Preparative access to medicinal chemistry related chiral alcohols using carbonyl reductase technology

Rowan, Andrew S.; Moody, Thomas S.; Howard, Roger M.; Underwood, Toby J.; Miskelly, Iain; He, Yanan; Wang, Bo

doi:10.1016/j.tetasy.2013.09.015

Cited by 37 publications

(13 citation statements)

References 35 publications

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“…High cis , cis -selectivity (>99%) and high enantioselectivity are observed (Scheme 29). Given the remarkable ADH active site plasticity that has already been observed, [15a] and the power of directed evolution, [7c, 12b, 23a] a menu of such biocatalytic transformations may well be forthcoming in the not-too-distant future, in which ‘double, dynamic reductive kinetic resolutions’ are achieved, setting two different dynamic centers, while selectively reducing a central carbonyl functionality, all in a single operation.…”

Section: Future Challengesmentioning

confidence: 99%

“…The reader is also pointed to other reviews on dehydrogenase enzymes that may be of interest. [12] Our own interest in dehydrogenase enzymes stems from their utility as “reporting enzymes” in a method for catalyst discovery that we have developed known as In Situ Enzymatic Screening (ISES). [13] In this approach, an alcohol dehydrogenase (ADH) oxidizes the alcoholic product or byproduct of a reaction of interest.…”

Section: Introductionmentioning

confidence: 99%

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Exploiting Enzymatic Dynamic Reductive Kinetic Resolution (DYRKR) in Stereocontrolled Synthesis

Applegate

Berkowitz

2015

Adv Synth Catal

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Over the past two decades, the domains of both frontline synthetic organic chemistry and process chemistry and have seen an increase in crosstalk between asymmetric organic/organometallic approaches and enzymatic approaches to stereocontrolled synthesis. This review highlights the particularly auspicious role for dehydrogenase enzymes in this endeavor, with a focus on dynamic reductive kinetic resolutions (DYRKR) to “deracemize” building blocks, often setting two stereocenters in so doing. The scope and limitations of such dehydrogenase-mediated processes are overviewed, as are future possibilities for the evolution of enzymatic DYRKR.

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Section: Future Challengesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Exploiting Enzymatic Dynamic Reductive Kinetic Resolution (DYRKR) in Stereocontrolled Synthesis

Applegate

Berkowitz

2015

Adv Synth Catal

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“…Within the Green Chemistry methodologies, it's possible to emphasize the biocatalysis that can be defined in general as the use of enzymes, whole cells of microorganisms or plants (Vandenberghe et al, 2013). These enzymes sources are biocatalysts in organic synthesis, a very desirable use due to the attractive characteristics of biocatalysis, such as its high selectivity, which can be chemo, regio and stereoselective providing the reduction or elimination of the use of protective groups and simplifying separation processes that can be performed under mild conditions of temperature and pressure, with consequent reduction of costs and waste (Carvalho, 2011;Clouthier and Pelletier, 2012) Among the various biocatalytic reactions we can highlight the bioreductions of prochiral carbonyl groups, these reactions generate chiral alcohols, which are start materials widely used in the synthesis of drugs, flavorings, essences and agricultural products (Ni and Xu, 2012;Rowan, 2013). The chiral alcohol menthol is the major compound followed by its carbonyl derivatives of the essential oil of the plant Mentha piperita L., popularly known as mint.…”

Section: Introductionmentioning

confidence: 99%

Carrot Roots as Clean and Sustainable Biocatalyst for Obtaining Natural Menthol

2018

Aust. J. Basic & Appl. Sci.

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Bioreduction of Essential Oil of Mentha piperita L. (EOMP) After the determination of the ideal reaction conditions using the bioreduction of acetophenone as model, the reaction was anew performed following the parameters of test B. The EOMP, however, already presents menthol as the major compound, but with the reduction of the carbonyl monoterpenoids present in this essential oil it is possible to significantly raise the menthol content in the sample (Moghtader, 2013). Daucus carota used the ketone monoterpenoids as substrates and promoted the bioreduction of these selectively for the menthol compound. The data show that the bioreduction reaction mediated by carrot pieces is also effective in the presence of multiple molecules as in the case of EOMP. Essential oils represent value-added substances in the industrial sector due to their bioactive and technological potential, they also represent renewable sources to obtain molecules of interest. The molecular modification of these compounds by biocatalytic methods is an economically viable alternative that minimizes processes of purification and extraction. The data obtained in the present work show a further advantage of the use of Daucus carota as a source of biocatalyst with the ability to biotransform substrates directly from a matrix and the EOMP without prior purification in the medium of the unbuffered aqueous solution leading to a clean and sustainable of menthol. CONCLUSIONS In summary, this work proposes a modification in the traditional biocatalytic methodology, where the EOMP is used as a source of multiple substrates. Daucus carota was able to promote the bioreduction of the ketone monoterpenoids present in the EOMP leading to a menthol enrichment in the sample with high selectivity. Thus promoting a cleaner and more sustainable reaction to obtain a compound of great industrial interest.

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“…Chirality is a key factor in the safety and efficacy of many drugs and thus the production of enantiopure drugs has become increasingly important in the pharmaceutical industry. 1 Chiral aromatic secondary alcohols are widely used in synthetic organic and medicinal chemistry as key intermediates for the synthesis of various pharmaceutical products such as Zetia ® (Ezetimibe), 2 Prozac ® (Fluoxetine) 3 and Emend ® (Aprepitant) 1 (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Extreme halophilic alcohol dehydrogenase mediated highly efficient syntheses of enantiopure aromatic alcohols

2017

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Enzymatic synthesis of enantiopure aromatic secondary alcohols (including substituted, hetero-aromatic and bicyclic structures) was carried out using halophilic alcohol dehydrogenase ADH2 from Haloferax volcanii (HvADH2). This enzyme showed an unprecedented substrate scope and absolute enatioselectivity. The cofactor NADPH was used catalytically and regenerated in situ by the biocatalyst, in the presence of 5% ethanol. The efficiency of HvADH2 for the conversion of aromatic ketones was markedly influenced by the steric and electronic factors as well as the solubility of ketones in the reaction medium. Furthermore, carbonyl stretching band frequencies ν (C[double bond, length as m-dash]O) have been measured for different ketones to understand the effect of electron withdrawing or donating properties of the ketone substituents on the reaction rate catalyzed by HvADH2. Good correlation was observed between ν (C[double bond, length as m-dash]O) of methyl aryl-ketones and the reaction rate catalyzed by HvADH2. The enzyme catalyzed the reductions of ketone substrates on the preparative scale, demonstrating that HvADH2 would be a valuable biocatalyst for the preparation of chiral aromatic alcohols of pharmaceutical interest.

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Preparative access to medicinal chemistry related chiral alcohols using carbonyl reductase technology

Cited by 37 publications

References 35 publications

Exploiting Enzymatic Dynamic Reductive Kinetic Resolution (DYRKR) in Stereocontrolled Synthesis

Exploiting Enzymatic Dynamic Reductive Kinetic Resolution (DYRKR) in Stereocontrolled Synthesis

Carrot Roots as Clean and Sustainable Biocatalyst for Obtaining Natural Menthol

Extreme halophilic alcohol dehydrogenase mediated highly efficient syntheses of enantiopure aromatic alcohols

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