Chemoenzymatic Synthesis of Synthons as Precursors for Enantiopure Clenbuterol and Other β2-Agonists

Blindheim, Fredrik Heen; Hansen, Mari Bergan; Evjen, Sigvart; Zhu, Wei; Jacobsen, Elisabeth Egholm

doi:10.3390/catal8110516

Cited by 6 publications

(6 citation statements)

References 22 publications

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“…Lipase-catalyzed kinetic resolution of racemates has been successful for several of these [7,8]. In attempts to obtain enantiopure building blocks for the β-agonist (R)-clenbuterol, asymmetrizations of ketones have been performed with ketoreductases giving high enantiomeric excess [9].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…The enantiomers of 5 was separated on chiral HPLC. protocols for the syntheses of enantiopure β-adrenergic receptor blockers and their chiral building blocks using Candida antarctica lipase B (CALB) as the chiral catalyst [11][12][13].…”

Section: Synthesis Of 1-chloro-3-(4-((2-isopropoxyethoxy)methyl)pheno...mentioning

confidence: 99%

“…We present here a chemoenzymatic protocol for the synthesis of enantiopure (S)-bisoprolol and its hemifumarate salt. We have previously developed and reported efficient synthesis protocols for the syntheses of enantiopure β-adrenergic receptor blockers and their chiral building blocks using Candida antarctica lipase B (CALB) as the chiral catalyst [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

“…This solid catalyst has been chosen because it can be filtered off and reused after use and because it leads to the formation of fewer byproducts than when concentrated sulfuric acid is used for this synthesis step [15]. protocols for the syntheses of enantiopure β-adrenergic receptor blockers and their chiral building blocks using Candida antarctica lipase B (CALB) as the chiral catalyst [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

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Chemoenzymatic Protocol for the Synthesis of Enantiopure β-Blocker (S)-Bisoprolol

Bocquin

Jacobsen

2022

Catalysts

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The β-blocker (S)-bisoprolol hemifumarate has been synthesised in 96% enantiomeric excess with 19% total yield in a six-step synthesis. A transesterification reaction of the racemic chlorohydrin 1-chloro-3-(4-((2-isopropoxyethoxy)methyl)phenoxy)propan-2-ol catalysed by lipase B from Candida antarctica resulted in the R-chlorohydrin in high enantiomeric purity. Reaction of this building block with isopropylamine in methanol gave (S)-bisoprolol, and further reaction with fumaric acid gave (S)-bisoprolol fumarate in 96% ee. Specific rotation value confirmed the absolute configuration of the enantiopure drug.

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“…Classical enzymatic kinetic resolution (EKR) relies on a simple and well-known phenomenon that due to the chirality of the active site of the enzyme, one enantiomer fits better into the active site than its counterpart and is therefore converted at a higher rate . The EKR methodology has become one of the most prevalent approaches used nowadays in the synthesis of optically active compounds (especially chiral sec -alcohols/esters, − carboxylic acids/esters, − and primary amines/amides − ) mostly because of the possibility of obtaining both enantiomeric forms of the respective racemic substrates in a single run at relatively mild temperatures. However, the applicability of the EKR process on an industrial scale is strongly limited as this method is not attractive from the practical point of view due to several drawbacks mainly associated with low reaction yields (in the best-case scenario, only one substrate enantiomer reacts for a theoretical maximum yield of 50%) and high cost of isolation and purification operations of the desired products.…”

Section: Introductionmentioning

confidence: 99%

From Waste to Value—Direct Utilization of α-Angelica Lactone as a Nonconventional Irreversible Acylating Agent in a Chromatography-Free Lipase-Catalyzed KR Approach toward sec-Alcohols

Poterała

Borowiecki

2021

ACS Sustainable Chem. Eng.

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Although the classical enzymatic kinetic resolutions (EKRs) are among the most important reactions in biocatalysis, the requirement of application of chromatographic purification technique, which is responsible for the generation of large amounts of waste organic solvents, is its major drawback. To minimize the environmental impact of such attempts and to address the current sustainability challenges, we decided to develop a novel EKR methodology, which relies on the usage of cheap, fully renewable, nontoxic, and irreversible acyl group donor reagent, namely, α-angelica lactone. The employed activated enol lactone-based acyl donor proved to be a versatile reagent enabling efficient and highly enantioselective (up to E ≫ 500) lipase-catalyzed resolution of a set of racemic sec-alcohols with up to >99% ee and near to quantitative isolation yields according to conversions achieved during the respective EKR procedure. Moreover, α-angelica lactone provided, in this case, an ability of fast and straightforward separation of the enzymatic reactions’ products via chromatography-free reactive liquid–liquid extraction (LLE) workup using either saturated aqueous sodium bisulfate in dimethylformamide (DMF) or Girard’s P reagent in a mixture of EtOH/AcOH (90:10, v/v), respectively. The NaHSO3/DMF LLE workup and the subsequent reisolation of the respective levulinate from the aqueous layer turned out to be less efficient than a separation with Girard’s P reagent. The selective LLE of optically active levulinate-Girard P-hydrazones from the respective alcohols and further hydrolysis of the respective hydrazides with diluted HClaq. could be performed with high levels of recovery of both EKR products isolated usually without loss of enantiomeric purity.

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Chemoenzymatic Synthesis of Synthons as Precursors for Enantiopure Clenbuterol and Other β2-Agonists

Cited by 6 publications

References 22 publications

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

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

Chemoenzymatic Protocol for the Synthesis of Enantiopure β-Blocker (S)-Bisoprolol

From Waste to Value—Direct Utilization of α-Angelica Lactone as a Nonconventional Irreversible Acylating Agent in a Chromatography-Free Lipase-Catalyzed KR Approach toward sec-Alcohols

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