Lipase-catalyzed Enantioselective Acetylation Research Articles

Chemoenzymatic synthesis of 2,6-disubstituted tetrahydropyrans with high σ1 receptor affinity, antitumor and analgesic activity.

1,3-Dioxanes 1 and cyclohexanes 2 bearing a phenyl ring and an aminoethyl moiety in 1,3-relationship to each other represent highly potent σ1 receptor antagonists. In order to increase the chemical stability of the acetalic 1,3-dioxanes 1 and the polarity of the cyclohexanes 2, tetrahydropyran derivatives 3 equipped with the same substituents were designed, synthesized and pharmacologically evaluated. The key step of the synthesis was a lipase-catalyzed enantioselective acetylation of the alcohol (R)-5 leading finally to enantiomerically pure test compounds 3a-g. With respect to σ1 receptor affinity and selectivity over a broad range of related (σ2, PCP binding site) and further targets, the enantiomeric benzylamines 3a and cyclohexylmethylamines 3b represent the most promising drug candidates of this series. However, the eudismic ratio for σ1 binding is only in the range of 2.5-3.3. Classical molecular dynamics (MD) simulations confirmed the same binding pose for both the tetrahydropyran 3 and cyclohexane derivatives 2at the σ1 receptor, according to which: i) the protonated amino moiety of (2S,6R)-3a engages the same key polar interactions with Glu172 (ionic) and Phe107 (π-cation), ii) the lipophilic parts of (2S,6R)-3a are hosted in three hydrophobic regions of the σ1 receptor, and iii) the O-atom of the tetrahydropyran derivatives 3 does not show a relevant interaction with the σ1 receptor. Further in silico evidences obtained by the application of free energy perturbation and steered MD techniques fully supported the experimentally observed difference in receptor/ligand affinities. Tetrahydropyrans 3 require a lower dissociative force peak than cyclohexane analogs 2. Enantiomeric benzylamines 3a and cyclohexylmethylamines 3b were able to inhibit the growth of the androgen negative human prostate cancer cell line DU145. The cyclohexylmethylamine (2S,6R)-3b showed the highest σ1 affinity (Ki(σ1)=0.95nM) and the highest analgesic activity invivo (67%).

Exploiting sequential lipase-catalyzed reactions to achieve enantiomerically pure chiral primary alcohols

The lipase-catalyzed enantioselective acetylation of benzofused cycloalkane-containing primary alcohols with vinyl acetate was performed and allowed the isolation of enantiopure alcohols.

ChemInform Abstract: Synthesis of Optically Active α-Hydroxy Acids by Kinetic Resolution Through Lipase-Catalyzed Enantioselective Acetylation.

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Facile preparation of methyl 5-aryl-4-hydroxyhex-2( E)-enoate, chiral synthon of bisabolane-type sesquiterpenes, based on lipase-catalyzed kinetic resolution and rearrangement of an aryl group

The lipase-catalyzed enantioselective acetylation of racemic methyl (4 S ∗,5 S ∗)-4-aryl-5-hydroxyhex-2( E)-enoates 1a– h was performed and efficient resolutions were achieved ( E >400) by using CAL-B. After brosylation of the obtained optically active 1a– h, solvolysis of brosylates 13a– h afforded the corresponding methyl (4 S ∗,5 S ∗)-5-aryl-4-hydroxyhex-2( E)-enoates 3a– h (26–94% yield). The yields of 3a and 3c on the solvolysis of the corresponding 13 were 92% and 40%, respectively, while solvolysis of the corresponding tosylate was reported at 70% and 17%, respectively. This procedure is a facile and practical route to the synthesis of bioactive and optically active bisabolane-type sesquiterpenes.

Chemoenzymatic synthesis of (+)-totarol, (+)-podototarin, (+)-sempervirol, and (+)-jolkinolides E and D

The enzymatic resolution products [(1 R,4a R,8a R)-1,2,3,4,4a,5,6,7,8,8a-decahydro-5,5,8a-trimethyl-2-oxo- trans-naphthalene-1-methanol-2-ethylene acetal (8a R)- 7 (98% ee) and {acetate of (1 S,4a S,8a S)-1,2,3,4,4a,5,6,7,8,8a-decahydro-5,5,8a-trimethyl-2-oxo- trans-naphthalene-1-methanol-2-ethylene acetal} (8a S)- 9 (>99% ee)] obtained by the lipase-catalyzed enantioselective acetylation of (±)- 7 in the presence of vinyl acetate as an acyl donor were converted to the α,β-unsaturated ketones (8a R)- 6 and (8a S)- 6, respectively. Concise syntheses of (+)-totarol 1, (+)-podototarin 2 and (+)-sempervirol 3 were achieved based on Michael reactions between (8a S)- 6 and the appropriate β-keto ester followed by aldol condensation. The first chiral syntheses of (+)-jolkinolides E 4 and D 5 were achieved from (5 R,10 R,12 R)-12-hydroxypodocarpa-8(14)-en-13-one 15 derived from (8a R)- 6.

First chiral synthesis of the N-terminal amino acid congener of nikkomycin Z based on lipase-catalyzed enantioselective acetylation of a primary alcohol possessing two stereogenic centers

A stereoselective synthesis of a versatile chiral synthon possessing two stereogenic centers, (2 S,3 S)-3-[2-(5-benzyloxypyridyl)]-2-methyl-1,3-propane diol 12 (>99% ee), was achieved by using a chemo-enzymatic method. The conversion of (2 S,3 S)- 12 to the homochiral intermediate (2 S,3 S,4 S)-2-benzyloxycarbonylamino-4-[2-(5-benzyloxypyridyl)]-4- tert-butyldimethylsilyloxy-3-methylbutanoic acid 2 corresponding to the N-terminal amino acid congener of nikkomycin Z 1 is described.

Resolution of Racemic Rhododendrol by Lipase-Catalyzed Enantioselective Acetylation

Both (R)- and (S)-enantiomers of rhododendrol were prepared in high enantiomeric exess by lipase from Pseudomonas cepacia (Amano PS)-catalyzed acetylation of racemic 1 with vinyl acetate at room temperature. Especially, in the case of using acetonitrile as the solvent, by-products 4 and 5 were minimized.

Resolution of racemic 3-aryloxy-1-nitrooxypropan-2-ols by lipase-catalyzed enantioselective acetylation

Both ( R)- and ( S)-enantiomers of 3-aryloxy-1-nitrooxypropan-2-ols ( R)-(−)- 1, ( S)-(+)- 2 were prepared in high enantiomeric excess by lipase from Pseudomonas cepacia (Amano PS) or Pseudomonas fluorescens (Amano AK)-catalyzed acetylation of racemic alcohols 1a– g with vinyl acetate in n-hexane at 4 or 22°C. The enantioselectivity of this transformation was dependent on the substitution pattern of the aryl ring with E-values ranging from 31 to 111.

Lipase-catalyzed kinetic resolution of Z-configured homoallylic alcohols

Racemic Z homoallylic alcohols were prepared by the BuSnCl 3-catalyzed addition of aldehydes to 1-(tributylstannyl)-2-butene. These alcohols were resolved for the first time by lipase-catalyzed enantioselective acetylation in up to 98% enantiomeric purity.

Synthesis of Optically Active α-Hydroxy Acids by Kinetic Resolution Through Lipase-Catalyzed Enantioselective Acetylation

Synthesis of Optically Active α-Hydroxy Acids by Kinetic Resolution Through Lipase-Catalyzed Enantioselective Acetylation

Synthesis of Optically Active α-Hydroxy Acids by Kinetic Resolution Through Lipase-Catalyzed Enantioselective Acetylation

The lipase-catalyzed acetylation of a broad spectrum of racemic 2-hydroxy acids 1 to their 2-acetoxy acids 2 was shown to proceed with high enantioselectivity. Thus, the microbial lipases, in particular from Candidaantarctica and Burkholderiaspecies, are convenient biocatalysts for the synthesis of optically active 2-hydroxy acids in excellent enantioselectivity (ee values up to > 99%). The absolute configurations of the 2-hydroxy acids 1 were assigned by comparison of the gas-chromatographic data with that of literature-known reference compounds, or by means of the exciton-coupled circular dichroism method (ECCD) on their bichromophoric 2-naphthoate 9-anthrylmethyl derivatives 3. These results establish that (S)-2-hydroxy acids 1 were preferentially acetylated by microbial lipases.

Chiral Pyridines: Optical Resolution of 1-(2-Pyridyl)- and 1-[6-(2,2'-Bipyridyl)]ethanols by Lipase-Catalyzed Enantioselective Acetylation.

The resolution of racemic 1-(2-pyridyl)ethanols 2a-n, including the 2,2'-bipyridyl and isoquinolyl derivatives, by lipase-catalyzed asymmetric acetylation with vinyl acetate is reported. The reactions were carried out in diisopropyl ether at either room temperature or 60 degrees C using Candida antarctica lipase (CAL) to give (R)-acetate and unreacted (S)-alcohol with excellent enantiomeric purities in good yields. The reaction rate was relatively slow at room temperature for substrates bearing an sp(3)-type carbon at the 6-position on the pyridine ring, such as 2c, 2d, and 2e, and for those bearing 1-hydroxypropyl and allyl groups at the 2-position on the pyridine ring, such as 2l and 2m. In such cases, a higher temperature was required. Thus, when the reaction was conducted at 60 degrees C, it was accelerated 3- to 7-fold without losing the high enantiospecificity. However, the reaction of homoallylic alcohol 2n was not complete, even when the reaction was continued for a longer period of time at 60 degrees C. This enzymatic resolution can be used practically in a wide range of reaction scales from 10 mg to 10 g or more. This catalyst can be used repeatedly with a 5-10% loss of the initial activity with each use.

Kinetic resolution of hydroxy vinylsilanes by lipase-catalyzed enantioselective acetylation

The lipase-catalyzed enantioselective acetylation of racemic hydroxy vinylsilanes 1 with vinyl acetate in methyl tert-butyl ether afforded the optically active hydroxy vinylsilanes 1 and the corresponding acetoxy vinylsilanes 2 in excellent enantiomeric excess (ee 93–99%).

Biocatalytic approaches to both enantiomers of [formula omitted

Both enantiomers of (2R ∗,3S ∗)-2- allyloxy-3,4,5,6-tetrahydro-2H- pyran-3-ol , a precursor of chiral auxiliary for asymmetric addition of organometallics, and its analog, (2 S,3 S)-2-ethoxy-3,4,5,6-tetrahydro-2 H-pyral-3-ol were prepared by biocatalytic optical resolutions. Lipase-catalyzed enantioselective acetylation of the racemate in organic solvent worked well with a high enantioselectivity. Pseudomonas cepacia lipase was most effective (E = 11–17) for the kinetic resolution. Under the optimized condition, the products, (2 R,3 S)-2-allyloxy-3,4,5,6-tetrahydro-2 H-pyran-3-ol and (2 S,3 S)-2-ethoxy analog with more than 97% e.e. were obtained in 31–45% yield with 52–62% conversion. The enantiomer, (2 S,3 R)-2-allyloxy compound was secured by two ways. The repetition of the lipase-catalyzed acetylation on partially enantiomerically enriched substrate afforded the acetate with a high e.e. (97%). A newly developed double resolution procedure in one-pot reaction was also successful. In this case, the apparent E value via two steps became as high as 71.

Synthesis of (9R)- and (9S)-10-fluorodecan-9-olide (fluoro-phoracantholide I) first lipase-catalyzed enantioselective esterification of β-fluoroalcohols

Synthesis of both enantiomers of fluoro-phoracantholide I, namely (9 S )-10-fluorodecan-9-olide ( (9S)-(−)- 1 and (9 R )-10-fluorodecan-9-olide (9R)-(+)- 1 , has been achieved through lipase-catalyzed enantioselective acetylation of methyl 10-fluoro-9-hydroxydecanoate ( 2a ) with acetic anhydride in the presence of Lipase Amano PS ( Pseudomonas cepacia ). The higher homologue, methyl 11-fluoro-10-hydroxyundecanoate ( 2b ) has also been resolved. These enzymatic resolutions by acetylation of ω-fluoro-(ω-1)-hydroxyalkanoic acid esters of longchain fatty acids represent the first lipase-catalyzed enantioselective esterifications of β-fluoroalcohols. Synthesis of both enantiomers of Fluoro-Phoracantholide I ( 1 ) key-step: enantioselective acetylation of β-fluoroalcohols with acetic anhydride and lipase of Pseudomonas cepacia .

(R)- and (S)-3-hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone by lipase-catalyzed resolution of the racemic mixture: New chiral auxiliaries related to pantolactone

( R)- and ( S)-3-Hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone (R)- and (S)-1 have been prepared by lipase-catalyzed enantioselective acetylation of (S)-1 from rac-1 with vinyl acetate. Controlled hydrolysis of the acetate (S)-2 gave (S)-1 . The configuration of (R)-1 and its p-bromobenzoate (R)-3 were established by X-ray diffraction analysis.

Preparation and Lipase-catalyzed Optical Resolution of 2,2,2-Trifluoro-1-(naphthyl) ethanols

The optical resolution of racemic 2,2,2-trifluoro-1-(naphthyl)ethanols (TFNEs) was achieved by lipase-catalyzed enantioselective acetylation with vinyl acetate in octane, S-acetates and R-alcohols being obtained. The introduction of a methyl group into the naphthalene ring at the 4-position (2b) or the 2-position (2c) markedly decreased the reactivity, in particular for 2c. 2,2,2-Trifluoro-1-(1-naphthyl)ethanol (2a) behaved differently from the regio-isomer, 2,2,2-trifluoro-1-(2-naphthyl)ethanol (2d): The enantioselectivity of lipases [LIP (Pseudomonas), PLC (Alcaligenes), and ALC (Achromobacter)] was high for 2a but low for 2d, whereas lipases [AK and PS (Pseudomonas)] exhibited higher selectivity for 2d than for 2a. Three other derivatives, 2,2,2-trifluoro-1-(phenyl)ethanol (2e), 2,2,2-trifluoro-1-(indol-3-yl)ethanol (2f), and 1-(1-naphthyl)ethanol (2g), were prepared, and their behaviors with respect to lipase-catalyzed acetylation were compared with 2a.