Access to Enantiopure α‐Alkyl‐β‐hydroxy Esters through Dynamic Kinetic Resolutions Employing Purified/Overexpressed Alcohol Dehydrogenases

Cuetos, Aníbal; Rioz‐Martínez, Ana; Bisogno, Fabricio R.; Grischek, Barbara; Lavandera, Iván; Gonzalo, Gonzalo de; Kroutil, Wolfgang; Gotor, Vicente

doi:10.1002/adsc.201200139

Cited by 46 publications

(30 citation statements)

References 82 publications

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“…-azido ketones 15 and -alkyl--keto esters, 16 and more importantly, with opposite stereopreference. Thus, ADH-A affords selectively the corresponding (S)-alcohols while LBADH the (R)-configured antipodes.…”

Section: Methodsmentioning

confidence: 99%

Highly enantioselective synthesis of α-azido-β-hydroxy methyl ketones catalyzed by a cooperative proline–guanidinium salt system

et al. 2014

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COMMUNICATIONThis journal is © The Royal Society of Chemistry 2012 J. Name., 2012, 00, 1-3 | 1 are typically accessed by a base-promoted aldol reaction of an -azidoketone 2 and a non-enolizable aldehyde 3 3 (Scheme 1). Scheme 1Although these protocols render the aldol aducts 1 with optimum chemical yield, undesired mixtures of anti and syn isomers are always present. In fact, to our knowledge, there are no methodologies described in the literature that allow gaining access to -azido--hydroxy ketones 1 in a controlled diastereo-and enantioselective manner. Proline is the most popular organocatalyst. This naturally occurring amino acid is cheap, readily available in both enantiomeric forms, and can be used for a wide range of synthetic transformations. 6 Aiming to avoid the use of other synthetically elaborated organocatalysts, our group, 4 and others, 7 have demonstrated how the addition of additives can enhance the reactivity and selectivity of this off-the-bench catalyst in classical transformations such as the aldol reaction. Moreover, the addition of additives can also expand the boundaries of proline as catalyst. In this sense, we have reported the first proline-catalyzed asymmetric synthesis of chlorohydrins through the intermolecular aldol reaction between chloroacetone and aromatic aldehydes, made feasible by the participation of a guanidinium salt as an additive. Motivated by our previous results, we decided to explore the behaviour of our catalytic guanidinium salt/proline system towards a reaction like that illustrated in Scheme 1. 4-Nitrobenzaldehyde, 4a, was adopted as the model substrate for preliminary reactions. Azidoacetone (5, 1-azidopropan-2-one) was prepared in multi-gram scale, in 96% yield, from chloroacetone and sodium azide. In correspondence with our previous work, we decided to evade the use of any organic solvent, apart from ketone 5, which acts as both reagent and reaction media.8 A careful optimization of the stoichiometries involved in the reaction, time, temperature, as well as the judicious choice of the anion accompanying the guanidinium salt, revealed ideal conditions (see Supporting Information (SI) for details, Tables S1-S5). So, when a suspension of (S)-proline (10 mol%), guanidinium salt 6 (15 mol%) and 4-nitrobenzaldehyde 4a, in a moderate excess of azidoacetone 5

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Section: Methodsmentioning

confidence: 99%

Highly enantioselective synthesis of α-azido-β-hydroxy methyl ketones catalyzed by a cooperative proline–guanidinium salt system

et al. 2014

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“…This short chain dehydrogenase, named SyADH, was isolated and the relevant gene cloned and expressed, and subsequently used for the non-selective oxidation of some small prochiral alcohols [13]. Like RasADH, SyADH has also recently been employed in the DKR of -alkyl--keto esters such as 5 [11], in this case to give (2R, 3S)-diol products 6 with excellent d.e.s and e.e.s RasADH and SyADH therefore present distinctly useful biocatalysts as they catalyse the transformation of sterically challenging substrates and with, in some cases, complementary stereo-and diastereo-selectivities to established ADHs. In the case of each of these enzymes, knowledge of their three-dimensional structure would not only provide information for the first time on the determinants of bulk-bulky ketone recognition in such ADHs, but also serve to inform the engineering of other ADHs for transformation of those substrates, or for the expanded substrate specificity of RasADH and SyADH themselves.…”

Section: Introductionmentioning

confidence: 99%

“…The stability of the enzyme could be augmented by the addition of calcium ions. RasADH was subsequently also applied to the reduction of -hydroxy ketones [10] and in the dynamic kinetic resolution (DKR) of -alkyl--keto esters such as 3 ( Figure 1) to give (2S, 3S)-products of type 4 [11].…”

Section: Introductionmentioning

confidence: 99%

Structures of Alcohol Dehydrogenases from Ralstonia and Sphingobium spp. Reveal the Molecular Basis for Their Recognition of ‘Bulky–Bulky’ Ketones

et al. 2013

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Alcohol dehydrogenases (ADHs) are applied in industrial synthetic chemistry for the production of optically active secondary alcohols. However, the substrate spectrum of many ADHs is narrow, and few, for example, are suitable for the reduction of prochiral ketones in which the carbonyl group is bounded by two bulky and/or hydrophobic groups; so-called 'bulky-bulky' ketones. Recently two ADHs, RasADH from Ralstonia sp. DSM 6428, and SyADH from Sphingobium yanoikuyae DSM 6900, have been described, which are distinguished by their ability to accept bulky-bulky ketones as substrates. In order to examine the molecular basis of the recognition of these substrates the structures of the native and NADPH complex of RasADH, and the NADPH complex of SyADH have been determined and refined to resolutions of 1.5, 2.9 and 2.5 Å respectively. The structures reveal hydrophobic active site tunnels near the surface of the enzymes that are well-suited to the recognition of large hydrophobic substrates, as determined by modelling of the bulkybulky substrate n-pentyl phenyl ketone. The structures also reveal the bases for NADPH specificity and (S)-stereoselectivity in each of the biocatalysts for n-pentyl phenyl ketone and related substrates.

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“…Hence, the bioreduction over the carbonyl moiety using an alcohol dehydrogenase is probably one of the most typical biocatalytic DKR systems, being described since 70's. [6] Recent examples include (Scheme 10a) the reduction of: i) α-substituted β-keto esters with commercial and overexpressed ADHs, [80,81] ii) α-substituted 1,3-diketones using commercial enzymes, [82] iii) α-substituted ketones employing overexpressed ADHs, [83] and iv) α-substituted aldehydes with an immobilized biocatalyst. [84] In all cases a pH close to neutral was enough to develop an efficient racemization of the labile position adjacent to the carbonyl reacting group.…”

Section: Using Alcohol Dehydrogenases (Adhs)mentioning

confidence: 99%

Why Leave a Job Half Done? Recent Progress in Enzymatic Deracemizations

Díaz‐Rodríguez¹,

Lavandera

Gotor³

2015

CGC

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Abstract. In recent years the usefulness of enzymatic systems to obtain a single stereoisomerically pure compound starting from a racemate has been expanded. Moreover, current advances in protein engineering, molecular biology and modeling tools are the basis to improve the catalytic properties of enzymes to face novel synthetic challenges. Also, medium engineering and novel immobilization methods of (bio)catalysts are enhancing the productivity of biocatalytic processes making them suitable for being scalable. The development of multienzymatic protocols and the combination of enzymes with other catalysts are providing a wide range of synthetic possibilities that are expanding the scope of these transformations even at industrial scale. Herein we will describe an overview of recent (chemo)enzymatic deracemizations, focusing on the strategy employed (dynamic kinetic resolution, stereoinversion, cyclic deracemization or enantioconvergent process), the type of substrate (e.g., alcohols, amines, carboxylic acid derivatives or carbonylic compounds), and the biocatalyst(s) used.

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Access to Enantiopure α‐Alkyl‐β‐hydroxy Esters through Dynamic Kinetic Resolutions Employing Purified/Overexpressed Alcohol Dehydrogenases

Cited by 46 publications

References 82 publications

Highly enantioselective synthesis of α-azido-β-hydroxy methyl ketones catalyzed by a cooperative proline–guanidinium salt system

Highly enantioselective synthesis of α-azido-β-hydroxy methyl ketones catalyzed by a cooperative proline–guanidinium salt system

Structures of Alcohol Dehydrogenases from Ralstonia and Sphingobium spp. Reveal the Molecular Basis for Their Recognition of ‘Bulky–Bulky’ Ketones

Why Leave a Job Half Done? Recent Progress in Enzymatic Deracemizations

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