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Lipase-catalyzed access to enantiomerically pure (R)- and (S)-trans-4-phenyl-3-butene-2-ol
Abstract
The enzymatic kinetic resolution of (RS)-trans-4-phenyl-3-butene-2-ol was investigated by screening a range of lipases both for enantioselective transesterification and for enantioselective hydrolysis of its acetate. The lipase from Pseudomonas cepacia immobilized on diatomaceous earth (PSL-D)-catalyzed asymmetric transesterification was performed on gram scale using isopropenyl acetate as an innocuous acyl donor in organic media affording the (S)-alcohol in high enantiomeric excess (>99% ee) and enantiomeric ratio E >150. The lipase (Candida antarctica B, CAL-B)-catalyzed asymmetric hydrolysis of the racemic acetate was performed on gram scale in phosphate buffer affording the (R)-alcohol in high enantiomeric excess (>99% ee) and enantiomeric ratio E >150. The investigation demonstrates that the transesterification of the racemic alcohol in organic solvent was faster than the hydrolysis of the corresponding acetate in phosphate buffer. A GC method was developed to achieve an effective analytical separation of the enantiomers of both substrate and product in one analysis using the chiral stationary phase heptakis(2,3-di-O-methyl-6-O-tert-butyldimethylsilyl)-β-cyclodextrin.
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... Verapamil [19], Baclofen [20], or β-aryl substituted lactones with antiproliferative activity [21]. Many studies concerning their kinetic resolution by transesterification [22][23][24][25] or hydrolysis [25,26] have been developed recently. To the best of our knowledge, Lecitase ® Ultra has not been reported yet as the biocatalyst in these processes. ...
... In the case of the hydrolysis of racemic propionate 4b, a good resolution was achieved after 2 h: ee of alcohol 3 92%, ee of unreacted propionate 4b 85%, conversion degree 57%, and high enantioselectivity (E = 65). Comparable results of the resolution of the enantiomers of acetate 4a with lipase B from C. antarctica were previously obtained by Ghanem and Schurig [26] during the hydrolysis carried out in phosphate buffer (pH 6) and toluene as the solvent for substrate. After 24 h, at 45% conversion, the ee of alcohol 3 and unreacted acetate 4a were 99% and 80%, respectively, with excellent enantioselectivity (E > 200). ...
... The reaction was continued at room temperature until the alcohol reacted completely (24 h, TLC). The reaction mixture was acidified with 1M HCl, the product was extracted with diethyl ether (3 × 40 mL) and separated through column chromatography (hexane/acetone, 10:1) to afford known esters: acetate 4a (2.7 g, 96% yield) [26] and propionate 4b [31] (2.9 g, 96% yield). Their spectroscopic data are consistent with those reported in the literature. ...
The possibility of using Lecitase® Ultra as a novel alternative biocatalyst for the kinetic resolution of model racemic allyl esters of (E)-4-phenylbut-3-en-3-ol: Acetate (4a) and propionate (4b) through their enantioselective hydrolysis was investigated. Reaction afforded (+)-(R)-alcohol (3) and unreacted (−)-(S)-ester (4a or 4b). Hydrolysis of propionate 4b proceeded with higher enantioselectivity than acetate 4a. (R)-Alcohol (3) with highest enantiomeric excess (93–99%) was obtained at 20–30 °C by hydrolysis of propionate 4b, while the highest optical purity of unreacted substrate was observed for (S)-acetate 4a (ee = 34–56%). The highest enantioselectivity was found for the hydrolysis of propionate 4b catalyzed at 30 °C (E = 38). Reaction carried out at 40 °C significantly lowered enantiomeric excess of produced alcohol 3 and enantioselectivity in resolution. Lecitase® Ultra catalyzed the enantioselective hydrolysis of allyl esters 4a,b according to Kazlauskas’ rule to produce (R)-alcohol 3 and can find application as a novel biocatalyst in the processes of kinetic resolution of racemic allyl esters.
... The authors have cited additional references within the Supporting Information. [39,40] ...
The biocatalytic asymmetric reduction of prochiral ketones offers a promising approach for producing optically active secondary alcohols. Alcohol dehydrogenases (ADHs) are enzymes that facilitate the reversible conversion of prochiral ketones into their corresponding optically active secondary alcohols, and thus are pivotal for this process. Most ADHs adhere to Prelog's rule in determining the stereopreference for the asymmetric reduction of prochiral ketones. This study focuses on the ΔP84/A85G mutation of TeSADH, demonstrating its capability to reduce aryl‐ring‐containing ketones to their corresponding alcohols in anti‐Prelog mode with high stereoselectivities. The study also highlights the crucial role of P84 in switching the stereopreference of TeSADH in the asymmetric reduction of aryl‐ring‐containing ketones. Furthermore, this mutant exhibits a broad substrate scope, including substrates accepted by the previously reported W110 mutants of TeSADH with opposite stereopreference. The ability to create mutants of the same enzyme with opposite stereopreferences presents intriguing opportunities for fascinating transformations, such as bienzymatic racemization, which can be utilized in dynamic kinetic resolution, and stereoinversion using two enantiocomplementary mutants of the same enzyme.
... Enantiomeric purities of the products of the kinetic resolution of racemic (E)-4-phenylbut-3-en-2-yl esters through Lecitase ™ Ultra-catalyzed hydrolysis were comparable or higher than those obtained previously involving commercially available lipase preparations. Among the different lipases tested by Ghanem et al. [65], the most effective biocatalyst of the kinetic resolution of acetate 2a was lipase B from Candida antarctica (CALB). Optically pure alcohol 1a and unreacted acetate 2a with only 80% ee were obtained after 24 h of reaction in the phosphate buffer (pH 6.0) with the addition of toluene as the co-solvent. ...
The influence of buffer type, co-solvent type, and acyl chain length was investigated for the enantioselective hydrolysis of racemic 4-arylbut-3-en-2-yl esters using Lecitase™ Ultra (LU). Immobilized preparations of the Lecitase™ Ultra enzyme had significantly higher activity and enantioselectivity than the free enzyme, particularly for 4-phenylbut-3-en-2-yl butyrate as the substrate. Moreover, the kinetic resolution with the immobilized enzyme was achieved in a much shorter time (24–48 h). Lecitase™ Ultra, immobilized on cyanogen bromide-activated agarose, was particularly effective, producing, after 24 h of reaction time in phosphate buffer (pH 7.2) with acetone as co-solvent, both (R)-alcohols and unreacted (S)-esters with good to excellent enantiomeric excesses (ee 90–99%). These conditions and enzyme were also suitable for the kinetic separation of racemic (E)-4-phenylbut-3-en-2-yl butyrate analogs containing methyl substituents on the benzene ring (4b,4c), but they did not show any enantioselectivity toward (E)-4-(4’-methoxyphenyl)but-3-en-2-yl butyrate (4d).
... The combined organic layers were dried with sodium sulfate and then concentrated. The remaining residue was treated with acetic anhydride (one drop) and pyridine (two drops) and incubated at room temperature for 6h to convert the produced alcohol to its acetate ester derivative, [26] which was analyzed by aG Ce quipped with ac hiral column. ...
Here, ketones bearing two bulky substituents, named bulky-bulky ketones, were successfully reduced to their corresponding optically-enriched alcohols using various mutants of Thermoanaerobacter pseudoethanolicus secondary alcohol dehydrogenase (TeSADH). Substituted 2-tetralones in particular were reduced to 2-tetralols with high conversion and high enantioselectivity. The pharmacological importance of substituted 2-tetralols as key drug-building blocks makes our biocatalytic reduction method a highly essential tool. We showed that changing the position of the substituent on the aromatic ring of 2-tetralones impacted their binding affinity and the reaction maximum catalytic rate. Docking studies with several TeSADH mutants explained how the position of the substituent on the tetralone influences the binding orientation of substituted 2-tetralones and their reaction stereoselectivity.
... The combined organic layers were washed with brine solution (5 mL), dried with sodium sulfate and then concentrated under vacuum. A fraction of the remaining residue was treated with pyridine and acetic anhydride as reported prior to its analysis by a GC equipped with a chiral column 14 . The percent conversion was 61 % and the optical purity was 97.2 %. ...
An asymmetric synthetic approach to produce (R)- and (S)-rhododendrol is described. W110A Thermoanaerobacter ethanolicus secondary alcohol dehydrogenase (W110A TeSADH), an (S)-specific mutant of TeSADH, is used in this approach. The enantioselective reduction of 4-(4'-hydroxyphenyl)-2-butanone catalyzed by W110A TeSADH yielded (S)-rhododendrol, the Prelog product. The anti-Prelog product, (R)-rhododendrol, is produced from (rac)-rhododendrol through enantiospecific kinetic resolution catalyzed by W110A TeSADH.
... Schurig and colleagues published a series of reports about the utility of isopropenyl acetate as an innocuous acyl donor in the lipase-catalyzed transesterification of secondary alcohols (Scheme 27). 46,47 Biphenyls are recognized as stable analogs of BINOL and are found in numerous natural products. The optically active 1,1'-binaphthyl-2-2'-diols (BINOL) have been used as versatile templates and chiral auxiliaries in catalysts employed successfully in asymmetric synthesis. ...
Chiral-center enantiomers have been shown to differ significantly in biological activity, pharmacodynamics, pharmacokinetics and toxicity. New developments in the stereoselective organic synthesis have enriched the vast literature of synthetic methodologies applicable to access natural products as well as bioactive molecules. These compounds also include new drugs, drug candidates and reagents used to explore biological processes. The article reviews the synthesis of optically pure drugs, biologically active intermediates and amino alcohols by using different methods. Chirality 00:000-000, 2013. © 2013 Wiley Periodicals, Inc.
... Kinetic resolution of allylic alcohols was first reported by Burgess and Jennings [74] as part of the study towards development of a simple active-site model for prediction of asymmetric induction and applied for the asymmetric synthesis of a statin analogue [75]. Schurig [76] have reported a kinetic resolution of trans-4-phenyl-3-butene-2-ol in high enantiomeric excess. The enantioselective transesterification as well as hydrolysis of its acetate has been studied (Scheme 16). ...
The synthesis of enantiomerically pure compounds employing new and efficient methods has emerged as an active area of research in the recent past. In spite of the development of many asymmetric catalytic methods, the resolution of racemic mixtures i.e., kinetic resolutions are preferred industrially. The only drawback of kinetic resolution is that a maximum of fifty percent of starting material can be utilized, and the other enantiomer is usually not utilized. This limitation has been addressed in many cases by coupling the acylation of one enantiomer with a racemization reaction for the in situ conversion of the undesired enantiomer to the desired products. Therefore a combination of lipases with transition metals or other related racemizing agents resulted in a single enantiomer. This process is termed ‘dynamic kinetic resolution’ and has been a focus of research in recent years towards asymmetric synthesis.This review enlightens the changing trends from kinetic resolution to the development of dynamic kinetic resolution, with an emphasis on the chiral intermediates of biological significance and the type of catalysts used along with the enzymes in such processes.
... A sample of the residue was treated with pyridine and acetic anhydride to convert the produced alcohol to the corresponding acetate as described. [19] The acetate products were analyzed by chiral column GC to determine the percentage conversion and ee of the pro- duced alcohols. The remaining residue was then purified by column chromatography on silica gel (hexane/ethyl acetate eluent). ...
The asymmetric reduction of benzylic and heteroaryl ketones to the corresponding (R)-alcohols using I86A Thermoanaerobacter ethanolicus alcohol dehydrogenase (I86A TeSADH) is described. This single amino acid mutation not only makes the active site of I86A TeSADH able to accommodate more sterically demanding substituents than those accommodated by wild-type TeSADH, but it also reverses the substrate stereospecificity of TeSADH.
... This reaction has been studied batchly producing good conversion and ee [174,247]. Resolution of other alcohols in organic solvents using the acetylation at moderate batch temperatures gave conversion of 3-68% and ee of 2-99% [248][249][250][251][252][253][254][255]. ...
A number of β-blocking drugs are available in the world market, only few compounds are found as single enantiomers. The need to use the single enantiomeric β-blockers affects development of drugs and technology. Many processes have been exploited to replace the existing racemates. Two main routes are established: (1) asymmetric syntheses and (2) racemic resolutions. The syntheses give medium-high yields and excellent enantiomeric excess, but the resolutions are limited by 50% yield. Both technologies involve new techniques such as dynamic kinetic resolution (DKR) and membrane-based extraction. The synthetic ways utilise various substrates and catalysts. A simultaneous formation is also afforded by these processes. They offer oriented alternatives to the single enantiomeric β-blockers. Resolutions of the racemates appear with many attractive separation methods. Direct or indirect resolutions show excellent characteristics and produce high enantiomeric excess. The existing processes operate continuously at mild operating temperatures compared to the asymmetric synthesis. In situ separation is also exploited. Development of the single enantiomeric β-blockers using the DKR based on enzymatic membrane(s) is encouraged. Integration of acetylation, racemisation and hydrolysis followed by separation of the enantiomers in the enzymatic membrane reactors could be a better option in resolution and separation of the β-blocker racemates.
This review explores linear cascade reactions by combining chemo-, photo- and biocatalysts for organic synthesis and strategies to overcome incompatibility issues.
Deracemization
Resolution of Alcohols by Lipase‐Catalyzed Esterification
Resolution of Alcohols by Lipase‐Catalyzed Transesterification
Resolution of Alcohols by Esterase‐Catalyzed Esterification
Resolution of Alcohols by Protease‐Catalyzed Esterification
Resolution of Alcohols by Immobilized Morchella esculenta ‐Catalyzed Transesterification
Resolution of Alcohols by Acylase‐Catalyzed Transesterification
Resolution of Alcohols by Hydrolysis of Esters or Carbonates
Resolution of Alcohols and Phenols by Alcoholysis
Resolution of Alcohols by Aminolysis of Esters
Dynamic Kinetic Resolution of Alcohols Mediated by Lipase and Metal Catalysis
Resolution of Alcohols by Nonenzymatic Acylation
Resolution of Alcohols by Oxidation
Resolution of Allylic Alcohols
Resolution of Haloalcohols
Resolution of 2,3‐Epoxy Alcohols
Resolution of Alcohols by Formation of an SiO Bond
Resolution of Alcohols by Dehydration of β‐Hydroxy Esters
Resolution of Aldols by a retro ‐Aldol Reaction
Resolution of 2‐Nitro Alcohols by CC Bond Cleavage
Resolution of tert ‐Cyclobutanols by Pd‐Catalyzed CC Bond Cleavage
Resolution of Secondary Alcohols by a Chiral Heteroatom Auxiliary
Resolution of Diols and Triols
Resolution of Alcohols by Preferential Crystallization
Resolution of Alcohols by Supramolecular Crystallization
Resolution of Alcohols by Sublimation
An efficient reactive system was established to produce (S)-2-phenylbutyric acid (2-PBA) through the enzymatic enantioselective hydrolysis of 2-phenylbutyrate ester (2-PBAE) in aqueous medium. Lipase CALA from Canadian antarctica and hexyl 2-phenylbutyrate (2-PBAHE) were identified upon screening as the best enzyme and substrate, respectively. Adding hydroxyethyl-β-cyclodextrin (HE-β-CD) to improve the solubility of the substrate resulted in a 1.5 times increase in substrate conversion while retaining a high enantioselectivity compared with that when HE-β-CD was not added. The effects of lipase concentration, substrate concentration and HE-β-CD concentration, temperature, pH, and reaction time on enantiomeric excess and conversion rate were investigated, and the optimal conditions were identified using response surface methodology (RSM). Under the optimal conditions, namely 50 mg/mL lipase CALA, 30 mmol/L substrate, 60 mmol/L HE-β-CD, pH of 6.5, temperature of 83 °C and reaction time of 18 h, the enantiomeric excess and overall conversion rate were 96.05% and 27.28%, respectively. This work provides an efficient alternative method for improving the conversion of aromatic ester substrates by including β-cyclodextrin in an aqueous hydrolysis reaction system.
Enantiomerically pure alcohols, as key intermediates, play an essential role in the pharmaceutical, agrochemical and chemical industries. Among the methods used for their production, biotechnological approaches are generally considered a green and effective alternative due to their mild reaction conditions and remarkable enantioselectivity. An increasing number of enzymatic strategies for the synthesis of these compounds has been developed over the years, among which seven primary methodologies can be distinguished as follows: (1) enantioselective water addition to alkenes, (2) enantioselective aldol addition, (3) enantioselective coupling of ketones with hydrogen cyanide, (4) asymmetric reduction of carbonyl compounds, (5) (dynamic) kinetic resolution of racemates, (6) enantioselective hydrolysis of epoxides, and (7) stereoselective hydroxylation of unactivated C-H bonds. Some recent reviews have examined these approaches separately; however, to date, no review has included all the above mentioned strategies. The aim of this mini-review is to provide an overview of all seven enzymatic strategies and draw conclusions on the effect of each approach.
Die asymmetrische Reduktion hydrophober Ketone durch die Xerogel‐immobilisierte W110A‐Sekundärer‐Alkohol‐Dehydrogenase aus Thermoanaerobacter ethanolicus (TeSADH) in organischen Lösungsmitteln liefert die (S)‐Alkohole in ähnlichen Ausbeuten wie das freie Enzym und manchmal sogar mit höherer Enantioselektivität. R=Phenylring enthaltender Substituent.
Here, we report the asymmetric reduction of selected phenyl-ring-containing ketones by various single and dual site mutants of Thermoanaerobacter pseudoethanolicus secondary alcohol dehydrogenase (TeSADH). Further expanding the size of the substrate binding pocket in the mutant W110A/I86A not only allowed substrates of the single mutants W110A and I86A to be accommodated within the expanded active site, but also expanded the enzyme's substrate range to ketones bearing two sterically demanding groups (bulky-bulky ketones), which are not substrates for TeSADH single mutants. We also report the regio- and enantioselective reduction of diketones using W110A/I86A TeSADH and single TeSADH mutants. The double mutant exhibited dual stereopreference generating the Prelog products most of the time and the anti-Prelog products in a few cases.
Secondary alcohol dehydrogenase (SADH) from Thermoanaerobacter ethanolicus reduces ketones to chiral alcohols, and generally obeys Prelog's Rule, with binding pockets for large and small alkyl substituents, giving (S)-alcohols. We have previously shown that mutations in both the large and small pockets can alter both substrate specificity and stereoselectivity. In the present work, Met-151 and Thr-153, residues located in the small pocket, were mutated to alanine. The M151A mutant SADH shows significantly lower activity and lower stereoselectivity for reduction of aliphatic ketones than wild-type SADH. Furthermore, M151A showed non-linear kinetics for reduction of acetone. T153A SADH shows lower activity but similar stereoselectivity for ketone reduction compared to wild-type SADH. The I86A/M151A/C295A and I86A/T153A/C295A triple mutant SADH show altered specificity for reduction of substituted acetophenones. These results confirm that these mutations are useful to combine with I86A/C295A SADH to expand the small pocket of SADH and broaden the substrate specificity.
As the (R)-enantiomer of racemic atenolol has no β-blocking activity and no lack of side effects, switching from the racemate to the (S)-atenolol is more favorable. Transesterification of racemic atenolol using free enzymes investigated as a resource to resolve the racemate via this method is limited. Screenings of enzyme, medium, and acetyl donor were conducted first to give Pseudomonas fluorescens lipase, tetrahydrofuran, and vinyl acetate. A statistical design of the experiment was then developed using Central Composite Design on some operational factors, which resulted in the conversions of 11.70-61.91% and substrate enantiomeric excess (ee) of 7.31-100%. The quadratic models are acceptable with R(2) of 95.13% (conversion) and 89.63% (ee). The predicted values match the observed values reasonably well. Temperature, agitation speed, and substrate molar ratio factor have low effects on conversion and ee, but enzyme loading affects the responses highly. The interaction of temperature-agitation speed and temperature-substrate molar ratio show significant effects on conversion, while temperature-agitation speed, temperature-substrate molar ratio, and agitation speed-substrate molar ratio affect ee highly. Optimum conditions for the use of Pseudomonas fluorescens lipase, tetrahydrofuran, and vinyl acetate were found at 45°C, 175 rpm, 2000 U, and 1:3.6 substrate molar ratio.
Thermoanaerobacter ethanolicus secondary alcohol dehydrogenase (SADH) reduces aliphatic ketones according to Prelog's Rule, with binding pockets for small and large substituents. It was shown previously that the I86A mutant SADH reduces acetophenone, which is not a substrate of wild-type SADH, to give the anti-Prelog R-product (Musa, M. M.; Lott, N.; Laivenieks, M.; Watanabe, L.; Vieille, C.; Phillips, R. S. ChemCatChem 2009, 1, 89–93.). However, I86A SADH did not reduce aryl ketones with substituents larger than fluorine. We have now expanded the small pocket of the active site of I86A SADH by mutation of Cys-295 to alanine to allow reaction of substituted acetophenones. As predicted, the double mutant I86A/C295A SADH has broadened substrate specificity for meta-substituted, but not para-substituted, acetophenones. However, the increase of the substrate specificity of I86A/C295A SADH is accompanied by a decrease in the kcat/Km values of acetophenones, possibly due to the substrates fitting loosely inside the more open active site. Nevertheless, I86A/C295A SADH gives high conversions and very high enantiomeric excess of the anti-Prelog R-alcohols from the tested substrates.
A thorough study on free-enzyme transesterification kinetic resolution of racemic atenolol in a batch system was investigated to gain knowledge for (S)-atenolol kinetics. Analyses of enzyme kinetics using Sigma-Plot 11 Enzyme Kinetics Module on the process are based-on Michaelis–Menten and Lineweaver–Burk plot, which give first-order reaction and ordered-sequential Bi–Bi mechanism, where Vmax, KM-vinyl acetate, and KM-(S)-atenolol are 0.80 mM/h, 29.22 mM, and 25.42 mM, respectively. Further analyses on enzyme inhibitions find that both substrates inhibit the process where (S)-atenolol and vinyl acetate develop competitive inhibition and mixed inhibition, respectively. Association of (S)-atenolol with free enzyme to inhibit the enzyme is higher than reaction of active enzyme–substrate complex with vinyl acetate.
In this report, effects of reaction parameters on kinetic resolution of racemic atenolol using Pseudomonas fluorescens lipase were investigated via transesterification for production of pharmacologically active eutomer (S)-atenolol with high enantiomeric purity. It was found that a temperature of 45 °C produced an acceptable enantioselectivity (E: 17). Good agitation speeds were found at 170–230 rpm producing E values of 12–15, whilst an enzyme activity of ≥2500 U gave 100% conversion of the (S)-atenolol. Substrate concentrations of 11.26–18.80 mM gave E values of 11.6–12.3. Variation of the substrate molar ratio yielded (S)-atenolol conversions of 44.67–61.58% with E = 12–23.
The enantioselective reduction of a broad range of prochiral α,β-unsaturated ketones 1a–1y using the oxazaborolidine-based catalyst providing chiral allylic alcohols 2a–2y with both high enantioselectivity and chemoselectivity is described. The optimum reaction conditions were found using the oxazaborolidine catalysts prepared in situ from the chiral amino alcohols and borane reagents. Various chiral amino alcohols 4a–4f were screened for this one-pot asymmetric reduction of α,β-enones. Amino alcohol 4a [(R)-DPP] and trimethylboroxine catalyze this asymmetric reduction in toluene at −20 °C within 0.5–2 h in a highly efficient manner. The synthesized chiral allylic alcohols 2a–2y are new compounds, which are valuable intermediates in the preparation of new ligands and in the synthesis of several natural molecules.
Two δ-iodo-γ-lactones and two γ-iodo-δ-lactones substituted at the β-position with phenyl or 4-methylphenyl ring have been synthesized in both enantiomeric forms. The starting materials were enantiomerically enriched allyl alcohols with an (E)-4-phenylbut-3-en-2-ol system (ee in the range 88–99 %), which were obtained by lipase-catalyzed transesterification. Alcohols were subjected to orthoacetate modification of the Claisen rearrangement. The high stereoselectivity of this reaction led to retention of (E)-configuration of the double bond and complete transfer of chirality from the allyl alcohol to the benzylic position C-3. As a result, chiral γ,δ-unsaturated esters with retained configuration of the stereogenic center were produced. Their hydrolysis and iodolactonization afforded new enantiomers of iodolactones with high or excellent ee (97–99 %). Their configuration at C-4 was a direct result of the configuration at C-3 of the acid subjected to iodolactonization, whereas stereocenters at C-5 and C-6 were formed as a consequence of the reaction mechanism. For most of the synthesized isomers, the predicted configurations were established by X-ray analysis. The presented chemoenzymatic pathway represents a useful strategy that can be applied in the asymmetric synthesis of variety of lactones from 4-arylbut-3-en-2-ols.
a b s t r a c t A series of 20 novel racemic iodo-, bromo-and chlorolactones, possessing b-phenyl-g-lactone or b-phenyl-d-lactone framework, were synthesized from commercially available aromatic aldehydes in convenient five-step syntheses. Some of them showed noticeable cytotoxic effect against two cancer lines, Jurkat (human leukaemia) and D17 (canine osteosarcoma). The highest activity, comparable with carboplatin, was observed for cis-5-(1-iodoethyl)-4-(4 0 -isopropylphenyl)dihydrofuran-2-one against Ju-rkat cell line.
The ester function of ethyl cis-(±)-2-hydroxycyclopentane-1-carboxylate [(±)-1] and ethyl (±)-5-hydroxycyclopent-1-enecarboxylate [(±)-2] was demonstrated to undergo hydrolysis, as a side-reaction, during asymmetric (E > 200) O-acylation with Candida antarctica lipase B (CAL-B) as catalyst and vinyl acetate as acyl donor in t-BuOMe at 30 °C. This competition of acylation and undesirable hydrolysis draws attention to CAL-B-catalyzed non-hydrolytic resolutions where the substrates contain any hydrolysable functions. Enantiomerically enriched cis-2-hydroxycyclopentane-1-carboxylic acid (ee = 90%) and 5-hydroxycyclopent-1-enecarboxylic acid (ee = 47%) were prepared through de novo CAL-B-catalyzed hydrolysis of (±)-1 and (±)-2 with added H2O in t-BuOMe at 30 °C.
A chemoenzymatic asymmetric synthesis of the title compound has been developed using an efficient lipase-catalyzed acylation and a chiral reagent-directed diastereoselective allylation as the key steps for incorporating the stereogenic centers. A cross metathesis was employed to obtain the required E-olefin geometry of the target compound.
For Abstract see ChemInform Abstract in Full Text.
Various terms for the quantitation of a mixture of enantiomers and diastereomers are discussed.
Ionic liquids are now recognized as solvents for use in lipase-catalyzed reactions; however, there still remains a serious drawback in that the rate of reaction in an ionic liquid is slower than that in a conventional organic solvent. To overcome this problem, attempts have been made to evolve phosphonium ionic liquids appropriate for lipase-catalyzed reaction; several types of phosphonium salts have been prepared and their capability evaluated for use as solvent for the lipase-catalyzed reaction. Very rapid lipase PS-catalyzed transesterification of secondary alcohols was obtained when 2-methoxyethyl(tri-n-butyl)phosphonium bis(trifluoromethanesulfonyl)imide ([MEBu3P][NTf2]) was used as solvent, affording the first example of a reaction rate superior to that in diisopropyl ether.
Chiral (R)- and (S)-allylic alcohols with an enantiomeric excess exceeding 99% have been prepared in good to high overall isolated yields through a two-step one-pot chemoenzymatic process based on the palladium-catalyzed Heck reaction of aryl iodides with butenone followed by an enzymatic reduction of the resultant vinylic substitution products. Alcohol dehydrogenases from Lactobacillus brevis and Thermoanaerobacter species were used to attain (R)- and (S)-stereoselectivity, respectively. (c) 2007 Elsevier Ltd. All rights reserved.
A series of homochiral α-tetralols, as well as their respective acetates, has been obtained by esterification of racemic tetralols, using Candida antarctica lipase (CALB—Novozym® 435) as the biocatalyst. This enzyme is shown to be highly efficient for the kinetic resolution of the substrates studied, affording the (+)-tetralols and the (+)-acetates in excellent enantiomeric excess (up to >99%) and very good yields (>40%).
Co-lyophilized Pseudomonas cepacia lipase with peracetylated β-cyclodextrin was immobilized by the sol–gel process. The gel-entrapped lipase/cyclodextrin was prepared by the hydrolysis of methyltrimethoxysilane (MTMS) in the presence of the co-lyophilized lipase with peracetylated β-cyclodextrin prepared with different weight ratios (enzyme to CD). This type of enzyme preparation was subsequently used in the kinetic resolution of a set of secondary alcohols using isopropenyl acetate as an innocuous acyl donor in toluene as the organic medium. The resulting chiral alcohols (substrate) and the corresponding acetates (product) were baseline separated in one analysis without derivatization using gas chromatography on a new chiral stationary phase (CSP) Chirasil-β-Dex containing an undecamethylene spacer (C11-Chirasil-Dex).
A simple and convenient synthesis of optically active alkenyl β-hydroxy sulfides with high enantiomeric excess by CBS-oxazaborolidine-catalyzed borane reduction of the corresponding β-keto sulfides and its application to synthesis of chiral alkenic diols have been established.
Enantiomeric gas chromatography (GC) has demonstrated the potential for a broad array of applications in diverse industries; it remains a dynamic area for analytical chiral separations. This article reviews original research papers published in the period from 2001 to present, dealing with the applications of chiral GC for direct enantiomeric separation of optically active components in natural products, asymmetric synthesis, environmental contaminants and those important to space science, agricultural, food, flavor and fragrance industries. The applications are the grouped by chiral stationary phase (CSP) types and fields of interest.
Controlled racemization of enantiopure phenyl-ring-containing secondary alcohols is achieved in this study using W110A secondary alcohol dehydrogenase from Thermoanaerobacter ethanolicus (W110A TeSADH) and in the presence of the reduced and oxidized forms of its cofactor nicotinamide-adenine dinucleotide. Racemization of both enantiomers of alcohols accepted by W110A TeSADH, not only with low, but also with reasonably high, enantiomeric discrimination is achieved by this method. Furthermore, the high tolerance of TeSADH to organic solvents allows TeSADH-catalyzed racemization to be conducted in media containing up to 50% (v/v) of organic solvents.
Over the last few years, there has been a dramatic increase in the number of publications in the field of lipase-catalyzed reactions performed in common organic solvents, ionic liquids or even non-conventional solvents. A fairly large percentage of these publications have emerged from organic chemists who have recognized the potential of biocatalysis as a viable and popular technique in organic synthesis. Considerable research has shown that reactions catalyzed by enzymes are more selective and efficiently performed than many of their analogues in the organic chemistry laboratory. This review article focuses on some of the recent developments in the rapidly growing field of lipase-catalyzed asymmetric access to enantiomerically pure/enriched compounds. The literature search is dated back to the last five years and covers some comprehensive examples.
Lipase-catalyzed kinetic resolution of racemates is considered to be one of the most fascinating topics in asymmetric catalysis. This review focuses on some of the recent developments in this rapidly growing field demonstrating the versatility of the method in the resolution of racemates. The literature search is dated back to the last five years and covers some comprehensive examples. The main emphasis is on the use of lipases in organic solvents.
The RuCl2(η1-Ph2PCH2CH2OCH3)2(diamine) complexes 2L1–2L5 have been prepared in high yields from the reaction of equimolar amounts of RuCl2(η2-Ph2PCH2CH2OCH3)21 with various kinds of chelating diamines L1–L5 to form five-membered chelates with ruthenium. These novel ruthenium(II) complexes have been used as catalysts in the asymmetric hydrogenation of the prochiral ketone trans-4-phenyl-3-butene-2-one 3, using 2-propanol and different types of cocatalysts. Whereas complexes with achiral diamines afforded the racemic alcohols, complexes with chiral diamines (R,R or S,S) allowed the formation of the corresponding enantiomerically enriched secondary alcohol (S or R) with ee values of 45%. In order to obtain the secondary alcohol with ee of >99%, the kinetic resolution of enantiomerically enriched trans-4-phenyl-3-butene-2-ol 3 was performed in a consecutive approach using either the lipase-catalyzed enantioselective transesterification of the alcohol with isopropenyl acetate as the acyl donor in toluene or the enantioselective hydrolysis of the corresponding acetate in buffer. The determination of the enantiomeric excess (ee) of the resulting enantiomerically enriched secondary alcohols was performed by gas chromatography using heptakis(2,3-di-O-methyl-6-O-tert-butyldimethylsilyl)-β-cyclodextrin as the chiral stationary phase.
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Substituted α,β-unsaturated ketones were selectively reduced to the corresponding allylic alcohols under mild reaction conditions. The allylic alcohols thus obtained were kinetically resolved by lipase catalyzed transesterification in the same pot to afford chiral allylic alcohols in excellent enantioselectivity. Various lipases were screened for this one-pot transesterification of allylic alcohols. Effects of different solvent have also been studied under these conditions. Pseudomonas cepacia lipase immobilized on ceramic particles (PS-C) and on diatomaceous earth (PS-D) catalyzes this transesterification in diisopropyl ether in a highly efficient manner.
Asymmetric Synthesis of (S)-Bis(trifluoromethyl)phenylethanol by Biocatalytic Reduction of Bis(trifluoromethyl)acetophenoneEnantioselective and Diastereoselective Enzyme-catalyzed Dynamic Kinetic Resolution of an Unsaturated KetoneEnzyme-catalysed Synthesis of α-Alkyl-β-hydroxy Ketones and Esters by Isolated KetoreductasesAsymmetric Reduction of Phenyl Ring-containing Ketones Using Xerogel-encapsulated W110A Secondary Alcohol Dehydrogenase from Thermoanaerobacter ethanolicus(R)- and (S)-Enantioselective Diaryl Methanol Synthesis Using Enzymatic Reduction of Diaryl KetonesHighly Enantioselective and Efficient Synthesis of Methyl (R)-o-Chloromandelate, Key Intermediate for Clopidogrel Synthesis, with Recombinant Escherichia coli
The Johnson–Claisen rearrangement of enantiopure allylic alcohols in triethylorthopropionate is the key step for the preparation of chiral molecules with benzylic stereogenic carbon atoms bearing an isopropyl moiety. The synthetic procedure is applied to the preparation of (R)- and (S)-3-methyl-2-phenylbutylamine.
Biocatalytic deracemisation of racemic allylic alcohols by whole cells of Candida parapsilosis ATCC 7330 resulted in the formation of the (R)-enantiomers in high enantiomeric excesses (up to >99%) and isolated yields (up to 79%).
In this chapter, examples are given of the application of highly reactive prochiral ketones as substrates for enzymatic reductions. 3,5-Dioxocarboxylates are polyketide-like compounds that can be used to synthesize all of the possible stereoisomers of the corresponding 1,3-diols by means of regio- and enantioselective enzymatic reduction. The results obtained from an investigation into the usefulness of the resulting hydroxyl ketones and 1,3-diols in organic synthesis led to the development of non-natural functionalized ynones as a starting material for the enzymatic route to enantiopure propargylic alcohols. A broad variety of substituted acetylenic ketones can be reduced enantioselectively by the oxidoreductases Lactobacillus brevis ADH (LBADH), Candida parapsilosis carbonyl reductase (CPCR), horse liver ADH (HLADH) and Thermoanaerobium brockii ADH (TBADH). The resulting propargylic alcohols can be obtained in either enantiomeric form, since (R)- and (S)-specific oxidoreductases can be applied. By varying the size of the substituents, the enantiomeric excess can be tuned, or the enantioselectivity can even be reversed. The obtained highly functionalized enantiopure alcohols are synthetically flexible chiral building blocks that offer new synthetic strategies for target- and diversity-oriented synthesis.
The first asymmetric synthesis of (+)-iso-6-cassine is described. Lipase-catalyzed resolution, enantioselective Overman rearrangement, and diastereoselective intramolecular amidomercuration were used for the installation of the three stereocenters in (+)-iso-6-cassine, and cross-metathesis was employed for the attachment of the side-chain.
Enantiomerically pure 1-arylpropenols 8 have been prepared by resolution of the corresponding racemates, using the lipase formulation Novozyme 435. Deprotonation of the latter alcohols with n-BuLi, followed by derivatization with (t-BuO)2CO, afforded the corresponding carbonates 5. Optimization of the process is presented.
A regioselective acylation of 2′-deoxypyrimidine nucleosides by an acid anhydride in a dry polar aprotic solvent is catalyzed by a lipase from Pseudomonas fluorescenbce.
The title asymmetric reaction is found to convert open chain enones into the corresponding optically active allylic alcohols in high optical (78–98% enantiomeric excess) and chemical (92–100%) yields.
This paper reviews the present state of enzyme-catalyzed acyltransfer reactions, which represent a highly useful method for the transformation of alcoholic and amino functional groups in a chemo-, regio- and enantioselective fashion.
Peracetylated β-cyclodextrin has been employed as a macrocyclic additive to enhance the enantiomeric ratio E and reaction rate in Pseudomonas cepacia lipase (PSL)-catalyzed enantioselective transesterification of 1-(2-furyl)ethanol in organic solvents. The beneficial action of the cyclodextrin used as a regulator of lipase was tentatively interpreted as increasing the conformational flexibility of the enzyme and undergoing host–guest complexation with the product, thereby preventing product inhibition and leading to an enhancement of the enantiomeric ratio E and the reaction rate. The effect of the organic solvent on the present cyclodextrin-mediated enzymatic transesterification has been studied.
A computer program for the treatment of the kinetics of asymmetric catalytic reactions proceeding through two consecutive steps was developed. This allows analysis, simulation and optimization of processes consisting of a sequential (i) asymmetrization of a bifunctional prochiral or meso-compound in a first step, followed by (ii) kinetic resolution of the chiral intermediate in a second step. A case study shows that—provided that the kinetics of both steps are matching—step two may considerably contribute to the asymmetrization reaction.
A new enzymatic method for the resolution of optically active alcohols from racemates is reported. It involves lipase-catalyzed esterification in organic solvents, with acetic, propionic, or butyric anhydrides as acylating agents. Lipase Amano P, from Pseudomonas fluorescens, adsorbed on Celite 577, was employed as stereoselective catalyst. Under these reaction conditions, the enzyme is not chemically modified by the anhydrides. A number of primary and secondary alcohols have been obtained in high optical purity by this procedure.
A novel enzymatic approach to the production of optically active alcohols and esters from racemates is developed. It involves the use of esterase catalyzed transesterifications carried out in biphasic aqueous-organic mixtures. Water-insoluble substrates constitute the organic phase, while the enzyme is located in the aqueous phase. Since the fraction of the latter phase can be made very low, such an arrangement solves the problem of both the competition of an alcohol (the nucleophile) with water in the enzymatic reaction and poor solubility of most organic esters and alcohols in water. By use of porous supports (Sepharose or Chromosorb) filled with aqueous solutions of hog liver carboxyl esterase as a stereoselective catalyst and methyl propionate as a matrix ester, the following optically active alcohols and their propionic esters were produced on a preparative scale: 3-methoxy-1-butanol, 3-methyl-1-pentanol, 3,7-dimethyl-1-octanol, and β-citronellol. To overcome a rather narrow substrate specificity of hog liver carboxyl esterase, a nonspecific lipase from yeast (Candida cylindracea) also was employed as a stereoselective transesterification catalyst. Using an aqueous solution of this enzyme confined to the pores of Chromosorb and tributyrin as a matrix ester, we have prepared gram amounts of the following optically active alcohols and their butyric esters: 2-butanol, sec-phenethyl alcohol, 2-octanol, 1-chloro-2-propanol and 2,3-dichloro-1-propanol (subsequently nonenzymatically converted to optically active propylene oxide and epichlorohydrin, respectively), 6-methyl-5-hepten-2-ol, and 1,2-butanediol.
Yeast lipase and porcine pancreatic lipase have been found to vigorously function in nearly anhydrous organic solvents and catalyze the rections of esterification and transesterification, respectively, in a highly stereoselective manner. With use of these enzymatic processes, a number of optically active alcohols, carboxylic acids, and their esters have been prepared on a gram scale.
The use of 3A or 4A molecular sieves (zeolites) substantially increases the scope of the titanium(IV)-catalyzed asymmetric epoxidation of primary allylic alcohols. Whereas without molecular sieves epoxidations employing only 5 to 10 mol % Ti(O-i-Pr)â generally lead to low conversion or low enantioselectivity, in the presence of molecular sieves such reactions generally lead to high conversion (>95%) and high enantioselectivity (90-95% ee). The epoxidations of 20 primary allylic alcohols are described. Especially noteworthy are the epoxidations of cinnamyl alcohol, 2-tetradecyl-2-propen-1-ol, allyl alcohol, and crotyl alcohol - compounds which heretofore had been considered difficult substrates for asymmetric epoxidation. In the case of allyl alcohol, the use of cumene hydroperoxide substantially increases both the reaction rate and the conversion, even in the absence of molecular sieves. In general, enantioselectivities are slightly depressed (by 1-5% ee) relative employing 50-100 mol % Ti(O-i-Pr)â. The epoxidation of low molecular weight allylic alcohols is especially facilitated and, in conjunction with in situ derivatization, provides for the synthesis of many epoxy alcohol synthons which were previously difficult to obtain. The kinetic resolution of four secondary allylic alcohols with 10 mol % Ti(O-i-Pr)â is also described. The role of molecular sieves in the reaction and the effects of variation in reaction stoichiometry, oxidant, and tartrate are discussed.
Competition experiments and measurements of enantioselectivities were used to develop a simple active-site model (Figure 1) for resolutions of beta-hydroxy-alpha-methylene carbonyl compounds III via acyl transfers mediated by lipase from Pseudomonas sp. (AK). Further experiments were used to test and refine this model with respect to resolutions of allylic, propargylic, homopropargylic, and other alcohols (Tables I-IV, respectively). The model proved extremely reliable for predicting the sense of the asymmetric induction, and the combined data collected in this paper give an indication of what structural features of the substrates can be correlated with high enantioselectivities in these resolutions. Furthermore, the results account for the conspicuous reversal of enantioselectivity previously observed in resolutions of gamma-hydroxy-alpha,beta-unsaturated esters 35. Kinetic resolutions of two substrates (allenol 14 and dienol 9) via asymmetric epoxidations were performed for comparison with the methodology presented in this paper.
The characteristics of the new chiral stationary phase heptakis(2,3-di-O-methyl-6-O-tert-butyldimethylsilyl)-β-cyclodextrin are outlined and compared with permethyl- and perethyl-β-cyclodextrins.
The sensitivity of twenty six microbial lipases towards acetaldehyde (an unavoidable by-product in lipase-catalysed acyl transfer reactions with vinyl esters) was investigated. The sensitivity of an individual enzyme strongly depends on its properties such as microbial source, molecular weight and relative lysine content. Whereas the majority of enzymes (from Pseudomonas, Rhizopus, Chromobacterium, Mucor and Candida antarctica sp.) proved to be remarkably stable, lipases from Candida rugosa and Geotrichum candidum lost most of their activity when exposed to acetaldehyde.
The separation of enantiomers by gas chromatography is performed on chiral stationary phases (CSPs) via hydrogen bonding, coordination and inclusion. Thus, typical chiral selectors are amino acid derivatives, terpene-derived metal coordination compounds and modified cyclodextrins. In Chirasil-type stationary phases the chiral selector is anchored to a polysiloxane backbone improving gas chromatographic performance. The present review article describes the state-of-the-art, scope and limitations, applications and mechanistic considerations at the advent of the millennium incorporating 16 figures and 168 references.
Prochiral aryl and dialkyl ketones were enantioselectively reduced to the corresponding alcohols using whole cells of the white-rot fungus Merulius tremellosus ono991 as a biocatalytic reduction system and ruthenium(II)–amino alcohol and iridium(I)–amino sulfide complexes as metal catalysts in asymmetric transfer hydrogenation. Comparison of the results showed that the corresponding chiral alcohols could be obtained with moderate to high enantioselectivities (e.e.s of up to 98%). The biocatalytic and transfer hydrogenation approaches appear to be complementary. The biocatalytic approach is the most suitable for the enantioselective reduction of chloro-substituted (aryl) ketones, whereas in the reduction of α,β-unsaturated compounds excellent results were obtained using the catalytic hydrogenation protocol.
Complete chirality transfer occurs in the smooth Claisen rearrangement of the trimethylsilyl (TMS) ketene acetals, which were prepared from allylic malonates (R)-1 (R=pentyl, 2-(Z)-pentenyl). These are in turn accessible by enantioselective reduction/esterification or by enzymatic kinetic resolution. The cis configuration in (+)-3 was achieved by highly syn-selective epoxidation of (+)-2, followed by suprafacial 1,2-H migration.
Asymmetric acetylation of racemic 1-(2-furyl)ethanol with the innocuous acyl donor isopropenyl acetate catalyzed by lipases in organic media afforded the chiral alcohol and acetate in high enantiomeric excess (up to 99%). The effect of molecular sieves as well as organic solvents on the kinetic resolution were studied. An effective separation of the enantiomers of both substrate and product was performed using gas chromatography on the chiral stationary phase heptakis-(2,3-di-O-methyl-6-O-tert-butyldimethylsilyl)-beta-cyclodextrin.
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