Kinetic Resolution Of Racemic Compounds Research Articles

Organocatalyzed Kinetic Resolution of Racemic Carboxylic Acids

AbstractThe kinetic resolution of racemic compounds is a reliable method to prepare important chiral molecules in highly optically enriched forms. Although methods for the catalytic kinetic resolution of chiral alcohols, amines, and epoxides have been extensively investigated, the kinetic resolution of racemic carboxylic acids has remained under‐developed despite the importance of chiral carboxylic acids. Excellent catalytic approaches for the kinetic resolution of racemic carboxylic acids via esterification using chiral organocatalysts have been reported by several research groups. Furthermore, the organocatalyzed lactonization of alkenyl and alkynyl carboxylic acids has also been adapted to achieve kinetic resolution. Herein, the methods typically used to produce the organocatalyzed kinetic resolution of racemic carboxylic acids are reviewed to elucidate the current status of this research.

Differentiating the Allyl and Propargyl Groups on α‐Quaternary Carboxylic Acids via Chiral Bifunctional Sulfide‐Catalyzed Kinetic Resolution

AbstractCatalytic kinetic resolution of racemic organic compounds is a reliable method to enantioselectively prepare important chiral molecules. Substrates for the kinetic resolution, however, generally required significantly different substituents at a chiral center. Catalytic kinetic resolution of racemic molecules possessing two similar substituents at a chiral center has remained a formidable challenge. In this context, we became interested in the catalytic kinetic resolution of racemic compounds bearing both allyl and propargyl groups, which are similar but useful substituents, at a chiral center. Herein, we report a kinetic resolution of α‐allyl‐α‐propargyl carboxylic acids bearing an all‐carbon quaternary stereocenter via chiral bifunctional sulfide‐catalyzed bromolactonization. The synthetic utility of the resultant optically active compounds obtained via kinetic resolution was also demonstrated.magnified image

Enantiopure planar chiral [2.2]paracyclophanes: Synthesis and applications in asymmetric organocatalysis

This short review focuses on enantiopure planar chiral [2.2]paracyclophanes (pCps), a fascinating class of molecules that possess an unusual three-dimensional core and intriguing physicochemical properties. In the first part of the review, different synthetic strategies for preparing optically active pCps are described. Although classical resolution methods based on the synthesis and separation of diastereoisomeric products still dominate the field, recent advances involving the kinetic resolution of racemic compounds and the desymmetrization of meso derivatives open up new possibilities to access enantiopure key intermediates on synthetically useful scales. Due to their advantageous properties including high configurational and chemical stability, [2.2]paracyclophanes are increasingly employed in various research fields, ranging from stereoselective synthesis to material sciences. The applications of [2.2]paracyclophanes in asymmetric organocatalysis are described in the second part of the review. While historically enantiopure pCps have been mainly employed by organic chemists as chiral ligands in transition-metal catalysis, these compounds can also be used as efficient catalysts in metal-free reactions and may inspire the development of new transformations in the near future.

Development of nanobiocatalysts through the immobilization of Pseudomonas fluorescens lipase for applications in efficient kinetic resolution of racemic compounds

The present work reports covalent immobilization of Pseudomonas fluorescens lipase (PFL) on functionalized multiwalled carbon nanotubes (MWCNTs) as a nanobiocatalyst (NBC). This nanobiocatalyst facilitates efficient kinetic resolution of (RS)-1-phenylethanol into (S)-1-phenylethanol [C=49.7%, eep=99.5%, ees=98.1% and E value=191.4]. The immobilized preparation (MWCNTs-PFL) showed ten-fold increase in activity, thermal stability upto 80 °C and recyclability (8 cycles). MWCNTs-PFL nanobioconjugate demonstrated better stability and enhanced activity compared to covalently immobilized PFL on other matrices (silver nanoparticles, gold nanoparticles and chitosan beads) used for the study. A statistical design [response surface methodology (RSM)] employed for the optimization of enzyme immobilization parameters made this study statistically more significant. Overall, the newly developed nanobiocatalyst has applications towards the kinetic resolution of racemic compounds.

Contributions on Kinetic Resolution by Lipases on the Development of Organic Synthesis in Brazil

In recent decades the need for new chiral compounds with high enantiomeric excesses has been rapidly emerging. Among the various methods used to achieve chiral compounds, one can highlight the enzymatic kinetic resolution of racemic esters, alcohols and amines and as the most versatile enzymatic methodology used in organic routes. Enzymes are used in biocatalytic routes to obtain enriched and enantiomerically pure compounds. The most remarkable biocatalysts for these processes are lipases, which have the capability of being used in organic media. Thus, the main purpose of this article was to present a review about studies conducted in Brazil involving the kinetic resolution of racemic compounds using lipases, also including unusual substrates containing heteroatoms, such as boron, silicon, selenium, tellurium and sulfur. Keywords: Biocatalysis, Lipases, Candida antarctica, Immobilization, Kinetic Resolution.

Catalytic enantioselective 1,3-dipolar cycloadditions of azomethine ylides for biology-oriented synthesis.

ConspectusCycloaddition reactions are among the most powerful methods for the synthesis of complex compounds. In particular, the development and application of the 1,3-dipolar cycloaddition, an important member of this reaction class, has grown immensely due to its powerful ability to efficiently build various five-membered heterocycles. Azomethine ylides are commonly used as dipoles for the synthesis of the pyrrolidine scaffold, which is an important motif in natural products, pharmaceuticals, and biological probes. The reaction between azomethine ylides and cyclic dipolarophiles allows access to polycyclic products with considerable complexity. The extensive application of the 1,3-dipolar cycloaddition is based on the fact that the desired products can be obtained with high yield in a regio- and stereocontrolled manner. The most attractive feature of the 1,3-dipolar cycloaddition of azomethine ylides is the possibility to generate pyrrolidines with multiple stereocenters in a single step. The development of enantioselective cycloadditions became a subject of intensive and impressive studies in recent years. Among many modes of stereoinduction, the application of chiral metal–ligand complexes has emerged as the most viable option for control of enantioselectivity.In chemical biology research based on the principle of biology-oriented synthesis (BIOS), compound collections are prepared inspired by natural product scaffolds. In BIOS, biological relevance is employed as the key criterion to generate hypotheses for the design and synthesis of focused compound libraries. In particular, the underlying scaffolds of natural product classes provide inspiration for BIOS because they define the areas of chemical space explored by nature, and therefore, they can be regarded as “privileged”. The scaffolds of natural products are frequently complex and rich in stereocenters, which necessitates the development of efficient enantioselective methodologies.This Account highlights examples, mostly from our work, of the application of 1,3-dipolar cycloaddition reactions of azomethine ylides for the catalytic enantioselective synthesis of complex products. We successfully applied the 1,3-dipolar cycloaddition in the synthesis of spiro-compounds such as spirooxindoles, for kinetic resolution of racemic compounds in the synthesis of an iridoid inspired compound collection and in the synthesis of a nitrogen-bridged bicyclic tropane scaffold by application of 1,3-fused azomethine ylides. Furthermore, we performed the synthesis of complex molecules with eight stereocenters using tandem cycloadditions. In a programmable sequential double cycloaddition, we demonstrated the synthesis of both enantiomers of complex products by simple changes in the order of addition of chemicals. Complex products were obtained using enantioselective higher order [6 + 3] cycloaddition of azomethine ylides with fulvenes followed by Diels–Alder reaction. The bioactivity of these compound collections is also discussed.

Recent advances and applications of the lipolytic activity of Carica papaya latex

The lipolytic enzymes of Carica papaya have been the subjects of a growing research activity in the last years due to the structural characteristics, substrate specificity over lipases from different sources and the wide availability from the large worldwide figures of papaya agro-waste. This review attempts to present an inclusive discussion of the recent advances of these lipolytic enzymes starting from findings related to their structure and mechanism and later examining the most employed pretreatments and the general optimized parameters for its use. Furthermore, individual sections comprising applications in glycerolipid modification, catalysis for the synthesis of non-glycerolipid products and the kinetic resolution of racemic compounds are discussed. The attractive features of CPL cited in this literature survey serve as an invitation for other research groups interested in the development of new and sustainable biochemical technologies.

Effect of co‐solvent addition on the reaction kinetics of the lipase‐catalyzed resolution of ibuprofen ester

AbstractBACKGROUND: The addition of co‐solvent is not limited to enhancing the catalytic rate, it could also assist in situ racemization in the dynamic kinetic resolution of racemic compounds by increasing the reactivity of the base catalyst employed. In the current work, reaction media with the presence of DMSO were investigated in Candida rugosa lipase (EC 3.1.1.3)‐catalyzed hydrolysis of ibuprofen ester that focuses on the thermodynamic effect, reaction stability and implication for the kinetic parameters.RESULTS: The introduction of 2% DMSO increased the reaction rate, conversion, and enantioselectivity of the Candida rugosa lipase‐mediated resolution. However, the performance of the particular enzymatic reaction was reduced when a higher DMSO concentration was added. At lower reaction temperatures, the medium with 2% DMSO exhibited an increase in enantioselectivity, which was attributed to a higher activation energy difference between the fast‐ and slow‐reacting enantiomers compared with the water‐isooctane medium. Additionally, the presence of DMSO had a significant effect on the kinetic parameters, shown by a lower value of Michaelis constant compared with that of a normal reaction without DMSO, which resulted in a fast reaction rate. Finally, inhibition due to the uncompetitive substrate inhibitor was reduced, while the non‐competitive product inhibitor consequently increased.CONCLUSION: This work has demonstrated that only 2% of DMSO can be tolerated by the free Candida rugosa lipase in the resolution of ibuprofen ester. However, it is still able to give significant positive effects on the hydrolysis rate, kinetic parameters and enantioselectivity as well as reaction stability. © 2012 Society of Chemical Industry

Transaminases for the synthesis of enantiopure beta-amino acids

Optically pure β-amino acids constitute interesting building blocks for peptidomimetics and a great variety of pharmaceutically important compounds. Their efficient synthesis still poses a major challenge. Transaminases (also known as aminotransferases) possess a great potential for the synthesis of optically pure β-amino acids. These pyridoxal 5'-dependent enzymes catalyze the transfer of an amino group from a donor substrate to an acceptor, thus enabling the synthesis of a wide variety of chiral amines and amino acids. Transaminases can be applied either for the kinetic resolution of racemic compounds or the asymmetric synthesis starting from a prochiral substrate. This review gives an overview over microbial transaminases with activity towards β-amino acids and their substrate spectra. It also outlines current strategies for the screening of new biocatalysts. Particular emphasis is placed on activity assays which are applicable to high-throughput screening.

ChemInform Abstract: Cinchona‐Based Catalysts for Desymmetrization of meso‐Compounds and (Dynamic) Kinetic Resolution of Racemic Compounds

AbstractReview: 77 refs.

Stereoselective Syntheses of 3-Substituted Flavene Derivatives and Asymmetric Dehydration via Kinetic Resolution

The 2-phenyl-2H-chromene structural core is a widespread element in natural flavonoids and has attracted intense attention since a wide range of biological activities associated with the scaffold have been identified. Accordingly, the development of facile synthetic strategies to access such heterocycles is of considerable interest and a few asymmetric synthetic methods have been reported recently. Although the asymmetric methods could provide enantioenriched flavene derivatives, their development for more functionalized flavene skeleton has proven to be a challenging synthetic task. In this communication, we wish to report diastereoselective Reformatsky reaction of flavene-3-carbaldehydes to provide β-(2H-3-flavenyl)-β-hydroxy esters and disclose a new enantioselective synthetic method for 3substituted flavene derivatives by asymmetric dehydration via kinetic resolution. We have initially investigated the substrate controlled diastereoselective addition of Reformatsky reagent to flavene-3-carbaldehydes 1, in which the chiral center at the C(2) position of 2H-chromene exerts control over the formation of new stereogenic center. In an initial experiment, to a solution of BrZnCH2CO2t-Bu (3 equiv) in THF was added a solution of flavene-3-carbaldehyde 1a in THF, and the resulting mixture was heated to reflux to afford the products 2a and 3a in 91% yield with a diastereomeric ratio (dr) of 71:29. (entry 1, Table 1) Different experimental conditions have been tested on flavene-3-carbaldehyde 1a to improve the diastereoselectivity of the addition. Since the diastereoselectivity could be enhanced by effecting the reaction at low temperature, different reaction temperatures have been tested on flavene-3-carbaldehyde 1a as summarized in Table 1. As the reaction temperature decreases, the dr is improved as shown in entries 1-5. The ratio of major 2a to minor product 3a was 79:21 at rt, whereas it was 90:10 at −15 °C. At −30 °C, much slower reaction gave products 2a and 3a with only 15% conversion after 5 h and a slightly improved dr of 92:8. (entry 5) Polar solvents were then screened in an attempt to increase the solubility of the reagent and to enhance the rate and the selectivity of the reaction. The use of THF-DMSO (1:1), THF-p-dioxane (1:1) and p-dioxane respectively as solvent (entries 6-9) did not increase the stereoselection and decreased the yield of the reaction. Under the optimized condition at −15 °C in THF, the reaction of o-methoxy substituted flavene aldehyde 1b gave slightly lower dr (entry 10) and p-methoxy substituted flavene aldehydes 1c-e reacted with Reformatsky reagent leading to 2c-e and 3c-e with drs ranging from 89:11 to 91:9, which are practically independent on the presence of the substituents on the aromatic rings and substitution pattern. While 4chloro substituent increase the selectivity up to 94:6 dr (entry 16), 2-methyl substituted chromenes 1f and 1g showed much lower selectivity (entries 14-15). Non-enzymatic kinetic resolution of racemic compounds using chiral catalyst is an area of great importance in contemporary organic synthesis. We recently reported the first example of the kinetic resolution in dehydration of alcohols using D-Phg-L-Pro-derived chiral ligand 5. Given

Modeling of two separate phase enzyme membrane reactors for kinetic resolution of naproxen ester

Enzyme membrane reactors are described case by case on considering membrane properties, enzymes, immobilization methods and operation modes such as mono/multiphases [1]. In practical application, they will be detailed chosen in order to make the integrated system performing in optimal conditions. To do this, an appropriate mathematical modeling is necessary in order to assess the influence of various parameters on the reactor performance, e.g., enzyme concentration, enzymatic activity, and diffusion coefficients of the substrates through the loaded membrane fibers. The reactor performance can be evaluated in advance based on the established models considering the diffusion of substrates, reactant consumption and product formation. In most cases, the modeled differential equations might be solved analytically or numerically with respect to the boundary conditions matching the membrane bioreactor operating conditions [2]. Some important studies have been described in previous works [3]; however, few theoretical studies on the enzymatic kinetic resolution of racemic compounds in the two-separate phase enzyme membrane reactor (TSP-EMR) have been reported [2]. In this work, the modeling of a multiphase reactor using immobilized lipase to carry out the hydrolysis of racemic ester has been developed considering mass transfer properties measured in a previous study [4]. The modeling and experimental results will be compared.

Catalytic asymmetric reactions using environmentally friendly reagents and catalyst: Asymmetric synthesis versus kinetic resolution

Kinetic resolution of racemic compounds is a familiar method for the preparation of optically active compounds. However, an inevitable and critical drawback from the point of view of green chemistry is the consequent wastage of half of the starting compound. A catalytic asymmetric synthesis of 5-arylcyclohex-2-enones was developed starting from racemic 5-(trimethylsilyl)cyclohex-2-enone, which overcomes the drawback of kinetic resolution. A chiral amidophosphane- or BINAP-Rh(I)-catalyzed asymmetric conjugate arylation of racemic 5-(trimethylsilyl)cyclohex-2-enone with arylboronic acids in dioxane-water (10:1) afforded trans- and cis-3-aryl-5-(trimethylsilyl)cyclohexanones in reasonably high enantioselectivity. Dehydrosilylation of the product mixture with Cu(II) chloride in dimethylformamide (DMF) gave 5-arylcyclohex-2-enones with up to 93 % ee in high yield. Enantiofacial selectivity with chiral phosphane-Rh(I) overrides the trans-diastereoselectivity that is maintained in the achiral or racemic phosphane-Rh(I)-catalyzed conjugate arylation of 5-(trimethylsilyl)cyclohex-2-enone.

Enzymatic membrane reactor for the kinetic resolution of racemic ibuprofen ester: modeling and experimental studies

The production of (S)-ibuprofen acid was studied in a hollow fiber membrane reactor, with the aim to develop a clean and ecofriendly technology. The modeling and simulation of enzymatic membrane reactor was studied for lipase-catalyzed hydrolysis of racemic ibuprofen ester in hollow fiber membrane reactor. Mathematical model was developed to simulate the behavior of enzymatic reaction in the membrane matrix region. The model equation was derived considering reaction over immobilized enzyme in the membrane porous support with the substrate flowing along the shell side. The model was simulated on the basis of experimental operating conditions, physical and hollow fiber geometrical parameters. The model equation was a nonlinear second-order differential equation and solved numerically using Matlab. The parameters studied were Thiele Modulus ( Φ 2 ) , Bodenstein number ( B 0 ) , transmembrane pressure (TMP) and intrinsic enzyme kinetic constants ( V max and K m ). Simulation results showed that a satisfactory product separation was achieved with 60% conversion of (S)-ester, enantiomeric excess of substrate, ee s in the range 35–43%, enantiomeric excess of product, ee p in the range 80–85%, and enantiomeric ratio ( E value) of 11.2–15.3 at 4.34 < B 0 < 13.89 and Φ 2 < 1 . The simulated results agreed with the experimental data within an error of ± 7.5 % . The reaction–separation functionality of EMR system has shown the potential of membrane reactor application for kinetic resolution of racemic compounds especially in overcoming the difficulties associated with conventional technology particularly in downstream separation and enzyme recovery.

Quantitative analysis of enantioselective enzymatic hydrolysis with non-enantioselective removal of chiral products

Kinetic resolution of racemic compounds by enzymatic hydrolysis with non-enantioselective separation of enantiomer products via a separator or ion-pair formation has been quantitatively analyzed. Theoretical results indicate that the removal of chiral products has profound effects on improving the conversion and enantiomeric excess for the desired chiral substrate or product. The analysis was confirmed from lipase-catalyzed hydrolysis of racemic methyl 2-chloropropionate in the presence of pyrrolidine in buffer saturated dichloromethane.

Overexpression, immobilization and biotechnological application of Pseudomonas lipases

Pseudomonas lipases play an important role in biotechnology both as hydrolases for detergent additives and as synthases catalyzing the kinetic resolution of racemic compounds. Large-scale production of Pseudomonas lipases requires correct folding and secretion through the bacterial membranes. Controllable expression of the gene lipH encoding a lipase-specific foldase proves to be important for overexpression in the homologous host Escherichia coli. Construction of appropriate His-tagged fusion proteins permitted overexpression, secretion and one-step purification of lipase from culture supernatants of the homologous host Pseudomonas aeruginosa. The immobilization of lipases in hydrophobic sol–gel materials derived from alkylsilane precursors of the type RSi(OCH 3) 3 or mixtures of RSi(OCH 3) 3 and Si(OCH 3) 4 provides highly active and chemically and thermally stable heterogeneous biocatalysts. The entrapped lipases are excellent catalysts in a variety of synthetic organic transformations. Using directed evolution based on error prone PCR, the enantioselectivity of the hydrolysis of a chiral ester, catalyzed by the lipase from P. aeruginosa, can be increased from ee 2 to ee 81% in just four mutagenesis cycles.

Stereoselective Biotransformations in Synthesis of Some Pharmaceutical Intermediates

Publisher Summary The chapter provides some specific examples of stereoselective biotransformations to prepare chiral intermediates required for the synthesis of pharmaceutical drugs. The search for selective enzyme inhibitors and receptor agonists or antagonists is one of the keys for target-oriented research in the pharmaceutical industry. It is now known that in many cases only one stereoisomer of a drug substance is required for efficacy and the other stereoisomer is either inactive or exhibits considerably reduced activity. New drugs for the clinic should be homochiral to avoid the possibility of unnecessary side effects due to an undesirable stereoisomer. Chiral drug intermediates can be prepared by different routes. One is to obtain them from naturally occurring chiral synthons mainly produced by fermentation processes. Second is to carry out resolution of racemic compounds. This can be achieved by preferential crystallization of stereoisomers or diastereoisomers and by kinetic resolution of racemic compounds by chemical or biocatalytic methods. Chiral synthons can also be prepared by asymmetric synthesis by either chemical or biocatalytic processes using microbial cells or enzymes derived therefrom. The advantages of microbial or enzyme-catalyzed reactions over chemical reactions are that they are stereoselective and that they can be carried out at ambient temperature and atmospheric pressure. This minimizes problems of isomerization, racemization, epimerization, and rearrangement that generally occur during chemical processes. Microbial cells or enzymes derived therefrom can be immobilized and reused during many cycles. The chapter provides some specific examples of stereoselective biotransformations to prepare chiral intermediates required for the synthesis of pharmaceutical drugs.

Chiral Thiazolidine-2-Thione Derived Iminium Salts as Reagents for Kinetic Resolution

Abstract There are currently few simple reagent systems available which can effect efficient kinetic resolution of racemic compounds. We report here a series of chiral bicyclic iminium salts, which can resolve racemic secondary alcohols to give both the unreacted alcohol and the sulphide resulting from reaction in moderate enantiomeric excess.