Asymmetric synthesis of (S)-phenylacetylcarbinol – closing a gap in C–C bond formation

Sehl, Torsten; Bock, Saskia; Marx, Lisa; Maugeri, Zaira; Walter, Lydia; Westphal, Robert; Vogel, Constantin; Menyes, Ulf; Erhardt, Martin; Müller, Michael; Pohl, Martina; Rother, Dörte

doi:10.1039/c6gc01803c

Cited by 26 publications

(39 citation statements)

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“…In that regard, studies on different ThDP-dependent DCs showedt hat the stereoselectivity can furtherb ei ncreased when the parallel orientation of the acceptor side chain (binding state I)i sd estabilised in addition to openingo fa nS-pocket to favour binding state II. [12,47] Comparison of the resultsf or the here tested EcTK variants with variants of GstTK described by Zhou et al [27] shows that effects of amino acid exchanges can also differ for TKs from different organisms. For GstTK exchange of L191, the corresponding residue to I189 in EcTK, was found to be decisive to create R-selective variantswith ee-values up to 84 %for the formation of 3b (SI Ta ble S1) and could additionally increase the specific activity at least 3-fold when replaced by glycine, alanine or valine.…”

Section: Summary Discussionmentioning

confidence: 78%

“…Thus, it cannot be assumed that an available pocket would fully shift the distribution to binding states II and IV (Figure ). In that regard, studies on different ThDP‐dependent DCs showed that the stereoselectivity can further be increased when the parallel orientation of the acceptor side chain ( binding state I ) is destabilised in addition to opening of an S ‐pocket to favour binding state II …”

Section: Resultsmentioning

confidence: 99%

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Towards a Mechanistic Understanding of Factors Controlling the Stereoselectivity of Transketolase

et al. 2018

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A structural model for thiamine‐diphosphate (ThDP)‐dependent transketolase (TK) was developed to analyse the effect of amino acid exchanges on the stereoselectivity of this synthetically important class of enzymes. In this study the carboligation of 3‐hydroxypyruvate as a donor and propanal, as well as pentanal, was studied. Based on literature data and additional mutagenesis studies using E. coli TK, a four‐state model was developed to explain the stereoselectivity of TKs by the relative orientation of donor and acceptor substrates in the active site prior to C−C‐bond formation. To enable a functional comparison of relevant amino acids of TKs from different species, a standard numbering scheme was developed. Using this concept, H26, H261, and F434 were identified as the key residues which mediate stereoselectivity, where two main factors influenced the arrangement of ThDP‐bound donor and acceptor prior to carboligation: the relative orientation of the substrate side chains and the orientation of the acceptor carbonyl group towards the donor hydroxy group. This model provides a first framework to understand the structure‐function relationships of TKs with respect to their stereoselectivity.

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Section: Summary Discussionmentioning

confidence: 78%

Section: Resultsmentioning

confidence: 99%

Towards a Mechanistic Understanding of Factors Controlling the Stereoselectivity of Transketolase

et al. 2018

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“…(R)-1-Hydroxy-1-phenylpropan-2-one ((R)-PAC), (S)-1-hydroxy-1-phenylpropan-2-one ((S)-PAC), (R)-2-hydroxy-1-phenylpropan-1-one ((R)-HPP), (S)-2-hydroxy-1phenylpropan-1-one ((S)-HPP) were synthesized (M. Pohl and D. Rother, Forschungszentrum Jülich; Germany) as described elsewhere. 25,26 2-Hydroxy-3-methoxy-1-(4-methoxyphenyl)-1propanone, 1-(2-chlorophenyl)-1-hydroxy-3-methyl-2-butanone and 1-(2-bromophenyl)-1-hydroxy-2-butanone were synthesized in the group of K. Zeitler (University Leipzig; Germany).…”

Section: Chemicals and Reagentsmentioning

confidence: 99%

Synthesis of α-hydroxy ketones and vicinal (R,R)-diols by Bacillus clausii DSM 8716^T butanediol dehydrogenase

et al. 2020

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a-hydroxy ketones (HK) and 1,2-diols are important building blocks for fine chemical synthesis. Here, we describe the R-selective 2,3-butanediol dehydrogenase from B. clausii DSM 8716 T (BcBDH) that belongs to the metal-dependent medium chain dehydrogenases/reductases family (MDR) and catalyzes the selective asymmetric reduction of prochiral 1,2-diketones to the corresponding HK and, in some cases, the reduction of the same to the corresponding 1,2-diols. Aliphatic diketones, like 2,3-pentanedione, 2,3-hexanedione, 5-methyl-2,3-hexanedione, 3,4-hexanedione and 2,3-heptanedione are well transformed. In addition, surprisingly alkyl phenyl dicarbonyls, like 2-hydroxy-1-phenylpropan-1-one and phenylglyoxal are accepted, whereas their derivatives with two phenyl groups are not substrates. Supplementation of Mn 2+(1 mM) increases BcBDH's activity in biotransformations. Furthermore, the biocatalytic reduction of 5-methyl-2,3-hexanedione to mainly 5-methyl-3-hydroxy-2-hexanone with only small amounts of 5-methyl-2-hydroxy-3-hexanone within an enzyme membrane reactor is demonstrated.

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“…reported the highly enantioselective synthesis of ( S )‐phenylacetylcarbinol [( S )‐PAC] and its derivatives in good yields by the wild‐type Ao:DCPIP OR using methylacetoin as a donor substrate . Before that, the synthesis of ( S )‐PAC was achieved only by rationally designed variants of R ‐selective enzymes …”

Section: Introductionmentioning

confidence: 99%

“…[8] Beforet hat, the synthesis of (S)-PAC was achieved only by rationally designed variantsofR-selective enzymes. [9] The relatede nzymeA coAB from Bacillus subtilis plays ak ey role in the biodegradation of methylacetoin. Metabolic engineeringp rovedi ts ability to generate an activated acetaldehyde from pyruvate or acetoin that is transferred to acetone, generating methylacetoin.…”

Section: Introductionmentioning

confidence: 99%

Structural and Mutagenesis Studies of the Thiamine‐Dependent, Ketone‐Accepting YerE from Pseudomonas protegens

et al. 2018

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A wide range of thiamine diphosphate (ThDP)-dependent enzymes catalyze the benzoin-type carboligation of pyruvate with aldehydes. A few ThDP-dependent enzymes, such as YerE from Yersinia pseudotuberculosis (YpYerE), are known to accept ketones as acceptor substrates. Catalysis by YpYerE gives access to chiral tertiary alcohols, a group of products difficult to obtain in an enantioenriched form by other means. Hence, knowledge of the three-dimensional structure of the enzyme is crucial to identify structure-activity relationships. However, YpYerE has yet to be crystallized, despite several attempts. Herein, we show that a homologue of YpYerE, namely, PpYerE from Pseudomonas protegens (59 % amino acid identity), displays similar catalytic activity: benzaldehyde and its derivatives as well as ketones are converted into chiral 2-hydroxy ketones by using pyruvate as a donor. To enable comparison of aldehyde- and ketone-accepting enzymes and to guide site-directed mutagenesis studies, PpYerE was crystallized and its structure was determined to a resolution of 1.55 Å.

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Asymmetric synthesis of (S)-phenylacetylcarbinol – closing a gap in C–C bond formation

Abstract: By the combination of biocatalyst design and reaction engineering, the so far not stereoselectively accessible (S)-phenylacetylcarbinol could be enzymatically synthesized with product concentrations >48 g L−1 and an enantiomeric excess up to 97%.

Cited by 26 publications

References 22 publications

Towards a Mechanistic Understanding of Factors Controlling the Stereoselectivity of Transketolase

Towards a Mechanistic Understanding of Factors Controlling the Stereoselectivity of Transketolase

Synthesis of α-hydroxy ketones and vicinal (R,R)-diols by Bacillus clausii DSM 8716^T butanediol dehydrogenase

Structural and Mutagenesis Studies of the Thiamine‐Dependent, Ketone‐Accepting YerE from Pseudomonas protegens

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Asymmetric synthesis of (S)-phenylacetylcarbinol – closing a gap in C–C bond formation

Abstract: By the combination of biocatalyst design and reaction engineering, the so far not stereoselectively accessible (S)-phenylacetylcarbinol could be enzymatically synthesized with product concentrations >48 g L−1 and an enantiomeric excess up to 97%.

Cited by 26 publications

References 22 publications

Towards a Mechanistic Understanding of Factors Controlling the Stereoselectivity of Transketolase

Towards a Mechanistic Understanding of Factors Controlling the Stereoselectivity of Transketolase

Synthesis of α-hydroxy ketones and vicinal (R,R)-diols by Bacillus clausii DSM 8716T butanediol dehydrogenase

Structural and Mutagenesis Studies of the Thiamine‐Dependent, Ketone‐Accepting YerE from Pseudomonas protegens

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Synthesis of α-hydroxy ketones and vicinal (R,R)-diols by Bacillus clausii DSM 8716^T butanediol dehydrogenase