Preparation of (R)- and (S)-6-hydroxybuspirone by enzymatic resolution or hydroxylation

6-Hydroxybuspirone is an active metabolite of the antianxiety drug buspirone. The (R)- and (S)-enantiomers of 6-hydroxybuspirone were prepared using an enzymatic resolution process. l-Amino acid acylase from Aspergillus melleus (Amano Acylase 30000) was used to hydrolyze racemic 6-acetoxybuspirone to (S)-6-hydroxybuspirone in 95% ee after 45% conversion. The remaining (R)-6-acetoxybuspirone with 88% ee was converted to (R)-6-hydroxybuspirone by acid hydrolysis. The ee of both enantiomers could be improved to 99% by crystallization as a metastable polymorph. (S)-6-Hydroxybuspirone was also obtained in 88% ee and 14.5% yield by hydroxylation of buspirone using Streptomyces antibioticus ATCC 14890.     

Resolution of 1-cyclohexylethylamine via diastereomeric salt formation with enantiopure 2-phenylacetic acids

The resolution of 1-cyclohexylethylamine 1 with enantiopure 2-phenylacetic acids via diastereomeric salt formation was investigated. (R)-2-Methoxy-2-phenylacetic acid 3 and the (S)-2-phenylpropionic acid 5 were found to be efficient resolving agents for obtaining the single enantiomer (S)-1 as the correspondingly less-soluble diastereomeric salt (resolution efficiency = 48% and 52%, respectively).     

Lipase catalyzed chemo-enzymatic synthesis of propranolol: A newer enzymatic approach

The biocatalytic processes are greener and safer alternatives for synthesis of drug and drug intermediates. This study reports one such approach of chemo-enzymatic synthesis of propranolol, a β-adrenergic receptor blocker. A green synthetic route was employed for synthesis of propranolol using enzymatic kinetic resolution. Racemic mixture of secondary alcohol [1-chloro-3-(naphthalen-1-yloxy)propan-2-ol] (RS)-5 was synthesized chemically in two step reaction and further its enzymatic kinetic resolution was carried out by using lipase to synthesize enantiomeric forms (R)-5 and S-(6) of propranolol. The kinetic resolution of (RS)-5 involves the transesterification of secondary racemic alcohol in which vinyl acetate is used as acyl donor. Initially, we screened commercially available lipases for kinetic resolution and of all the screened lipases Addzyme 001 showed the best results. The several reaction parameters such as organic solvent, acyl donor, temperature, reaction time and enzyme concentration were optimized to improve rate of reaction and to achieve maximum enantioselectivity. Addzyme 001 at 40 mg shows the maximum conversion rate of 49% using cyclohexane as the organic solvent, vinyl acetate as the acyl donor and it was found that the reaction yield was higher for (R)-5 along with the (S)-6 (eep = 98%, ees = 97%) at 40 °C in 48 h. Further, the treatment of (R)-5 with isopropyl amine resulted into formation of (S)-propranolol eep = 98%, and overall yield 29% independently. To synthesize (R)-propranolol, S-(6) acetate was produced enzymatically and was further deacylated by chemical hydrolysis for the production of (R)-propranolol. This study reports newer approach for synthesis of (R) and (S) propranolol using chemoenzymatic route.     

A convenient resolution of racemic lavandulol through lipase-catalyzed acylation with succinic anhydride: simple preparation of enantiomerically pure (R)-lavandulol

(R)- and (S)-lavandulol and their esters are important compounds in perfumery and have recently become significant in pheromone research. (R)-Lavandulol and its esters, as well as the esters of (S)-lavandulol have been identified as sex and aggregation pheromones in two mealybugs, in thrips and in weevils. We report a convenient resolution of racemic lavandulol through lipase-catalyzed acylation with succinic anhydride. This method does not require tedious chromatographic separation and is particularly suitable for the preparation of enantiomerically pure (R)-lavandulol with 98% ee in one resolution cycle. The (S)-lavandulol with 90% ee can be obtained by a second resolution cycle.     

Resolution approaches to enantiomers of 4-formyl[2.2]paracyclophane

Three techniques for the resolution of 4-formyl[2.2]paracyclophane were examined with the separation of the diastereomeric derivatives with (R)- and (S)-2-hydrazino-2-oxo-N-(1-phenylethyl)acetamide followed by their hydrolysis being found to be the most efficient, allowing (Rp)- and (Sp)-4-formyl[2.2]paracyclophanes to be obtained with 99.5% and 98.7% ee, respectively.     

‘Easy-on,easy-off’ resolution of chiral 1-phenylethylamine catalyzed by Candida antarctica lipase B

An ‘easy-on, easy-off’ process for the effective resolution of (±)-1-phenylethylamine was designed using the lipase B of Candida antarctica. This two step lipase-catalyzed process for the resolution of a chiral arylalkylamine involves a high-conversion enantioselective condensation of (R)-(+)-1-phenylethylamine with capric acid (conversion 99%, <24 h), followed by the hydrolysis of the corresponding synthesized (R)-(+)-amide (conversion 98%, 48 h). As a result, this efficient enzymatic process yields both (R)- and (S)-enantiomers of 1-phenylethylamine in high enantiomeric purity.     

Enantioselective synthesis of (S)-timolol via kinetic resolution of terminal epoxides and dihydroxylation of allylamines

An efficient enantioselective synthesis of (S)-timolol has been described using chiral Co-salen-catalyzed kinetic resolution of less expensive (±)-epichlorohydrin with 3-hydroxy-4-(N-morpholino)-1,2,5-thiadiazole in good overall yield (55%) and excellent enantioselectivity (98%). Synthesis of (S)-timolol has also been achieved using hydrolytic kinetic resolution as well as asymmetric dihydroxylation routes in 90% ee and 56% ee, respectively.     

Resolution of 3-methyl-3-phospholene 1-oxides by molecular complex formation with TADDOL derivatives

The antipodes of 1-phenyl-3-methyl-3-phospholene 1-oxide 1a were separated in good yield and in high enantiomeric excess (∼99% ee) by resolution via formation of diastereomeric complexes with (4R,5R)-(−)- and (4S,5S)-(+)-4,5-bis(diphenylhydroxymethyl)-2,2-dimethyldioxolane 2 (TADDOL) or (−)-(2R,3R)-α,α,α′,α′-tetraphenyl-1,4-dioxaspiro[4.5]decan-2,3-dimethanol 3. The method was also suitable for the resolution of the 1-ethoxy-3-phospholene derivative 1b, suggesting that our novel procedure may be of general value, both for the resolution of chiral phosphine oxides and phosphinates.     

Enzyme-catalysed improved resolution of (RS)-4-cyano-4-(3,4-dimethoxyphenyl)-4-isopropyl-1-butanol

Resolutions of (RS)-4-cyano-4-(3,4-dimethoxyphenyl)-4-isopropyl-1-butanol 1 using various enzymes were performed. Among them, Pseudomonas fluorescens resolved it with moderate stereoselectivity (E=13) and reacted faster with the (S)-enantiomer. To optimize enzyme-catalysed reaction conditions for the resolution, the effect of solvents and additives was studied. In n-hexane:ethyl acetate (9:1), both reaction rate and selectivity were high. When pyridine, potassium carbonate and molecular sieves were used as additives, the enantiomeric excess of the (R)-enantiomer was 99, 99 and 98% at 52–60% conversion, respectively. However, in diisopropyl ether, the enantiomeric excess of unreacted alcohol (R)-1 was up to 99% at 70% conversion without additives.     

Practical chemical and enzymatic technologies for (S)-1,4-benzodioxan-2-carboxypiperizine intermediate in the synthesis of (S)-doxazosin mesylate

(S)-1,4-Benzodioxan-2-carboxypiperazine (S)-2, the key chiral intermediate for the synthesis of (S)-doxazosin, was prepared utilizing two approaches: (i) enzymatic resolution of ethyl 1,4-benzodioxan-2-carboxylate with an esterase (Serratia) followed by amide formation; (ii) direct resolution of 1,4-benzodioxan-2-carboxypiperazine 2 with d-tartaric acid. An efficient process for the conversion of (S)-2 to (S)-doxazosin mesylate was developed (80% yield, 99.9% e.e.).     

Lipase-mediated kinetic resolution of (RS)-1-bromo-3-[4-(2-methoxy-ethyl)-phenoxy]-propan-2-ol to (R)-1-bromo-3-(4-(2-methoxyethyl) phenoxy) propan-2-yl acetate

A novel biocatalytic method for the enantioselective synthesis of (R)-bromo-3-[4-(2-methoxy-ethyl) phenoxy]-2-propanol [(R)-BMEPP], a precursor for the synthesis of (S)-metoprolol, an anti hypertensive drug is described. We have developed kinetic resolution of rac-BMEPP by transesterification using Candida rugosa lipase and vinyl acetate as the acyl donor affording the product with excellent conversion (49%) and ee (>99%). Various reaction parameters (source of enzyme, reaction media, and concentration of substrate and acylating agent) for the enzymatic kinetic resolution have been reported.     

Enantioselective enzymatic acylation of 1-(3′-bromophenyl)ethylamine

An efficient biocatalytic process has been developed for the resolution of 1-(3′-bromophenyl)ethylamine (RS)-1 by way of enantioselective lipase-mediated (R)-selective acylation with ethyl 2-methoxyacetate to afford (S)-amine (S)-1 and (R)-2″-methoxyacetamide ((R)-2) in 91–95% and 90–92% isolated yield, respectively, and both with >99% ee.     

Solvent dependency though not solvate formation in the derivative–derivative resolution of N-formylphenylalanine

The efficiency of the resolution of N-formylphenylalanine was remarkably improved using (S)-(+)-2-benzylaminobutanol resolving agent in acetone. The efficiency of the resolution strongly depended on the quality of the solvent. Nevertheless, solvate formation did not occur during the process. The nature of the solvent-dependence was studied. The solid-melt binary phase diagram of the diastereomeric salts formed during the resolution by (S)-(+)-2-benzylaminobutanol was measured and discussed. It was recognized that the (S)-(+)-benzylaminobutanol (S)-(+)-N-formylphenylalanine salt exists in two polymorphic modifications.The effect of structurally related chiral and achiral auxiliary reagents in the above resolution was also studied. Thus, (S)-(+)-2-benzylaminobutanol was applied together with an (R)-(+)-1-phenylethylamine auxiliary resolving agent and benzylamine was used as a half-equivalent achiral basic reagent in a Pope–Peachey type resolution of N-formylphenylalanine by (S)-(+)-2-benzylaminobutanol. The results are compared to those obtained by the structurally related (R)-(+)-1-phenylethylamine chiral auxiliary.     

A green resolution–separation process for aliphatic secondary alcohols

In order to obtain both enantiomers of aliphatic secondary alcohols via a greener method, the four-step resolution–separation process involving lipase-catalyzed enantioselective esterification and hydrolysis as well as two separation procedures both via heterogeneous azeotropic distillation was developed. (S)-2-Pentanol (ee = 98.6%), (R)-2-pentanol (ee >99%), (S)-2-octanol (ee = 98.2%), and (R)-2-octanol (ee = 98.5%) were all produced in high purity (>98%) and high yield (>90%). In addition to the two model substrates, this method could also be applied to the resolution of other aliphatic secondary alcohols.     

Lipase-mediated kinetic resolution of rigid clofibrate analogues with lipid-modifying activity

The lipase-catalysed kinetic resolution of methyl esters of (±)-5-chloro-2,3-dihydro-1-benzofuran-2-carboxylic acid, (±)-6-chloro-2,3-dihydro-4H-1-benzopyran-2-carboxylic acid, and (±)-6-chloro-2,3-dihydro-4H-1-benzopyran-3-carboxylic acid, rigid analogues of clofibrate, was effected with fair to moderate enantioselectivities (E=1.0–4.8), enantiomeric excesses of up to 86% and workable reaction rates. Enantiomerically pure (R)- and (S)-5-chloro-2,3-dihydro-1-benzofuran-2-carboxylic acids were obtained by fractional crystallisation of the diastereomeric salts of the corresponding racemic acid with (+)- and (−)-amphetamine from ethanol; the absolute configuration of the products were established by chemical correlation.     

Desymmetrisation of (4R,5S)-4,5-diphenylimidazolidine-2-thione using pentafluorophenyl active esters

(4R,5S)-4,5-Diphenylimidazolidine-2-thione is efficiently desymmetrised by stereorandom deprotonation with NaHMDS, followed by kinetic resolution of the resulting racemic intermediate with an enantiomerically pure pentafluorophenyl active ester. The levels of diastereocontrol were found to be excellent (86-92% de at ∼30% conversion). This desymmetrisation reaction is an example of a masked resolution.     

Chemoenzymatic synthesis of (5S)- and (5R)-hydroxymethyl-3,5-dimethyl-4-(methoxymethoxy)-5H-thiophen-2-one: a precursor of thiolactomycin and determination of its absolute configuration

A convenient enantioselective synthesis of (5S)- and (5R)-hydroxymethyl-3,5-dimethyl-4-(methoxymethoxy)-5H-thiophen-2-one, a key intermediate in the synthesis of thiolactomycin has been carried out by a Carica papaya lipase-mediated resolution protocol to provide (R)-2 in a 94% ee and its enantiomer (S)-9 in a 98% ee. The absolute configuration at the C-5 position has been determined by Mosher’s method.     

An improved synthesis of (S)-(+)- and (R)-(−)-[2.2]paracyclophane-4-carboxylic acid

Treatment of 4-bromo[2.2]paracyclophane with n-butyllithium followed by CO₂ produced [2.2]paracyclophane-4-carboxylic acid, 1. Both enantiomeric forms [63% of (+)-(S)-1 and 48% of (−)-(R)-1] were obtained by resolution via the corresponding diastereomeric α-(p-nitrophenylethylammonium salts.     

Resolution of P-Sterogenic 1-Phenylphosphin-2-en-4-one 1-Oxide into Two Enantiomers by (R,R)-TADDOL and Conformational Diversity of the Phosphinenone Ring and TADDOL in the Crystal State

The resolution of racemic 1-phenylphosphin-2-en-4-one 1-oxide (2), was achieved through the fractional crystallization of its diastereomeric complexes with (4R,5R)-(−)-2,2-dimethyl -α,α,α′,α′-tetraphenyl-dioxolan-4,5-dimethanol (R,R-TADDOL) followed by the liberation of the individual enantiomers of 2 by flash chromatography on silica gel columns. The resolution process furnished the two enantiomers of 2 of 99.1 and 99.9% e.e. at isolated yields of 62 and 59% (counted for the single enantiomer), respectively. The absolute configurations of the two enantiomers were established by means of X-ray crystallography of their diastereomerically pure complexes, i.e., (R)-2•R,R)-TADDOL and (S)-2•(R,R)-TADDOL. The structural analysis revealed that in the (R)-2•(R,R)-TADDOL complex, the P-phenyl substituent occupied a pseudoequatorial position, whereas in (S)-2•(R,R)-TADDOL, it appeared in both the pseudoequatorial and the pseudoaxial positions in four symmetrically independent molecules. Concurrent conformational changes of the TADDOL molecules were best described by the observed changes of a pseudo-torsional CO...OC angle that could be considered as a possible measure of TADDOL conformation in its receptor–ligand complexes. The structural analysis of the (R,R)-TADDOL molecule revealed that efficiency of this compound for use as an effective resolving factor comes from its ability to flexibly fit its structure to both enantiomers of a ligand molecule, producing a rare case of resolution for both pure enantiomers with one chiral separating agent. The resolved (R)-2 was used to assign the absolute configuration of a recently described (−)-1-phenylphosphin-2-en-4-one 1-sulfide by chemical correlation. In addition, an attempted stereoretentive reduction of (R)-2 by PhSiH₃ at 60 °C revealed an unexpectedly low barrier for P-inversion in 1-phenylphosphin-2-en-4-one.     

An efficient method for the resolution of rac-VANOL by molecular complexation with (1S,2S)-(+)-diaminocyclohexane

An efficient and convenient process has been developed for the resolution of VANOL using commercially available (1S,2S)-(+)-diaminocyclohexane as the resolving reagent, with (R)- and (S)-VANOL being isolated in 86% and 74% yields, respectively. The resolving reagent was recovered in 91% yield and could be reused without any decrease in its efficiency. The X-ray structural analysis of a molecular crystal consisting of (R)-VANOL and (1S,2S)-(+)-diaminocyclohexane revealed that hydrogen bonding interactions between the functional groups of the host and guest molecules dominated the stereochemistry of the guest in the molecular complex.