Vinyl Butanoate Research Articles

Green Chemo-Enzymatic Protocols for the Synthesis of Enantiopure β-Blockers (S)-Esmolol and (S)-Penbutolol

The β-blocker (S)-esmolol, has been synthesized in 97% enantiomeric excess and 26% total yield in a four-step synthesis, with a transesterification step of the racemic chlorohydrin methyl 3-(4-(3-chloro-2-hydroxypropoxy)phenyl)propanoate, catalysed by lipase B from Candida antarctica from Syncozymes, Shanghai, China. The β-blocker (S)-penbutolol, has been synthesized in 99% enantiomeric excess and in 22% total yield. The transesterification step of the racemic chlorohydrin 1-chloro-3-(2-cyclopentylphenoxy)propan-2-ol was catalyzed by the same lipase as used for the esmolol building block. We have used different bases for the deprotonation step of the starting phenols, and vinyl butanoate as the acyl donor in the transesterification reactions. The reaction times for the kinetic resolution steps catalysed by the lipase varied from 23 to 48 h, and were run at 30–38 °C. Specific rotation values confirmed the absolute configuration of the enantiopure drugs, however, an earlier report of the specific rotation value of (S)-esmolol is not consistent with our measured specific rotation values, and we here claim that our data are correct. Compared to the previously reported syntheses of these two enantiopure drugs, we have replaced toluene or dichloromethane with acetonitrile, and replaced the flammable acetyl chloride with lithium chloride. We have also reduced the amount of epichlorohydrin and bases, and identified dimeric byproducts in order to obtain higher yields.

Improved racemate resolution of pentan-2-ol and trans-(Z)-cyclooct-5-ene-1,2-diol by lipase catalysis

Lipases are important catalysts in chiral synthesis due to their wide substrate recognition combined with a high stereoselectivity. We demonstrate here that the state, free or immobilized, of Candida antarctica lipase B (CaLB) affects enantioselectivity and also alters the temperature dependancy of the enzyme. This indicates that CaLB undergoes various conformations induced by its interaction with the different immobilization supports studied. Molecular imprinting experiments, using immobilized enzyme co-dried with mimic substrate molecules, enhanced the enantiomeric ratio two-fold or three-fold, depending on the immobilization support. The structure of the acyl donor has a pronounced effect on CaLB catalyzed resolution, due to the proximity of the acyl and alcohol moieties during catalysis. When the acylation of pentan-2-ol was examined, we found that the 3C methyl propanoate donor afforded the highest resolution. Trans-(Z)-cyclooct-5-en-1,2-diol was used as a model racemic substrate to study the ability of lipase to catalyze the resolution of difunctionalized compounds. There was a clear enhancement in the enantiomer selectivity of the biotransformation of the diol when vinyl butanoate is used as the acyl donor. The conversion and enantiomeric excess of (1R,2R)-monoacetates were enhanced, using immobilized CaLB, when the chain length of the donors increased from C2 to C4.

Highly enantioselective CALB-catalyzed kinetic resolution of building blocks for β-blocker atenolol

Both enantiomers of 4-(3-chloro-2-hydroxypropoxy)phenyl)acetamide has been synthesized in 98.5–99% enantiomeric excess by use of lipase B from Candida antarctica as catalyst. The R-alcohol is a building block for the cardioselective β-blocker (S)-atenolol ((S)-2-(4-(2-hydroxy-3-(isopropylamino)propoxy)phenyl)acetamide. Performing kinetic resolutions of 3-chloro-1-phenoxy-2-propanol and 3-bromo-1-phenoxy-2-propanol with vinyl butanoate as acyl donor and the same CALB enzyme, but a different preparation, showed higher E-values than previously reported.

Lipase Catalysed Kinetic Resolution of Stiripentol

Kinetic resolution of rac-Stiripentol, catalysed by lipase A from Candida antarctica by esterification with vinyl butanoate was performed with an E-value of 24. This allowed isolation of (3S)-Stiripentol with an ee of 86 % and the corresponding (3R)-butanoate with an ee of 87 %. Enzymatic hydrolysis of the ester product gave (3R)-Stiripentol with 94 % ee.

Advances in the kinetic and dynamic kinetic resolution of piperazine-2-carboxylic acid derivatives with Candida antarctica lipase A; structural requirements for enantioselective N-acylation

The kinetic resolution of piperazine-2-carboxylic acid was studied as its N-4and N-1-Bocpiperazine-2-carboxylic acid methyl esters, rac-1 and -2, respectively. Lipase A from Candida antarctica (CAL-A) catalyzed highly enantioselective (E>200 for rac-1 and 200 for rac-2) Nacylation of both compounds with 2,2,2-trifluoroethyl butanoate in TBME. Aldehyde-based dynamic kinetic resolution of rac-1 with vinyl butanoate in acetonitrile gave up to 75% product yield with S-absolute configuration in 48 hours. The present results together with literature data suggest that CAL-A –catalyzed N-acylation is enhanced in terms of reaction rate or enantioselectivity when an electron rich structure, such as carboxylic ester or aromatic ring, is attached to the asymmetric center next to the secondary ring nitrogen.

Chemoenzymatic synthesis of enantiopure 1-phenyl-2-haloethanols and their esters

Several secondary haloalcohols have been resolved by esterification catalyzed by lipases A and B from Candida antarctica (CALA and CALB, respectively). Immobilized CALB (Novozym 435) gave better selectivities and faster reaction rates than CALA (Novozyme 735) with all of the substrates. Vinyl butanoate was the favoured acyl donor compared to vinyl acetate due to remarkably faster reactions. The alcohols (R)-2a, (R)-2c and the butanoates (S)-3a-c have been isolated with 98–99% enantiomeric excess (ee) in good yields.

Chemical modification of olive pomace by various esters and silane

AbstractThe olive pomace was modified chemically to improve the interface between the polymer matrix and the cellulosic fillers. The modification was done using various ester types having the same nature, however, with different chain lengths and one silane. Before the surface treatment, the olive pomace was extracted with acetone to remove contaminants on the surface, using Soxhlet apparatus. The transesterification of olive pomace with the different ester components, i.e., vinyl acetate, vinyl propanoate, and vinyl butanoate, and the condensation reaction with dichlorodimethylsilane was confirmed by Fourier transform infrared (FTIR) analysis. Moreover, the treatment of olive pomace with vinyl acetate improves the thermal stability and the sample records higher onset temperature of degradation as measured by thermogravimetric analysis (TGA). The results obtained indicated also that the reaction between the hydroxyl groups of waste flour and the acetyl, propionyl, pivalyl, and silane groups have occurred. The modified wood flours exhibited a decrease in the hydrophilicity as supported by the lower moisture content. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010

Kinetic resolution of fluorinated propargyl alcohols by lipase-catalyzed enantioselective transesterification

In order to obtain optically active fluorinated propargyl alcohols, a lipase-catalyzed kinetic resolution has been carried out. The effect of lipase types, organic solvents, reaction temperature, and acyl donors was examined in the lipase-catalyzed transesterification of 1,1,1-trifluoro-4-phenyl-3-butyn-2-ol. Various enantiomerically pure fluorinated propargyl alcohols have been successfully prepared in good enantiomeric excess (>84%) by Novozym 435-catalyzed transesterification with vinyl butanoate at 60 °C in n-hexane. In some cases, the enantiomeric purities were excellent (>99% ee).

Enzymatic preparation of acylated derivatives of silybin in organic and ionic liquid media and evaluation of their antitumor proliferative activity

Biocatalytic preparation of acylated derivatives of silybin using several acyl donors (free fatty acids or their esters), catalyzed by immobilized Candida antarctica lipase B, was performed in various organic solvents as well as in imidazolium-based ionic liquids containing either or anions. Total conversion of silybin was achieved in acetone using short-chain acyl donors (vinyl butanoate) at a 10:1 molar ratio of acyl donor to silybin. The enzymatic process in ionic liquids depended strongly on the alkyl chain length of the cation as well the anion used. Higher conversion yields (up to 75.8%) and reaction rates (up to 0.31 mmol h−1 g−1 biocatalyst) were obtained in the as compared with - containing ionic liquids. The amounts of silybin ester formed in a one-step biocatalytic process were high (>40 g L−1) in both reaction media. The antiproliferative effect of acylated silybin derivatives on the growth of K562 human leukemia cells was estimated and compared with that of silybin.

Insect pest control agents: Novel chiral butanoate esters (juvenogens)

During the investigation of ester derivatives (juvenogens, biochemically activated insect hormonogenic compounds) of biologically active alcohols with potential application in insect pest control, a need for availability of all existing stereoisomers of ethyl N-{2-[4-(2-butanoyloxycyclohexyl)methyl]phenoxy}ethyl carbamate occurred. They were synthesized from their chiral precursors, the corresponding stereoisomers of 2-(4-methoxybenzyl)cyclohexyl butanoate, by removing their protecting group (methyl), and by subsequent condensation of the aromatic hydroxyl moiety with ethyl N-(2-bromoethyl) carbamate. The requested enantiomers of 2-(4-methoxybenzyl)cyclohexyl butanoate were obtained by a Candida antarctica lipase-mediated transesterification and chiral resolution of the respective racemic cis- and trans-isomers of 2-(4-methoxybenzyl)cyclohexanol either directly or after a subsequent chemical esterification of the chiral precursor. In this synthesis, two convenient butanoic acid activating esters, vinyl butanoate and 2,2,2-trifluoroethyl butanoate, were employed, and the chiral precursors in the synthesis of the target molecules were obtained in 41–48% yields (i.e., 82–96% conversion), and with enantiomeric purity ee = 96–98%, respectively. The enantiomeric purity of the products was determined by chiral HPLC analysis, and their absolute configuration was assigned on the basis of analyzing the 1H and 19F NMR spectra of their diastereoisomeric Mosher acid (3,3,3-trifluoromethyl-2-methoxy-2-phenylpropanoic acid) esters.

Synthesis of optically pure halogenated phenyl 2-hydroxypropanones by lipase-catalyzed enantioselective transesterification

Lipase-catalyzed enantioselective transesterification has been performed to obtain chiral halogenated phenyl 2-hydroxypropanones, key intermediates of pharmaceuticals. Effects of organic solvents, reaction temperature, and substrate concentration were also investigated in Novozym 435-catalyzed transesterification of 1-(2,4-difluorophenyl)-2-hydroxypropanone with vinyl butanoate. Optically pure halogenated phenyl 2-hydroxypropanones and their esters have been successfully prepared in good yields (>40%) and excellent enantiopurities (>99%) by Novozym 435-catalyzed transesterification at 30 °C in hexane.

Resolution of 2-phenoxy-1-propanols through the enantioselective acylation mediated by Achromobacter sp. lipase as biocatalyst

Enantioselective acylation employing vinyl alkanoates as acyl donors was exploited for the resolution of 2-(substituted phenoxy)-1-propanols carrying different substituents on the benzene ring using Achromobacter sp. lipase. These primary alcohols with an oxygen atom at the stereocenter, were resolved with moderate to good enantioselectivity, based on the enantiomeric ratio E (up to 27), through acylation with vinyl butanoate in diisopropyl ether, after the examination of potential factors affecting the reaction such as organic solvents and acyl donors. Using this procedure, enantiomerically enriched (R)-2-(4-chlorophenoxy)-1-propanol was prepared in 97% e.e. and 33% yield in a gram-scale reaction.

Room Temperature Ionic Liquids in the Kinetic Resolution of Adrenaline‐Type Aminoethanols by Burkholderia cepacia Lipase under Normal and Microwave Conditions

AbstractThe lipase PS‐C II (lipase from Burkholderia cepacia immobilized on ceramic particles)‐catalyzed acylations of N‐acylated 2‐amino‐1‐phenylethanol (rac‐1) and N‐acylated norphenylephrine (rac‐2) have been studied in imidazolium‐ and pyridinium‐based ionic liquids, in tert‐butyl methyl ether (TBME) and in their mixtures. Enzymatic chemo‐ and enantioselectivities in the presence of hydrophobic EMIM⋅NTf2 and hydrophilic EMIM⋅BF4 have been studied in more detail using high substrate concentrations. The preparative‐scale kinetic resolution of rac‐1 and rac‐2 (both 0.45 M) with vinyl butanoate in the mixture of EMIM⋅NTf2 with TBME (2 : 1) took 9 and 27 hours, respectively. Microwave‐assisted acylation of rac‐1 and rac‐2 in the presence of EMIM⋅NTf2 proceeded similarly to the reactions under normal conditions.

Immobilization does not influence the enantioselectivity of CAL-B catalyzed kinetic resolution of secondary alcohols

Decreasing enantioselectivity ( E-value) by increasing conversion has been observed in transesterification reactions of secondary alcohols catalyzed by a pure protein formulation of lipase B from Candida antarctica (Novozym 525 F). Addition of a range of enantiopure alcohols caused a temporary increase in selectivity of the transesterification reaction of 3-chloro-1-phenoxy-2-propanol with vinyl butanoate. The corresponding immobilized lipase B, (Novozym 435) showed a similar relationship between the E-value and degree of conversion.

Practical Resolution of 3‐Phenyl‐2H‐azirine‐2‐methanol at Very Low Temperature by Using Lipase Immobilized on Porous Ceramic and Optimized Acylating Agent.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Aldehyde-based racemization in the dynamic kinetic resolution of N-heterocyclic α-amino esters using Candida antarctica lipase A

The present research introduces approaches for the dynamic kinetic resolution of the methyl esters of proline and pipecolic acid. As the result, a method was developed which is based on the acylation of the secondary amino group of the amino esters with vinyl butanoate by Candida antarctica lipase A. In the optimized method, acetaldehyde as a racemizing agent is released in situ from vinyl butanoate in the presence of triethylamine, allowing ca. 90% of the racemic proline and 70% of the pipecolic acid methyl esters to be acylated in the forms of highly enantiopure (ee=97%) butanamides with the S-absolute configurations.

Lipase-catalyzed kinetic resolution of 7-, 8- and 12-membered alicyclic β-amino esters and N-hydroxymethyl-β-lactam enantiomers

Enzymatic kinetic resolutions of methyl cis-2-aminocycloheptane-, 2-aminocyclooctane- and 2-aminocyclododecanecarboxylates with Candida antarctica lipase A in diisopropyl ether ( E >200) and of the corresponding N-hydroxymethyl-β-lactams with Pseudomonas cepacia lipase in dry acetone ( E from 27 to >200) has been performed with 2,2,2-trifluoroethyl butanoate as the best acyl donor, with both enantiomers being obtained. trans-13-Hydroxymethyl-13-azabicyclo[10.2.0]tetradecan-14-one was resolved with vinyl butanoate and Candida antarctica lipase B ( E=26) in acetone.

Practical Resolution of 3-Phenyl-2H-azirine-2-methanol at Very Low Temperature by Using Lipase Immobilized on Porous Ceramic and Optimized Acylating Agent

Abstract A synthetically useful primary alcohol, 3-phenyl-2H-azirine-2-methanol, was resolved efficiently by a reaction at −40 °C with a lipase immobilized on the porous ceramic (Toyonite) and vinyl butanoate in ether (E value of 130 and TTN/h value of 7800).

Preparation of novel phenylfuran-based cyanohydrin esters: lipase-catalysed kinetic and dynamic resolution

A series of novel ( R)-5-phenylfuran-2-yl cyanomethyl butanoates were prepared by Pseudomonas cepacia lipase-catalysed dynamic kinetic resolution in toluene. The method exploits a basic resin both for the racemization and formation of phenylfuran-based cyanohydrins and for the decomposition of acetone cyanohydrin in one-pot with enzymatic enantioselective acylation using vinyl butanoate. The lipase-catalysed methanolysis of racemic 5-phenylfuran-2-yl cyanomethyl butanoates in toluene with E ≫100 was shown to be usable when the corresponding ( S)-butanoates are needed. Candida antarctica lipase A provided racemic cyanohydrin butanoates with quantitative chemical yields under mild conditions.

Resolution of 2-aryloxy-1-propanols via lipase-catalyzed enantioselective acylation in organic media

2-Aryloxy-1-propanols, primary alcohols with an oxygen atom at the stereocenter, were resolved with good to high enantioselectivity by acylation with vinyl butanoate mediated by Pseudomonas sp. lipase in di- iso-propyl ether. Potential factors affecting the enantioselectivity of the enzymatic acylation were examined: solvents, acyl donors and temperature. Using this enantioselective acylation procedure, enantiomerically pure ( R)-2-(4-chlorophenoxy)-1-propanol was prepared on a gram scale.