scholarly journals Synthesis of enantiomerically pure alcohols and amines via biocatalytic deracemisation methods

2019 ◽  
Vol 9 (20) ◽  
pp. 5487-5503 ◽  
Author(s):  
Musa M. Musa ◽  
Frank Hollmann ◽  
Francesco G. Mutti
Keyword(s):  
Kinetic Resolution ◽  
Enantiomeric Excess ◽  
Enantiomerically Pure ◽  
Theoretical Maximum

Deracemisation via chemo-enzymatic or multi-enzymatic approaches is the optimum substitute for kinetic resolution, which suffers from the limitation of a theoretical maximum 50% yield albeit high enantiomeric excess is attainable.

scholarly journals The production of enantiomerically pure 1-phenylethanol by enzymatic kinetic resolution method using response surface methodology

2020 ◽  
Vol 44 (5) ◽  
pp. 1352-1365
Author(s):  
Ayşe BOZAN ◽  
Rahime SONGÜR ◽  
Ülkü MEHMETOĞLU
Keyword(s):  
Response Surface Methodology ◽  
Reaction Time ◽  
Response Surface ◽  
High Performance ◽  
Kinetic Resolution ◽  
Enantiomeric Excess ◽  
Reaction Parameters ◽  
Enantiomerically Pure ◽  
Enzymatic Kinetic Resolution ◽  
Optimum Reaction

As the enantiomers of 1-phenylethanol are valuable intermediates in several industries, the lipase catalyzed kinetic resolution of (R,S) -1-phenylethanol is a relevant research topic. In this study, the goal was to determine the optimum reaction parameters to produce enantiomerically pure 1-phenylethanol by lipase (Novozyme 435) catalyzed kinetic resolution using response surface methodology (RSM). Reactions were performed with 40–400 mM (R,S)-1-phenylethanol, 120–1200 mM vinyl acetate and 2–22 mg/ mL biocatalyst concentrations (BCL), at 20–60 °C and with a stirring rate of 50–400 rpm for 5–120 min. The samples were analyzed using high performance liquid chromatography (HPLC) with a Chiralcel OB column. Optimum reaction parameters to reach 100% enantiomeric excess for the substrate (ees) were determined as follows: substrate concentration (Cs): 240 mM, BCL: 11 mg/mL, at 42 °C with a reaction time of 75 min. Model validation was performed using these conditions and ees was calculated as 100%, which indicates the predicted model was efficient and accurate. When compared to the literature, it was observed that the reaction time decreased significantly. This is an important result considering the industrial scale perspective.

scholarly journals Chemoenzymatic Synthesis of Apremilast: A Study Using Ketoreductases and Lipases

2021 ◽  
Author(s):  
Kimberly Vega ◽  
Daniel Cruz ◽  
Artur Oliveira ◽  
Marcos da Silva ◽  
Telma de Lemos ◽  
...  
Keyword(s):  
Aspergillus Niger ◽  
Ethyl Acetate ◽  
Kinetic Resolution ◽  
Enantiomeric Excess ◽  
The Other ◽  
Chemoenzymatic Synthesis ◽  
Hydrolysis Reaction ◽  
Chiral Alcohol ◽  
Enantiomerically Pure ◽  
Enantiomeric Ratio

The key step in the chemoenzymatic synthesis of apremilast was to produce the chiral alcohol (R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanol, (R)-3. Two enzymatic approaches were evaluated to obtain (R)-3, one using ketoreductases and the other lipases. Bioreduction of 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone (2), using ketoreductase KRED‑P2-D12, led to (R)-3 with 48% conversion and 93% enantiomeric excess (ee). Kinetic resolution of rac-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl acetate (rac-4), via hydrolysis reaction, with 20% of n-butanol, catalyzed by lipase from Aspergillus niger yielded (R)-3 with > 99% ee, 50% conversion and E-value (enantiomeric ratio) > 200. The reaction between enantiomerically pure (R)-3 and 4-acetylamino-isoindol-1,3-dione (8) afforded apremilast in 65% yield and 67% ee.

scholarly journals Lipase Catalyzed Synthesis of Enantiopure Precursors and Derivatives for β-Blockers Practolol, Pindolol and Carteolol

Catalysts ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 503
Author(s):  
Morten Gundersen ◽  
Guro Austli ◽  
Sigrid Løvland ◽  
Mari Hansen ◽  
Mari Rødseth ◽  
...  
Keyword(s):  
Building Block ◽  
Kinetic Resolution ◽  
Enantiomeric Excess ◽  
Catalytic Amount ◽  
Building Blocks ◽  
Β Blocker ◽  
Β Blockers ◽  
Optical Rotations ◽  
Reported Data ◽  
By Products

Sustainable methods for producing enantiopure drugs have been developed. Chlorohydrins as building blocks for several β-blockers have been synthesized in high enantiomeric purity by chemo-enzymatic methods. The yield of the chlorohydrins increased by the use of catalytic amount of base. The reason for this was found to be the reduced formation of the dimeric by-products compared to the use of higher concentration of the base. An overall reduction of reagents and reaction time was also obtained compared to our previously reported data of similar compounds. The enantiomers of the chlorohydrin building blocks were obtained by kinetic resolution of the racemate in transesterification reactions catalyzed by Candida antarctica Lipase B (CALB). Optical rotations confirmed the absolute configuration of the enantiopure drugs. The β-blocker (S)-practolol ((S)-N-(4-(2-hydroxy-3-(isopropylamino)propoxy)phenyl)acetamide) was synthesized with 96% enantiomeric excess (ee) from the chlorohydrin (R)-N-(4-(3-chloro-2 hydroxypropoxy)phenyl)acetamide, which was produced in 97% ee and with 27% yield. Racemic building block 1-((1H-indol-4-yl)oxy)-3-chloropropan-2-ol for the β-blocker pindolol was produced in 53% yield and (R)-1-((1H-indol-4-yl)oxy)-3-chloropropan-2-ol was produced in 92% ee. The chlorohydrin 7-(3-chloro-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one, a building block for a derivative of carteolol was produced in 77% yield. (R)-7-(3-Chloro-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one was obtained in 96% ee. The S-enantiomer of this carteolol derivative was produced in 97% ee in 87% yield. Racemic building block 5-(3-chloro-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one, building block for the drug carteolol, was also produced in 53% yield, with 96% ee of the R-chlorohydrin (R)-5-(3-chloro-2-hydroxypropoxy)-3,4-dihydroquinolin-2(1H)-one. (S)-Carteolol was produced in 96% ee with low yield, which easily can be improved.

Stereochemistry of epoxide carbonylation using bimetallic Lewis acid/metal carbonyl complexes

2004 ◽  
Vol 76 (3) ◽  
pp. 557-564 ◽  
Author(s):  
Y. D. Y. L. Getzler ◽  
Viswanath Mahadevan ◽  
E. B. Lobkovsky ◽  
G. W. Coates
Keyword(s):  
Lewis Acid ◽  
Kinetic Resolution ◽  
Metal Carbonyl ◽  
Carbonyl Complexes ◽  
Enantiomerically Pure ◽  
Metal Carbonyl Complexes ◽  
Pure Complex

The stereochemistry of epoxide carbonylation using bimetallic [Lewis acid]+[Co(CO)4]- complexes is reported. The achiral complex [(salph)Al(THF)2][Co(CO)4] stereospecifically carbonylates cis- and trans-2-butene oxide to the trans- and cis-β-lactones, respectively. Preliminary experiments regarding the carbonylative kinetic resolution of racemic trans-2-butene oxide using the enantiomerically pure complex [(R,R-salcy)Al(THF)2][Co(CO)4] are also reported.

scholarly journals ω-Amino Acid:Pyruvate Transaminase from Alcaligenes denitrificans Y2k-2: a New Catalyst for Kinetic Resolution of β-Amino Acids and Amines

2004 ◽  
Vol 70 (4) ◽  
pp. 2529-2534 ◽  
Author(s):  
Hyungdon Yun ◽  
Seongyop Lim ◽  
Byung-Kwan Cho ◽  
Byung-Gee Kim
Keyword(s):  
Amino Acids ◽  
Kinetic Resolution ◽  
Specific Activity ◽  
Expression System ◽  
Enantiomeric Excess ◽  
Selective Enrichment ◽  
Alcaligenes Denitrificans ◽  
Keto Acids ◽  
Optically Pure ◽  
High Stereoselectivity

ABSTRACT Alcaligenes denitrificans Y2k-2 was obtained by selective enrichment followed by screening from soil samples, which showed ω-amino acid:pyruvate transaminase activity, to kinetically resolve aliphatic β-amino acid, and the corresponding structural gene (aptA) was cloned. The gene was functionally expressed in Escherichia coli BL21 by using an isopropyl-β-d-thiogalactopyranoside (IPTG)-inducible pET expression system (9.6 U/mg), and the recombinant AptA was purified to show a specific activity of 77.2 U/mg for l-β-amino-n-butyric acid (l-β-ABA). The enzyme converts various β-amino acids and amines to the corresponding β-keto acids and ketones by using pyruvate as an amine acceptor. The apparent Km and V max for l-β-ABA were 56 mM and 500 U/mg, respectively, in the presence of 10 mM pyruvate. In the presence of 10 mM l-β-ABA, the apparent Km and V max for pyruvate were 11 mM and 370 U/mg, respectively. The enzyme exhibits high stereoselectivity (E > 80) in the kinetic resolution of 50 mM d,l-β-ABA, producing optically pure d-β-ABA (99% enantiomeric excess) with 53% conversion.

scholarly journals Continuous Flow Preparation of Enantiomerically Pure BINOL(s) by Acylative Kinetic Resolution

2020 ◽  
Vol 362 (6) ◽  
pp. 1370-1377 ◽  
Author(s):  
Junshan Lai ◽  
Rifahath M. Neyyappadath ◽  
Andrew D. Smith ◽  
Miquel A. Pericàs
Keyword(s):  
Continuous Flow ◽  
Kinetic Resolution ◽  
Enantiomerically Pure

scholarly journals Parallel Interconnected Kinetic Asymmetric Transformation (PIKAT) with an Immobilized ω-Transaminase in Neat Organic Solvent

Molecules ◽  
2020 ◽  
Vol 25 (9) ◽  
pp. 2140 ◽  
Author(s):  
Wesley Böhmer ◽  
Lucien Koenekoop ◽  
Timothée Simon ◽  
Francesco G. Mutti
Keyword(s):  
Kinetic Resolution ◽  
Enantiomeric Excess ◽  
Molar Ratio ◽  
Chiral Amines ◽  
Aqueous Environment ◽  
Chiral Amine ◽  
Parallel Kinetic Resolution ◽  
Pharmaceutical Manufacture ◽  
Prochiral Ketones ◽  
Asymmetric Transformation

Comprising approximately 40% of the commercially available optically active drugs, α-chiral amines are pivotal for pharmaceutical manufacture. In this context, the enzymatic asymmetric amination of ketones represents a more sustainable alternative than traditional chemical procedures for chiral amine synthesis. Notable advantages are higher atom-economy and selectivity, shorter synthesis routes, milder reaction conditions and the elimination of toxic catalysts. A parallel interconnected kinetic asymmetric transformation (PIKAT) is a cascade in which one or two enzymes use the same cofactor to convert two reagents into more useful products. Herein, we describe a PIKAT catalyzed by an immobilized ω-transaminase (ωTA) in neat toluene, which concurrently combines an asymmetric transamination of a ketone with an anti-parallel kinetic resolution of an amine racemate. The applicability of the PIKAT was tested on a set of prochiral ketones and racemic α-chiral amines in a 1:2 molar ratio, which yielded elevated conversions (up to >99%) and enantiomeric excess (ee, up to >99%) for the desired products. The progress of the conversion and ee was also monitored in a selected case. This is the first report of a PIKAT using an immobilized ωTA in a non-aqueous environment.

Determination of enantiomeric excess by chiral liquid chromatography without enantiomerically pure starting standards

2012 ◽  
Vol 26 (10) ◽  
pp. 1241-1246 ◽  
Author(s):  
F. G. Sánchez ◽  
A. Navas Díaz ◽  
E. Sánchez Torreño ◽  
A. Aguilar ◽  
I. Medina Lama ◽  
...  
Keyword(s):  
Liquid Chromatography ◽  
Enantiomeric Excess ◽  
Enantiomerically Pure
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