Dynamic kinetic resolution of racemic gamma-aryl-delta-oxoesters. Enantioselective synthesis of 3-arylpiperidines

Cyclodehydration of racemic gamma-aryl-delta-oxoesters with (R)- or (S)-phenylglycinol stereoselectively affords bicyclic delta-lactams, in a process that involves a dynamic kinetic resolution. Subsequent reduction of these lactams leads to enantiopure 3-arylpiperidines. Starting from racemic aldehyde esters, this short sequence has been applied to the synthesis of (R)-3-phenylpiperidine and the antipsychotic drug (-)-3-PPP (an (S)-3-arylpiperidine), whereas starting from racemic ketone esters enantiopure cis-2-alkyl-3-arylpiperidines are prepared.     

Dynamic kinetic resolution via dual-function catalysis of modified cinchona alkaloids: asymmetric synthesis of alpha-hydroxy carboxylic acids

A highly enantioselective catalytic transformation of racemic alpha-hydroxy acids to optically active alpha-hydroxy acids is reported. A new procedure was developed for the condensation of racemic alpha-hydroxy acids with trichloromethyl chloroformate (diphosgene) at room temperature in the presence of activated charcoal to form 5-substituted-1,3-dioxolane-2,4-diones in 90-100% yield. An efficient dynamic kinetic resolution of 5-aryl dioxolanediones was realized via a modified cinchona alkaloid-catalyzed alcoholytic opening of the dioxolanedione ring, generating a variety of optically active alpha-hydroxy esters in 91-96% ee and 61-85% chemical yield. In this dynamic kinetic resolution, the modified cinchona alkaloid was found to serve dual catalytic roles, mediating both the rapid racemization of the 5-aryl dioxolanediones and the enantioselective alcoholytic ring opening of the 5-aryl dioxolanediones. Consequently, both enantiomers of the 5-aryl dioxolanediones were converted to highly enantiomerically enriched aromatic alpha-hydroxy esters in yields (61-85%), far exceeding the maximum of 50% for a normal kinetic resolution. This development not only represents an expansion of the scope of asymmetric acyl-transfer catalysis of synthetic catalysts but also provides a new approach for the development of efficient chemical dynamic kinetic resolutions promoted by a single catalyst. 5-Alkyl dioxolanediones were resolved by a conventional but highly enantioselective kinetic resolution to provide alpha-hydroxy acids and esters in high optical purity and good yields.     

Synthesis,characterization and assignment of the absolute configuration of 4,4-dimethyl-5-oxo-tetrahydrofuran-3-carboxylic acid and its esters: a combined experimental and theoretical investigation

The synthesis of a new, optically active, paraconic-acid derivative 4,4-dimethyl-5-oxo-tetrahydrofuran-3-carboxylic acid and its methyl and ethyl esters was accomplished by a procedure involving the kinetic enzymatic resolution of the racemic ethyl ester. Thus, ethyl (+)-4,4-dimethyl-5-oxo-tetrahydrofuran-3-carboxylate, derived from a ring fission, was isolated at low conversion values, with 94% ee using HLAP as the enzymatic source. The corresponding enantiomerically pure acid was also obtained.The absolute configuration of the products was determined based on the results of an extensive computational study of the specific rotation of the acid and methyl ester. Four different wavelengths were considered and comparisons with the sign and magnitude of the corresponding experimental observations were carried out. Solvent effects on both the conformational space and the specific rotation were included in the computations using the Polarizable Continuum Model.The assigned absolute configuration of the title compounds is (R)-(+), which is in agreement with a tentative experimental assignment based on an analysis of the circular dichroism curves.     

Enzymatic kinetic resolution and chemoenzymatic dynamic kinetic resolution of delta-hydroxy esters. An efficient route to chiral delta-lactones

A successful kinetic resolution of a racemic mixture of delta-hydroxy esters 1 was obtained via lipase-catalyzed transesterification (E value up to 360). The combination of the enzymatic kinetic resolution with a ruthenium-catalyzed alcohol racemization led to an efficient dynamic kinetic resolution (ee up to 99% and conversion up to 92%). The synthetic utility of this procedure was illustrated by the practical syntheses of delta-lactones (R)-6-methyl- and (R)-6-ethyl-tetrahydropyran-2-one and (S)-5-(tert-butyldimethylsiloxy)heptanal. The former are important building blocks in the synthesis of natural products and biologically active compounds, and the latter is a key intermediate in the synthesis of widely used commercial insecticide Spinosyn A.     

Lipases A and B from Candida antarctica in the enantioselective acylation of ethyl 3-heteroaryl-3-hydroxypropanoates: aspects on the preparation and enantiopreference

The preparative scale kinetic resolution of racemic ethyl 2- and 3-furyl- and 2- and 3-thienyl-3-hydroxypropanoates has been performed by Candida antarctica lipases A and B with vinyl esters. A study based on the present work together with the literature has been carried out in terms of lipase enantiopreference and substrate structure. We also discuss the excellent behavior of the lipase A in O-acylations of secondary alcohols with respect to enantiopreference.     

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.     

Dynamic Kinetic Resolution of 2,3-Dihydrobenzo[b]furans: Chemoenzymatic Synthesis of Analgesic Agent BRL 37959

An efficient asymmetric synthesis of (S)-2,3-dihydrobenzo[b]furan-3-carboxylic acid (8?a) and (S)-5-chloro-2,3-dihydrobenzo[b]furan-3-carboxylic acid (8?b) was established. Key to the success was the highly stereoselective enzymatic kinetic resolution of the corresponding methyl or ethyl esters that was further developed into a dynamic process. As a reliable and fast tool for analysing the enantiomeric excess, HPLC coupled with a CD detector was utilized. The route was completed by a Friedel-Crafts acylation of ethyl (S)-5-chloro-2,3-dihydrobenzo[b]furan-3-carboxylate (7?c) followed by saponification leading to (S)-5-chloro-2,3-dihydrobenzo[b]furan-3-carboxylic acid (2), an analgesic agent.     

Enantioseparation of Tropic Acid and Its Esters by CEKC Using Sulfated β-Cyclodextrin as a Chiral Selector

Capillary electrokinetic chromatography was successfully applied to the enantioseparation of tropic acid and its four alkyl esters (methyl, ethyl, propyl and butyl), with the same chiral center, Separation was with sulfated β-cyclodextrin (4%, m/v) containing 20 mM phosphate buffer at pH 3.0 as background electrolyte at 20 °C. The results showed that, besides hydrogen-bonding interactions between these compounds with sulfated β-CD, for tropic acid and its methyl ester the steric hindrance effect was also an important factor. However, for the other esters (ethyl, propyl and butyl), the hydrophobicity effect was higher.     

Enantioseparation of Tropic Acid and Its Esters by CEKC Using Sulfated β-Cyclodextrin as a Chiral Selector

Capillary electrokinetic chromatography was successfully applied to the enantioseparation of tropic acid and its four alkyl esters (methyl, ethyl, propyl and butyl), with the same chiral center, Separation was with sulfated β-cyclodextrin (4%, m/v) containing 20 mM phosphate buffer at pH 3.0 as background electrolyte at 20 °C. The results showed that, besides hydrogen-bonding interactions between these compounds with sulfated β-CD, for tropic acid and its methyl ester the steric hindrance effect was also an important factor. However, for the other esters (ethyl, propyl and butyl), the hydrophobicity effect was higher.

     

Convenient enzymatic resolution of alcohols using highly reactive, nonharmful acyl donors, 1-ethoxyvinyl esters

1-Ethoxyvinyl esters 3, a new type of acyl donors for enzymatic resolution of racemic alcohols, were disclosed to be superior to the contemporary major reagents, vinyl esters 1 and isopropenyl esters 2. Three features of 3 are noticeable: (1) 3 generates ethyl acetate as a single coproduct, which does not affect any enzymes, while acetaldehyde liberated from 1 deactivates some kinds of lipases. (2) The reactivity of 3 was not less than that of 1 and much higher than that of 2, and the optical purity of the products was as high as that of 1 and 2. Especially, it was generally observed that 3 showed higher reactivity than 1 for reactions using Candida rugosa lipases, one of the most commonly employed lipases, having liberal applicability to substrates but sensitive to acetaldehyde. Twelve examples of the kinetic resolution of racemic secondary alcohols (5 and 10) and one desymmetrization of meso-alcohol 7 were presented employing the acetate 3a or the octanoate 3b and four types of lipases. (3) A one-pot procedure for the preparation of 3 from the corresponding carboxylic acid and the subsequent enzymatic resolution of alcohols, which has not been reported using 1 or 2, was elucidated. The chemical and optical yields of the products by this procedure were similar to those obtained using isolated 3.     

Kinetic Resolution of (R,S)-2-Butanol Using Enzymatic Synthesis of Esters

Kinetic resolution of (R,S)-2-butanol using enzymatic synthesis of esters has been studied. (R,S)-2-Butanol is commonly found as a racemic mixture, and the products of its esterification are racemic mixtures too. This work is of great significance in the field of the enzymatic kinetic resolution due to the little information found in literature about the resolution of (R,S)-2-butanol as pure compound. So, this article is a contribution about the enzymatic resolution of (R,S)-2-butanol. The reaction here studied is the esterification/transesterification of (R,S)-2-butanol in organic media (n-hexane) using as biocatalyst the lipase Novozym 435?. The main target of this study is to analyze the influence of certain variables in this reaction. Some of these variables are acyl donor (acids and esters), concentration of substrates, enzyme/substrate ratio, and temperature. The main conclusions of this study are the positive effect of higher substrates concentration (1.5 M) and larger amount of enzyme (13.8 g mol(-1) substrate) on kinetic resolution rate but not a very noticeable effect on enantiomeric excesses. The longer the carboxylic acid chain is, the better results are obtained. Besides to achieve a satisfactory kinetic resolution, it is recommendable to select reaction times (180 min) at which the highest substrate enantiomeric excess is reached (~60%). The temperature has not an appreciable influence on the resolution in the range studied (40-60 °C). When an ester (vinyl acetate) is used as acyl donor, the resolution shows better results than when using a carboxylic acid as acyl donor (ee(s)?~90% at 90 min). Moreover, Michaelis-Menten parameters, v(max) and K(M), were determined, 0.04 mol l(-1) min(-1) and 0.41 mol l(-1), respectively.     

Catalytic hydrogenation of carboxamides and esters by well-defined Cp*Ru complexes bearing a protic amine ligand

A novel catalytic method for the straightforward hydrogenation of carboxamides and esters to primary alcohols has been developed. Chiral modification in the ligand sphere of the well-defined Cp*Ru catalyst molecule opens up a new possibility for the development of an enantioselective hydrogenation of racemic substrates via dynamic kinetic resolution.     

(R)-(+)-N-methylbenzoguanidine ((R)-NMBG) catalyzed kinetic resolution of racemic secondary benzylic alcohols with free carboxylic acids by asymmetric esterification

(R)-(+)-N-Methylbenzoguanidine ((R)-NMBG) was found to function as an efficient acyl-transfer catalyst for the kinetic resolution of racemic secondary benzylic alcohols in the presence of achiral carboxylic acids and pivalic anhydride. The use of a tertiary amine in this reaction is not necessary to attain good chemical yields of the products. It was determined that diphenylacetic acid could be employed as the most suitable acyl donor for achieving a high enantioselectivity for the kinetic resolution of the racemic secondary benzylic alcohols having normal aliphatic alkyl chains at the C-1 positions. On the other hand, a less-hindered carboxylic acid, such as 3-phenylpropanoic acid, functioned as a better acyl donor for the kinetic resolution of racemic secondary benzylic alcohols having branched aliphatic alkyl chains at the C-1 positions.     

Lipase-catalyzed acylation in a continuous down-flow fixed-bed reactor

The kinetic resolution of racemic 1-phenylethanol with ethyl acetate was investigated in a down-flow fixed-bed reactor operated in a continuous mode mainly at the molar ratio of 1: 3 in 400 mL toluene at 70°C. The catalytic activity of the immobilized lipase was studied by: (i) changing the flow rates, (ii) utilizing different substrate concentrations, (iii) applying step changes using ethyl acetate, ethyl benzene, acetic acid, acetophenone etc., (iv) investigating the inhibitory effect of either the desired or the stoichiometric products (R)-1-phenylethyl acetate and ethanol, respectively), (v) elucidating the effect of water on the activity and stability of the immobilized lipase. The residence time distribution and the reactor hydrodynamics were also discussed along with kinetic modelling. The results were linked to the one-pot reactions.     

Catalytic dynamic kinetic resolutions with N-heterocyclic carbenes: asymmetric synthesis of highly substituted β-lactones

New DKR type: An N-heterocyclic carbene (NHC)-catalyzed dynamic kinetic resolution of racemic α-substituted β-keto esters has been developed. This method relies on the epimerization of an NHC-enol intermediate before subsequent aldol/acylation events. Highly substituted β-lactones are produced in good yield with good to excellent selectivities (see scheme).     

Asymmetric reduction of alpha-(trimethylsilyl)methyl-beta-ketosulfoxide with DIBAL under basic conditions

The reaction of the alpha-carbanion of p-tolyl 2-(trimethylsilyl)ethyl sulfoxide with esters followed by reduction with DIBAL gave alpha-(trimethylsilyl)methyl-beta-hydroxysulfoxides with high stereoselectivity. The stereoselective reaction was demonstrated to proceed through a dynamic kinetic resolution pathway via a six-membered cyclic transition state involving Si-O interaction. These reactions provide a convenient route for the synthesis of optically pure allylic alcohols.     

Lipase-catalyzed kinetic resolution of Baylis–Hillman products

Lipase-catalyzed kinetic resolution of the various Baylis–Hillman products, α-methylene-β-hydroxy compounds, were examined. When lipase PS was used as a biocatalyst in acetonitrile, transesterification of racemic ethyl 3-hydroxy-2-methylenebutanoate or 3-hydroxy-2-methylenepentanoate proceeded in a practical enantiomeric excess. The resolution by hydrolysis of the acetate derivatives was also tried. In contrast, in case of racemic ethyl 3-acetoxy-2-methylenepentanoate, under the conditions using lipase AK, the E value of the resolution was >321.     

One-pot synthesis of optically active allyl esters via lipase-vanadium combo catalysis

The combination of vanadium-oxo compounds (3 or 4) with a lipase produced the regio- and enantioconvergent transformation of racemic allyl alcohols (1 or 2) into optically active allyl esters. In this system, the vanadium compounds catalyzed the continuous racemization of the alcohols along with the transposition of the hydroxyl group, while the lipase effected the chemo- and enantioselective esterification to achieve the dynamic kinetic resolution.     

Alternative approach to the synthesis of optically active β-keto sulfoxides by furylhydroperoxides enantioselective oxidations

Enantiomerically enriched β-keto sulfoxides are obtainable by an alternative method to the classical reaction of the enantiomerically pure α-sulfinyl anion with esters or by Andersen's synthesis, through Sharpless modified kinetic resolution of racemic β-keto sulfoxides. High e.e.s are achieved by combining asymmetric oxidation and kinetic resolution using furylhydroperoxides as oxidants.     

Acylative kinetic resolution of racemic aromatic β-hydroxy esters catalyzed by chiral nucleophilic N-(1-arylethyl)benzoguanidines

An efficient acylative kinetic resolution of racemic aromatic β-hydroxy esters with cyclohexanecarboxylic anhydride was achieved using newly designed (R)-N-methylbenzoguanidine ((R)-NMBG) derivatives. A series of (R)-NMBG derivatives was synthesized by modifying the original (R)-NMBG catalyst with the introduction of branched N-substituents containing a stereogenic center, and their catalytic performance was evaluated. (R,R)-N-(1-(β-1-Naphthyl)ethyl)benzoguanidine [(R,R)-NβNpEtBG] was found to function as an efficient acyl transfer catalyst for the reaction of a broad variety of substrates, regardless of the substituent type and substitution pattern.