectivity (E value) towards the hydrolysis of racemic butyl 2-(4-ethylphenoxy)propionate in an aqueous buffer solution, although the enzymatic activity was decreased. The origin of the enantioselectivity enhancement by chemical modification of the lipase is attributed to a significant deceleration in the initial reaction rate for the incorrectly binding enantiomer.

Complex‐Catalyzed Hydrogenation Reactions in Aqueous Media

AbstractFor Abstract see ChemInform Abstract in Full Text.

Copper-catalyzed enantioselective conjugate addition of diethylzinc to acyclic enones in the presence of planar-chiral phosphaferrocene-oxazoline ligands.

[reaction: see text] A new subclass of chiral phosphaferrocene-oxazoline ligands has been applied to the copper-catalyzed asymmetric conjugate addition of diethylzinc to acyclic enones, furnishing good enantioselectivity. The ligand design readily lends itself to modification, thereby facilitating optimization of ee. Although the dominant stereocontrol element in these 1,4-addition processes is the central chirality of the oxazoline subunit of the ligand, not the planar chirality of the phosphaferrocene, altering the phosphaferrocene subunit can provide useful enhancement of enantioselectivity.

Enhancement of enantioselectivity by THF in asymmetric mo-catalyzed olefin metathesis. Catalytic enantioselective synthesis of cyclic tertiary ethers and spirocycles.

Mo-catalyzed enantioselective rearrangement of achiral cyclopentenyl tertiary ethers to chiral cyclohexenyl tertiary ethers are reported. These olefin metathesis transformations proceed efficiently and with high levels of enantioselectivity. A noteworthy feature of these reactions is that added tetrahydrofuran exerts a remarkably positive influence on the enantioselectivity of the metathesis-based rearrangement. The first examples of catalytic asymmetric synthesis of spirocyclic structures by enantioselective olefin metathesis are also disclosed.

Directed evolution of selective enzymes and hybrid catalysts

The methods of directed evolution, developed in the 1990s, can be applied successfully to the creation of enantioselective enzymes for use in synthetic organic chemistry. The combination of appropriate molecular biological methods for random mutagenesis and expression coupled with high-throughput screening systems for the determination of ee-values forms the basis of this novel approach to asymmetric catalysis. The principle is illustrated by the dramatic enhancement of enantioselectivity of a lipase as the catalyst in the hydrolytic kinetic resolution of a chiral ester, the selectivity factor improving from E=1.1 to E=51. Reversal of enantioselectivity is also possible. Finally, the concept of directed evolution of selective hybrid catalysts has been delineated.

Complex-Catalyzed Hydrogenation Reactions in Aqueous Media

The review summarizes recent work in the field of hydrogenation reactions catalyzed by transition metal complexes in aqueous media. This development was stimulated by the availability of water-soluble ligands and facilitated the recycling of the catalyst from multiphase systems. Another possibility is the immobilization of the catalytic system on insoluble or water-soluble polymers. The asymmetric hydrogenation of prochiral substrates was realized in several examples with remarkable success. An enhancement of enantioselectivity and activity was achieved in the hydrogenation of amino acid precursors in microheterogeneous (aqueous micellar) systems. Beside the reduction of the C=C bond, also reported are the reduction of C=O and C=N bonds including methods which involve transfer hydrogenation.

The effect of water on the enantioselective hydrogenation of ethyl pyruvate and butane-2,3-dione using cinchona-modified Pt/Al2O3

A detailed study of Pt/alumina modified with cinchona alkaloids for the catalytic enantioselective hydrogenation of ethyl pyruvate to ethyl lactate and of butane-2,3-dione to 3-hydroxybutan-2-one is reported. Catalytic and 1H NMR spectroscopic studies have been carried out on both systems to investigate the influence of water on modifier conformation and enantioselectivity. Interestingly, the presence of small amounts of water has been shown to result in an increase the proportion of the open 3 conformer of cinchonidine when it is present in dilute solutions. Increased enantioselectivity, coupled with an increase in the proportion of the open 3 conformation of cinchonidine, is observed after pretreatment of the pyruvate ester with the modifier prior to admission to the reaction vessel. In contrast, no analogous effects are observed with butane-2,3-dione. It is proposed that the enhancements in enantioselectivity are a consequence of hydrolysis of ethyl pyruvate by a process that is catalysed by the basic cinchona modifier. The pyruvic acid formed during the hydrolysis interacts with the modifier and this leads to a further enhancement in the concentration of open 3 conformer present. The results contribute to an understanding of the widely variable enantioselectivities reported in the literature for this reaction.

Asymmetric Azidation−Cycloaddition with Open-Chain Peptide-Based Catalysts. A Sequential Enantioselective Route to Triazoles

A family of beta-substituted histidine-containing peptides has been synthesized to probe the effect of noncovalent conformational rigidification on catalyst enantioselectivity. Unambiguous enhancement of enantioselectivity in the conjugate addition of azide to alpha,beta-unsaturated carboxylate derivatives has been achieved, enabling application to a sequential asymmetric azidation/cycloaddition for the synthesis of optically enriched triazoles and triazolines.

Enhancement of enzyme activity and enantioselectivity via cultivation in nitrile metabolism by Rhodococcus sp. CGMCC 0497.

Racemic 2-phenylpropionitrile was resolved enantioselectively by nitrile-converting enzymes in cells of Rhodococcus sp. CGMCC 0497 to S-(+)-2-phenylpropionic acid and R-(-)-2-phenylpropionamide. By optimization of the culture conditions, great enhancement of enzyme activity and enantioselectivity was achieved. Furthermore, the relationship between cell-growth periodicity and enzyme accumulation was studied; the addition of inducer was delayed by 1 day and the reaction was further improved. This unusual strategy has almost never been reported with other nitrile-converting strains. The resulting culture broth, containing methacrylamide as the inducer, beef extract as the nitrogen source and glucose as the carbon source, with methacrylamide added 24 h later, seemed to be most suitable. S-(+)-2-Phenylpropionic acid and R-(-)-2-phenylpropionamide were produced with yields of 48% (enantiomeric excess, 96%) and 42% (enantiomeric excess, 97%) respectively with no nitrile left after 3 h, or with yields of 52% and 39% (enantiomeric excess, 93% and 99%) respectively after 6 h.

Chemoenzymatic synthesis and properties of Schiff bases containing (R)-1-(9-anthryl)ethylamine.

Racemic 1-(9-anthryl)ethylamine (10), obtained in 70% overall yield from commercial 9-cyanoanthracene, was kinetically resolved by the Candida antarctica A lipase-catalyzed acetylation with isopropyl acetate as acyl donor, affording (R)-(+)-10 with 95.8% enantiomeric excess (e.e.) (E-value 43.5), which afforded Schiff bases (R)-4 and(R)-8. (1)H-NMR, CD, and MM2 calculations offer a consistent picture of the conformational properties of these potential ligands and an explanation for the limited enhancement of enantioselectivity in cyclopropanation of styrene by their Cu(I) complexes, as compared with previously studied ligands in this series.

Crown ether strategy toward chemical activation of biological protein functions

AbstractThe chemical activation of biological proteins is outlined, in which small molecules are used to alter the chemical and physical properties of biological proteins through direct or indirect interactions. Crown ethers have the potential to modulate the protein functions by supramolecular complexations, because they bind alkylammonium and other ionic residues of the proteins as well as ionic components in their systems. Two interesting examples are described in which crown ether derivatives improved the protein functions: (1) enhancement of reactivity and enantioselectivity in lipase‐catalyzed asymmetric reactions; and (2) generation of catalytic activity in the oxidation with cytochrome c. This chemical activation based on crown ether chemistry can be viewed as a complementary method to biological mutation in modifying the biological protein functions.

Variations in the enantioselectivity of salt-activated subtilisin induced by lyophilization.

Including excess salt during lyophilization has been shown to increase the activity of freeze-dried subtilisin Carlsberg (SC) in anhydrous media by over 20,000-fold [Ru et al. (1999) Biotechnol Bioeng 63:233-241]. In the present study, salt-activated SC (KCl-SC) showed a 30% enhancement in enantioselectivity compared to the salt-free enzyme in a variety of organic solvents. Activity toward both enantiomers of N-acetyl-phenylalanine methyl ester (APME) increased in tandem by 2-3 orders of magnitude in all solvents, indicating that the mechanism of salt activation is inherent to the enzyme and does not strongly favor one enantiomer over the other. However, activity and enantioselectivity of salt-activated SC could be manipulated through changes in the lyophilization conditions. Variations in lyophilization time, initial KCl concentration, and initial lyophilization volume altered enantioselectivity over 2-fold. The changes in enantioselectivity reflected the activity for the L enantiomer, while the activity toward the D enantiomer was mostly unaffected. The results indicate that the lyophilization time and final water content of the KCl-SC are important determinants of enzyme activity for the L enantiomer, suggesting that the favored reaction is more sensitive to the structural integrity of the salt-activated enzyme.

Aqueous micellar and non-micellar effects during the asymmetric hydrogenation of dehydroamino acid derivatives: influence of amphiphiles on enantioselectivity and α-CH/CD exchange

The effect of different amphiphiles on the CH/CD exchange in the homogeneously catalysed asymmetric hydrogenation/deuteration of methyl ( Z)-α-acetamidocinnamate or methyl α-acetamidoacrylate in an aqueous micellar medium has been investigated in connection with the effect of amphiphiles on the enhancement of enantioselectivity. In comparison with the exchange of α-CH/CD in water, the amphiphiles inhibit the reaction in the order: cationic<zwitterionic≪anionic. In mixtures of cationic (cetyltrimethylammonium hydrogen sulfate, C 16H 33N(CH 3) 3 +HSO 4 −) and anionic amphiphiles (sodium dodecyl sulfate, SDS) the H/D-exchange amount is low in the presence of an excess of SDS, but it increases rapidly near a CTA +HSO 4 − mole fraction of 0.5 to give a high level of exchange. The enantioselectivity drops to a minimum in the 1:1 mixture because of the low solubility of the cationic–anionic aggregates and the absence of micelles. The results obtained with mixed micelles of Brij 35 (polyethyleneoxide(23) monododecylether, C 12E 23) and SDS are quite different. This mixture is dispersible and able to form micelles over the entire range of mole fractions (0 to 1). As a consequence, the isotope exchange is almost constant from a mole fraction of 0.3–0.9 of SDS. The enantioselectivity is nearly constant over the whole range. The inhibition of H/D exchange in the presence of long-chain alkyl sulfates seems to be caused by a specific interaction with the catalytic rhodium complex.

Lipase-catalyzed optical resolution of racemic naproxen in biphasic enzyme membrane reactors

A lipase-immobilized membrane reactor was applied for the optical resolution of racemic naproxen, and the effect of various operation conditions on reaction rate and enantio-selectivity was examined. The membrane reactor consisted of an organic phase dissolving naproxen ester, a lipase-immobilized polyamide membrane, and an aqueous phase to recover the reaction products. The lipase immobilized in the membrane reactor showed a stable activity for more than 200 h of continuous operation, while the native lipase in emulsioned stirred tank reactor quickly lost its activity showing an half-life time of about 2 h. When crude lipase was used, the biphasic enzyme membrane reactor gave smaller enantio-selectivity compared to the native lipase in the emulsioned tank reactor, whilst the use of pure lipase gave similar results to the native lipase. This paper discusses that other hydrolases present in the crude enzyme powder caused the decrease of enantio-selectivity. Enantio-selectivity depended on the substrate concentration, amount of enzyme loaded in the membrane and immobilization site. In fact, these parameters affect the organic/aqueous interface that plays an important role in the enhancement of enantio-selectivity.

ChemInform Abstract: Microbial Desymmetrization of 3‐Arylglutaronitriles, an Unusual Enhancement of Enantioselectivity in the Presence of Additives.

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Engineering the active site of ascorbate peroxidase.

The oxidation of a number of thioethers, namely methyl phenyl sulphide (1), ethyl phenyl sulphide (2), isopropyl phenyl sulphide (3), n-propyl phenyl sulphide (4), p-chlorophenyl methyl sulphide (5), p-nitrophenyl methyl sulphide (6) and methyl naphthalene sulphide (7), by recombinant pea cytosolic ascorbate peroxidase (rAPX) and a site-directed variant of rAPX in which the distal tryptophan 41 residue has been replaced with an alanine (W41A) has been examined. The electronic spectrum (pH 7.0, mu = 0.10 M, 25.0 degrees C) for the ferric derivative of W41A (lambda(max)/nm = 411, 534, 560, 632) is indicative of an increased quantity of 6-coordinate, high-spin and/or 6-coordinate, low-spin haem compared to rAPX. Steady state oxidation of sulphides 1-4 and 7, gave values for kcat that are approximately 10-fold and 100-fold, respectively, higher for W41A than for rAPX. For rAPX, essentially racemic mixtures of R- and S-sulphoxides were obtained for all sulphides. With the exception of sulphide 7, the W41A variant shows substantial enhancements in enantioselectivity, with R : S ratios varying between R : S = 63 : 37 (sulphides 1 and 4) and R : S = 85 : 15 (sulphide 6). Incubation of sulphide 2 with rAPX or W41A and [(18)O] H(2)O(2) shows 95% (rAPX) and 96% (W41A) transfer of labelled oxygen to the substrate. Structure-based modelling techniques have provided a fully quantitative rationalization of all the experimentally determined R : S ratios and have indicated that reorientation of the sidechain of Arg38, such that access to the haem is much less restricted, is influential in controlling the stereoselectivity for both rAPX and W41A.

Microbial desymmetrization of 3-arylglutaronitriles, an unusual enhancement of enantioselectivity in the presence of additives

In the presence of an organic additive such as acetone or β-cyclodextrin or in a biphasic system of hexane and aqueous phosphate buffer, microbial desymmetrization of 3-arylglutaronitriles catalyzed by Rhodococcus sp. AJ270 cells proceeded regiospecifically and enantioselectively to produce S-(+)-3-aryl-4-cyanobutyric acids in high enantiomeric excess. Convenient chemoenzymatic syntheses of optically active R-(−)-4-amino-3-phenylbutyric acid and 4 R-(−)-4-phenyltetrahydropyran-2-one are described.