Racemic Acetate Research Articles

Resolution of Racemic Aryloxy-Propan-2-yl Acetates via Lipase-Catalyzed Hydrolysis: Preparation of Enantiomerically Pure/Enantioenriched Mexiletine Intermediates and Analogs

The lipase kinetic resolution (KR) of aryloxy-propan-2-yl acetates, via hydrolysis, produced enantiomerically pure/enantioenriched mexiletine intermediates and analogs. Racemic acetates rac-1-(2,6-dimethylphenoxy)propan-2-yl acetate (rac-5a), rac-1-(2,4-dimethylphenoxy)propan-2-yl acetate (rac-5b), rac-1-(o-tolyloxy)propan-2-yl acetate (rac-5c) and rac-1-(naphthalen-1-yloxy)propan-2-yl acetate (rac-5d) were used as substrates. A preliminary screening (24 h, phosphate buffer pH 7.0 with 20% acetonitrile as co-solvent, 30 °C and enzyme:substrate ratio of 2:1, m:m) was carried out with twelve lipases using acetate 5a as substrate. Two enzymes stood out in the KR of 5a, the Amano AK lipase from Pseudomonas fluorescens and lipase from Thermomyces lanuginosus (TLL) immobilized on Immobead 150. Under these conditions, both the (R)-1-(2,6-dimethylphenoxy)propan-2-ol [(R)-4a] and the remaining (S)-1-(2,6-dimethylphenoxy)propan-2-yl acetate [(S)-5a] were obtained with enantiomeric excess (ee) > 99%, 50% conversion and enantiomeric ratio (E) > 200. The KR study was expanded to racemic acetates 5b-d, leading to the corresponding chiral remaining acetates with ≥95% ee, and the alcohols 4b-d with ≥98% ee, and conversion values close to 50%. The best conditions for KRs of rac-5b-d involved the use of lipase from P. fluorescens or TLL immobilized on Immobead 150, 24 or 48 h and 30 °C. These intermediates had their absolute configurations determined using 1H NMR spectroscopy (Mosher’s method), showing that the KRs of these acetates obeyed the Kazlauskas’ rule. Molecular docking studies corroborated the experimental results, indicating a preference for the hydrolysis of (R)-5a-d.

Enantioselective bio-deacylation of arylalkyl acetates using tertiary amines as additive under promiscuous conditions

Herein, we describe the impact of the introduction of tertiary amines as additive during the enzymatic kinetic resolution via deacylation of some arylalkyl acetates 1a-8a under promiscuous conditions. Two CAL-B preparations were examined: Novozym®435 and CHIRAZYME® L-2, c.-f. C2, lyo. The influence of the introduction of seven amines is checked: Triethylamine (Et3N), Pyridine, 4-Dimethylaminopyridine (4-DMAP), 1,4-Diazabicyclo[2.2.2]octane (DABCO), Cinchonine, Cinchonidine, Quinine and Quinidine; and that in two organic solvent: diisopropylether (DIPE) and tertiobutylmethyl ether (TBME).Among the examined amines, the use of DABCO as additive recorded the best results in terms of reactivity and selectivity. It was to be highlighted that this additive was reported as an enzyme activator for the first time in the enzymatic kinetic resolution via hydrolysis of racemic acetates under non-aqueous conditions. Both CAL-B preparations showed the same behavior in the presence of the chosen additives during the biodeacylation of the resolved acetates. No direct correlation between the pKa values of several used additives and the CAL-B activation rates has been revealed.An ideal enzymatic kinetic resolution was recorded with the acetate 4a (Conv 50% and E > >200).

1-Hydroxymethyl-7-oxabicyclo[2.2.1]hept-2-ene skeleton in enantiopure form through enzymatic kinetic resolution.

AbstractLipase‐catalysed enantioselective acetylation and deacetylation routes were investigated to prepare 1,5,6‐trisubstituted 7‐oxabicyclo[2.2.1]hept‐2‐ene skeleton in enantio‐pure form. The racemic alcohol (6) used in acetylation reaction was accessed through Diels‐Alder reaction of TBDMS‐protected furfuryl alcohol with maleic anhydride, followed by reduction‐benzylation‐desilylation sequence. After systematic screening of lipases and solvents, Candida antarctica B on acrylic resin in pentane was identified as the best system that gave >98% ee towards the (+) acetate with 40% conversion, in 30 minutes. Absolute stereochemistry of this product was confirmed by X‐ray diffraction analysis of its 3,5‐dinitrobenzoate derivative (9). Enantioselective deacetylation of the racemic acetate of this starting material was then studied with the same set of lipases. After various optimization studies, Candida antarctica B in toluene as the solvent was found to be the most effective that gave 49% conversion with >99% ee towards the (+)‐alcohol (8) at the end of 18 hours.

Chemoenzymatic Synthesis of Luliconazole Mediated by Lipases

A straightforward chemoenzymatic synthesis of luliconazole has been developed. The key step involved the preparation of the enantiomerically pure β‐halohydrin (1S)‐2‐chloro‐1‐(2,4‐dichlorophenyl)‐1‐ethanol through kinetic resolution of the corresponding racemic acetate. This was achieved by a hydrolytic approach, mediated by the lipase from Thermomyces lanuginosus or Novozym 435®. The latter enzyme proved to be a robust biocatalyst for the kinetic resolution, and the (S)‐β‐halohydrin was obtained with high selectivity (ee > 99 %, E > 200) after just 15 min, at 45 °C. It could be reused five times with maintenance of high values of both conversion and enantioselectivity. Subsequently, the (S)‐β‐halohydrin was subjected to a mesylation reaction; the mesylated derivative reacted with 1‐cyanomethylimidazole in the presence of CS2 to give luliconazole in 43 % yield with >99 % ee.

Chemo-enzymatic synthesis of (R)-5-hydroxymethyl-2-isopropyl-5-methylcyclopent-1-en-1-yl trifluoromethylsulfonate, a potential chiral building block for multicyclic terpenoids

The chemo-enzymatic synthesis of (R)-5-hydroxymethyl-2-isopropyl-5-methylcyclopent-1-en-1-yl trifluoromethylsulfonate, a potential chiral building block for polycyclic terpenoids containing a five–membered ring having isopropyl and angular methyl substituents, such as erinacin A and dolatriol, was achieved over 11 steps from ethyl 2-oxocyclopentane-1-carboxylate. The key synthetic precursor for this triflate was ethyl (1S,2R)-2-hydroxycyclopentanecarboxylate (>99% ee), which was prepared by a lipase-catalyzed enantioselective hydrolysis of the corresponding racemic acetate. The antipodal (S)-triflate is expected to be the synthetic intermediate for another group of terpenoids involving hamigeran B and stolonidiol. Enantiomerically pure (1R,2S)-hydroxyester (>99% ee) was prepared in high yield using the asymmetric reduction of the oxoester with commercially available carbonyl reductase, “Chiralscreen® OH”-E001.

Fungal mediated kinetic resolution of racemic acetates to (R)-alcohols using Fusarium proliferatum

Fungal mediated kinetic resolution of seven acyclic/aromatic acetates was achieved using Fusarium proliferatum to furnish (R)-alcohols in high enantiomeric excess (>95%). The kinetic resolution was established as one-pot two-step de-esterification/oxidation biocatalytic process. Further, the preparative scale synthesis of (R)-(+)-1-phenylethanol was accomplished through de-esterification/oxidation of (±)-1-phenylethyl acetate using the whole cell of F. proliferatum NCIM 1105.

Facial preparation of magnetic lipase as efficient biocatalyst to resolute esters enantioselectively

Magnetic lipase was prepared by a facial and cost-effective method. Lipase from Pseudomonase cepacia was covalently linked to Fe3O4 nanoparticles, which were produced by co-precipitating Fe2+and Fe3+ ions in ammonia solution and subsequent coating with 3,4-dihydroxylaldehyde. Magnetic Fe3O4 nanoparticles modified with 3,4-dihydroxylaldehyde bonded lipase efficiently(47 mg/g). The resulting magnetic-lipase is active(0.68 μmol·min–1·mg–1) and enantioselective(e.e. of the product >98%) in the hydrolysis of racemic 1-phenylethyl acetate. Furthermore, as a heterogeneous catalyst, the magnetic-lipase can be magnetically recycled, and a retained activity of 48% was obtained even after 6 cycles.

Apples as enantiospecific bioreagents in the hydrolysis of racemic esters and oxygenation of alcohols obtained during the process

Biotransformation carried out by apples (<em>Malus silvestris</em>) resulted in enantiospecific hydrolysis of racemic acetates, the derivatives of secondary aromatic-aliphatic or terpenic alcohols. The alcohols are oxygenated to ketones (reversible reaction). The differences in the rate of the hydrolysis of enantiomeric esters enable isolation of pure, unreacted R-acetates.

Enzyme-catalyzed kinetic resolution of N-Boc-trans-3-hydroxy-4-phenylpyrrolidine

AbstractThe first enzyme-catalyzed kinetic resolution of tert-butyl-3-hydroxy-4-phenylpyrrolidine-1-carboxylate is presented. Enzyme, solvent and temperature optimization resulted in a new resolution method with E = 40 enantioselectivity. The acetate derivative of the (+)-(3S,4R) enantiomer formed while the (−)-(3R,4S) isomer remained intact. Very good enantioselectivities (E > 200) were achieved in the enzyme-catalyzed alcoholysis of the racemic acetate in i-propanol and t-butanol where the (+)-(3S,4R) enantiomer was prepared in pure form (ee > 99.7%). Absolute configuration of the (−)-(3R,4S)-enantiomer was determined by single crystal X-ray diffraction method.

A green route to enantioenriched (S)-arylalkyl carbinols by deracemization via combined lipase alkaline-hydrolysis/Mitsunobu esterification

Herein we report results of the chemoenzymatic deracemization of a range of secondary benzylic acetates 1a–9a via a sequence of hydrolysis with CAL-B lipase in non-conventional media, combined with esterification of the recovered alcohol according to the Mitsunobu protocol following an enzymatic kinetic resolution (KR). The KR of racemic acetates 1a–9a via an enzymatic hydrolysis, with CAL-B lipase and Na2CO3, in non-aqueous media was optimized and gave high selectivities (E≫200) at good conversions (C >49%) for all of the substrates studied. This method competes well with the traditional one performed in a phosphate buffer solution. The deracemization using Mitsunobu inversion gave the (S)-acetates in moderate to excellent enantiomeric excess 75%<ee<99%, in acceptable isolated yields 70%<yield<89%, and with some variations according to the acetate structure.

Green methodology for enzymatic hydrolysis of acetates in non-aqueous media via carbonate salts

Herein we report a new approach to enantiomerically enriched acetates using a lipase-catalyzed hydrolysis in non-aqueous media by alkaline carbonate salts. The use of sodium carbonate in the enzymatic hydrolysis with Candida antarctica lipase B (CAL-B) of racemic acetates shows a large enhancement of the reactivity and selectivity of this lipase. The role of the carbonate salts, the amount and the nature of the alkaline earth metal on the efficiency of this new pathway are investigated. The enzymatic kinetic resolution of acetates 1a–9a, by enzymatic-carbonate hydrolysis under mild conditions is described. In all cases, the resulting alcohols and remaining acetates were obtained in high ee values (up to >99%) while the selectivities reached E>500.

Lipase‐Catalyzed Kinetic Resolution of 2‐Phenylethanol Derivatives and Chiral Oxa‐Pictet–Spengler Reaction as the Key Steps in the Synthesis of Enantiomerically Pure Tricyclic Amines

AbstractA series of 5,6,7,8,9,10‐hexahydro‐5,9‐epoxybenzocycloocten‐6‐amines have been synthesized and pharmacologically evaluated in receptor binding studies (σ1, σ2, NMDA, κ, and μ receptors). The first key step of the synthesis was a chiral oxa‐Pictet–Spengler reaction with enantiomerically pure 2‐phenylethanol derivatives (S)‐ and (R)‐14. After transformation of the dimethylamide 18 into the ester 19, the tricyclic system 20 was established by Dieckmann cyclization reaction. Finally, amino moieties were introduced diastereoselectively into the 6‐position by reductive amination and SN2 reaction. The enantiomerically pure building blocks (S)‐14 (&gt;99.0 % ee) and (R)‐14 (98.4 % ee) were synthesized by enantioselective acetylation of racemic alcohol 14 catalyzed by Pseudomonas fluorescens lipase and enantioselective hydrolysis of racemic acetate 16 catalyzed by Candida rugosa lipase. The absolute configurations were determined by theoretical calculations of the specific optical rotation and CD spectra, as well as by X‐ray crystal structure analysis of (S,S,S)‐25 by the three‐beam interference method. Although enantiomerically pure dimethylamines (S,R,S)‐ and (R,S,R)‐29 with an axial amino moiety showed low‐to‐moderate affinity towards σ1 and σ2 receptors, a promising σ2 affinity (Ki = 2.9 μM) was found for (S,S,S)‐24 with an equatorially oriented dimethylamino group.

ChemInform Abstract: Combination of Novozym 435‐Catalyzed Hydrolysis and Mitsunobu Reaction for Production of (R)‐γ‐Lactones.

AbstractWith a view to obtaining the naturally occurring (R)‐lactones, the resolution of racemic acetates, e.g. (I), is combined with a Mitsunobu reaction for the inversion of obtained (S)‐alcohols, cf.

ChemInform Abstract: A Simple Total Synthesis of Both Enantiomers of γ-Amino-β- hydroxybutanoic Acid (GABOB) by Enzymatic Kinetic Resolution of Cyanohydrin Acetates

Abstract Both ( R )-and ( S )-3-cyano-e-hydroxy-propionic acid ethyl ester have been obtained via enzymatic kinetic resolution of the racemic acetate using lipase from Candida cylindracea and lipase from porcine pancreas respectively. Their selective reduction affords the corresponding ( R )-and ( S )-GABOB with high optical purity.

ChemInform Abstract: Enzymatic Preparation of Enantiomerically Pure and Selectively Protected 1,2- and 1,3-Diols.

The optically pure, selectively protected 1,2- and 1,3-diol derivatives (R)- and (S)-1–8 have been prepared by enzymatic hydrolysis of their racemic acetates and chloroacetates in the presence of ester hydrolase from Pseudomonas fluorescens(SAM-1).

ChemInform Abstract: Highly Diastereoselective Inter-Esterification Reactions Involving a Racemic Acetate and a Racemic Carboxylic Acid Catalyzed by Lipase Enzymes.

ChemInform Abstract: Highly Diastereoselective Inter-Esterification Reactions Involving a Racemic Acetate and a Racemic Carboxylic Acid Catalyzed by Lipase Enzymes.

ChemInform Abstract: Simple Preparation of the Optically Active γ-Hydroxy Vinylstannanes Using Lipase-Catalyzed Hydrolysis.

An efficient optical resolution of γ-hydroxy vinylstannanes was achieved by the lipase-catalyzed enantioselective hydrolysis of the corresponding racemic acetates using lipase PS(Pseudomonas sp.).

ChemInform Abstract: Resolution of N‐Protected Amino Alcohols by Porcine Pancreatic Lipase.

AbstractThe resolution of 2‐amino alcohols (II), protected by urethane‐type groups, either via porcine pancreatic lipase (PPL) hydrolysis of the corresponding racemic acetates (I) or via PPL‐catalyzed transesterification of racemic alcohols (II) is studied.

CaL-B a highly selective biocatalyst for the kinetic resolution of furylbenzthiazole-2-yl-ethanols and acetates

A highly stereoselective enzymatic kinetic resolution of novel various substituted racemic furylbenzthiazole-2-yl-ethanols and their acetates has been developed. Both processes, the enzymatic acylation of the racemic alcohols and the enzymatic methanolysis of racemic acetates yielded highly enantiomerically enriched (ee >98%) resolution product, when CaL-B was used as a biocatalyst in acetonitrile. The absolute configuration of the obtained ( R)-(+)-1-(5-(4-chlorobenzo[d]thiazol-2-yl)furan-2-yl)ethanol was determined by a detailed 1H NMR study of rac- and (+)-1-(5-(4-chlorobenzo[ d]thiazol-2-yl)furan-2-yl)ethanol Mosher derivatives.

ChemInform Abstract: A Concise Synthesis of Homochiral Sedamines and Related Alkaloids. A New Reductive Application of Jacobsen′s Catalyst.

Abstract Two methods for the generation of both enantiomers of sedamine [1-methyl-2-(2-phenyl-2-hydroxy-1-ethyl)piperidine] in high optical purity have been elaborated. The first utilises the lipase-mediated kinetic resolution of racemic acetates and the second involves the NaBH 4 mediated reduction of ketones catalysed by Jacobsen's catalyst. Some related applications of these reactions are also disclosed.