Controlled racemization of optically active organic compounds: Prospects for asymmetric transformation

Ebbers, Eelco J.; Ariaans, G. J. A.; Houbiers, J. P. M.; Bruggink, Alle; Zwanenburg, B.

doi:10.1016/s0040-4020(97)00324-4

Cited by 306 publications

(219 citation statements)

References 165 publications

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“…[4] The most common racemization catalysts for secondary alcohols are transition-metal-based hydrogen-transfer catalysts, which racemize the alcoholi nadehydrogenation-hydrogenation (oxidation-reduction) pathway. [5] When such ar acemization catalyst is combinedw ith ak inetic resolution catalyst (e.g.…”

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confidence: 99%

Heterogeneous Acid‐Catalyzed Racemization of Tertiary Alcohols

Görbe

Lihammar

Bäckvall

2017

Chemistry A European J

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Tertiary alcohols are important structural motifs in natural productsa nd building blocks in organic synthesis buto nly few methods are known for their enantioselective preparation. Chiral resolution is one of these approaches that leaves one enantiomer (50 %o ft he material) unaffected. An attractive method to increase the efficiency of those resolutions is to racemizet he unaffected enantiomer.I nt he present work, we have developed a practical racemization protocol for tertiary alcohols. Five different acidic resin materials were tested. The Dowex 50WX8 was the resin of choice since it was capable of racemizing tertiary alcohols withouta ny byproductf ormation. Suitable solvents and ab iphasic system were investigated, andt he optimized system was capable of racemizing differently substituted tertiarya lcohols.The stereoselective synthesis of organic moleculesi so fahigh demandi nt he pharmaceutical anda grochemical industry. Three strategies are presently used for the preparation of enantiomerically pure compounds,o ne of them being the chiral pool synthesis, where chiral natural products are used as buildingb locks for the synthesis of complex molecules. [1] The other two strategies include resolution of racemates [2] and asymmetrics ynthesis, where in the latter case chiral reagents or catalysts are used. [3] Although asymmetrics ynthesis based on catalysis (asymmetric catalysis) is av ery powerful method for obtaining enantiomerically pure compounds, the most commonm ethod used in chemical industry for obtaining such compounds is still by resolution. In ar esolution, which could be crystallization, chiral chromatography,o rk inetic resolution, two enantiomers are separated and the desired enantiomer is collected. The drawback of the resolution strategy is that only 50 %o ft he material is used, and the unwanted enantiomer is discarded. As olutiono ft his problem is to racemize the unwanted enantiomer and to recirculate the racemic mixture, which increases efficiency.T herefore, there is ah igh demand of efficient racemizationm ethods in industrial applications.Racemizationc an be achieved by av ariety of techniques: thermalr acemization, enzyme-catalyzed racemization, racemization via meso-intermediates, racemization by nucleophilic substitution, racemizationb yr adicala nd redox reactions, photochemical racemization, and acid-or base-catalyzed racemization. [4] The most common racemization catalysts for secondary alcohols are transition-metal-based hydrogen-transfer catalysts, which racemize the alcoholi nadehydrogenation-hydrogenation (oxidation-reduction) pathway. [5] When such ar acemization catalyst is combinedw ith ak inetic resolution catalyst (e.g. an enzyme)aso called "dynamic kinetic resolution" (DKR) can be achieved. [6] Te rtiary alcohols and their esters are important compounds, which are found in anumber of natural products. [7] These compounds are also important buildingb locks in synthetic chemistry. [8] The synthesis of optically pure tertiary alcohols is still a challengin...

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Heterogeneous Acid‐Catalyzed Racemization of Tertiary Alcohols

Görbe

Lihammar

Bäckvall

2017

Chemistry A European J

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“…In a previous study, immobilized lipase from Rhizomucor miehei was used with iso-octane as solvent and butanol as etherification agent and reported high ester yields 49.9 and enantiomeric excess 93.8 of ibuprofen 78 . The stability of enzyme action up to 100 h as well as the low cost and simple scale-up of the system makes this process an alternative option for highly stereoselective esterification in organic 84,87,88 . Nature of the solvent and its water content are of paramount importance in organic media which are not found in aqueous media.…”

Section: Enzymatic Kinetic Resolutionmentioning

confidence: 99%

Synthesis of Chirally Pure Enantiomers by Lipase

Bhardwaj

Gupta

2017

J. Oleo Sci.

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“…[21][22][23] We therefore classified stereogenic carbon atoms according to their attached substituents.E ach substituent is identified as one of sixty types, [24] which encompass more than 99.95 %ofall such substituents in the GOSTAR database. [25] Thet en most frequently occurring substituents are listed in Figure 1; the Hr equired for general-base-catalyzed racemization is prominent.[24] Groups labelled *w ere selected for experimental study.Based on prevalence,e arlier work, [21][22][23] and chemical intuition, several compounds were selected for detailed kinetic studies. [26][27][28] Ther ate constants for general-basecatalyzed racemization were derived for ar ange of 11 arylglycine derivatives (1, 2 and 3), 12 hydantoins (4, 5 and 6)a nd 5t hiohydantoins (7 and 8).…”

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confidence: 99%

“…[1,[15][16][17][18][19][20] Chiral centers with certain combinations of substituents have been posited to be prone to general-basecatalyzed racemization although with little supporting data. [21][22][23] We therefore classified stereogenic carbon atoms according to their attached substituents.E ach substituent is identified as one of sixty types, [24] which encompass more than 99.95 %ofall such substituents in the GOSTAR database. [25] Thet en most frequently occurring substituents are listed in Figure 1; the Hr equired for general-base-catalyzed racemization is prominent.…”

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Quantitative Prediction of Rate Constants for Aqueous Racemization To Avoid Pointless Stereoselective Syntheses

et al. 2017

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Racemization has alarge impact upon the biological properties of molecules but the chemical scope of compounds with knownr ate constants for racemization in aqueous conditions was hitherto limited. To address this remarkable blind spot, we have measured the kinetics for racemization of 28 compounds using circular dichroism and 1 HNMR spectroscopy. We show that rate constants for racemization (measured by ourselves and others) correlate well with deprotonation energies from quantum mechanical (QM) and group contribution calculations.Such calculations thus provide predictions of the second-order rate constants for general-basecatalyzedr acemization that are usefully accurate.W hen applied to recent publications describing the stereoselective synthesis of compounds of purported biological value,t he calculations reveal that racemization would be sufficiently fast to render these expensive syntheses pointless.Thalidomide racemizes in am atter of hours and yet it remains ap oster child for enantioselective synthesis which would not have saved its victims.[1] Thes tatus quo in enantioselective synthesis thus ignores the cruel blind spot that we address in this paper:racemization.Although necessary in dynamic kinetic resolution protocols, [2,3] racemization and epimerization can caus es afe compounds to become toxic or lose efficacy, [4][5][6][7][8][9][10][11] lead to misidentification of chiral compounds extracted from natural sources, [12] etc.I gnoring racemization thus leads to wasted material and human resources.Racemization is ap articular problem because its detection requires chiral analytical methods. [13,14] Hence,f ew reports disclose rate constants for racemization under aqueous conditions. [1,[15][16][17][18][19][20] Chiral centers with certain combinations of substituents have been posited to be prone to general-basecatalyzed racemization although with little supporting data. [21][22][23] We therefore classified stereogenic carbon atoms according to their attached substituents.E ach substituent is identified as one of sixty types, [24] which encompass more than 99.95 %ofall such substituents in the GOSTAR database. [25] Thet en most frequently occurring substituents are listed in Figure 1; the Hr equired for general-base-catalyzed racemization is prominent.[24] Groups labelled *w ere selected for experimental study.Based on prevalence,e arlier work, [21][22][23] and chemical intuition, several compounds were selected for detailed kinetic studies. [26][27][28] Ther ate constants for general-basecatalyzed racemization were derived for ar ange of 11 arylglycine derivatives (1, 2 and 3), 12 hydantoins (4, 5 and 6)a nd 5t hiohydantoins (7 and 8). Briefly,a ts everal buffer concentrations,c ircular dichroism spectroscopy (CD) followed the decrease in ellipticity and/or 1 HNMR spectroscopy the incorporation of Dfrom deuterated buffers.T he pseudo- first-order rate constants for these processes were corrected for hydrolysis side reactions if required. [24] Plotting the firstorder rate constants for ...

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Controlled racemization of optically active organic compounds: Prospects for asymmetric transformation

Cited by 306 publications

References 165 publications

Heterogeneous Acid‐Catalyzed Racemization of Tertiary Alcohols

Heterogeneous Acid‐Catalyzed Racemization of Tertiary Alcohols

Synthesis of Chirally Pure Enantiomers by Lipase

Quantitative Prediction of Rate Constants for Aqueous Racemization To Avoid Pointless Stereoselective Syntheses

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