Enzymatic Chemoselective Aldehyde–Ketone Cross‐Couplings through the Polarity Reversal of Methylacetoin

Bernacchia, Giovanni; Bortolini, Olga; Bastiani, Morena De; Lerin, Lindomar Alberto; Loschonsky, Sabrina; Massi, Alessandro; Müller, Michael; Giovannini, Pier Paolo

doi:10.1002/anie.201502102

Cited by 23 publications

(30 citation statements)

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“…27 For example, the use of 2,3-butanedione as an acetyl anion donor with various acceptors such as ethyl pyruvate (e.g. 27 For example, the use of 2,3-butanedione as an acetyl anion donor with various acceptors such as ethyl pyruvate (e.g.…”

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confidence: 99%

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Sutherland

2015

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Sutherland

2015

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“…Acetohydroxy acid synthases (AHASs) are a large group of ThDP‐dependent enzymes that are distantly related to YerE. Physiologically, they catalyze the synthesis of acetolactate and acetohydroxy acids . AHASs accept α‐keto acids but are not known to accept nonactivated ketones.…”

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confidence: 99%

“…Moreover, as with Yp YerE, esters of pyruvate can act as acceptor substrates. Compared to Yp YerE, Ao:DCPIP OR affords the same enantioselectivity for the addition of acetaldehyde to cyclohexane‐1,2‐dione but opposite enantiomers with aromatic acceptor substrates . Recently, Giovannini et al.…”

Section: Introductionmentioning

confidence: 99%

“…Physiologically,t hey catalyzet he synthesis of acetolactate anda cetohydroxy acids. [4,5] AHASsa ccept aketo acids buta re not known to accept nonactivated ketones.…”

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confidence: 99%

“…Compared to YpYerE, Ao:DCPIPO Ra ffords the same enantioselectivityf or the addition of acetaldehyde to cyclohexane-1,2-dioneb ut opposite enantiomersw ith aromatic acceptors ubstrates. [5] Recently,G iovannini et al 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 ad onors ubstrate. [8] Beforet hat, the synthesis of (S)-PAC was achieved only by rationally designed variantsofR-selective enzymes.…”

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confidence: 99%

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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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(S)‐Selectivity in Phenylacetyl Carbinol Synthesis Using the Wild‐Type Enzyme Acetoin:Dichlorophenolindophenol Oxidoreductase from Bacillus licheniformis

et al. 2016

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Thiamine diphosphate (ThDP)-dependent enzymes are well known biocatalysts for the asymmetric synthesis of α-hydroxy ketones with preferential (R)selectivity. Pharmaceutically relevant phenylacetyl carbinol (PAC) is prepared with absolute (S)-configuration only in few occasions using enzyme variants suitably designed through rational site-directed mutagenesis approaches. Herein, we describe the synthesis of (S)-phenylacetyl carbinol products with extended reaction scope employing the readily available wild-type ThDP-dependent enzyme acetoin:dichlorophenolindophenol oxidoreductase (Ao:DCPIP OR) from Bacillus licheniformis. On a semipreparative scale, cross-benzoin-like condensations of methylacetoin (donor) and differently substituted benzaldehydes proceed with almost complete chemoselectivity yielding the target (S)-1-hydroxy-1phenylpropan-2-one derivatives with high conversion efficiencies (up to 95%) and good enantioselectivities (up to 99%).Ao:DCPIP OR accepts hydroxy-and nitro-benzaldehydes and also sterically demanding substrates such as 1naphthaldehyde and 4-(tert-butyl)benzaldehyde, which are typically poor acceptors in enzymatic transformations. The explorative synthesis of (S)-phenylpropionyl carbinol mediated by Ao:DCPIP OR via carboligation of benzaldehyde with 3,4-hexanedione is also reported.

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Enzymatic Chemoselective Aldehyde–Ketone Cross‐Couplings through the Polarity Reversal of Methylacetoin

Cited by 23 publications

References 42 publications

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

(S)‐Selectivity in Phenylacetyl Carbinol Synthesis Using the Wild‐Type Enzyme Acetoin:Dichlorophenolindophenol Oxidoreductase from Bacillus licheniformis

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