Enantiocomplementary C–H Bond Hydroxylation Combining Photo‐Catalysis and Whole‐Cell Biocatalysis in a One‐Pot Cascade Process

Peng, Yongzhen; Li, Danyang; Fan, Jiajie; Xu, W.; Xu, Jian; Yu, Hui‐Lei; Lin, Xianfu; Wu, Qi

doi:10.1002/ejoc.201901682

Cited by 23 publications

(15 citation statements)

References 58 publications

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“…Nonetheless, H 2 O 2 is an easy-to-use commodity chemical, and its use as a liquid reagent allows its concentration in the reaction solution to be controlled more easily than the concentration of O 2 . Our results complement recent studies using photocatalysts for converting alkylbenzenes to ketones, − as well as recent studies using cytochrome P450s, peroxygenase enzymes, and artificial metalloenzymes to convert alkylbenzenes to alcohols, ketones, or amines. − Relative to peroxygenase enzymes, the HRP–NHPI system offers the advantage of not requiring the substrate to fit within a confined active site, making it compatible for use with bulky substrates. Another practical advantage is the commercial availability of HRP, which avoids the need for recombinant enzyme expression and purification.…”

supporting

confidence: 84%

A Horseradish Peroxidase–Mediator System for Benzylic C–H Activation

2022

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Enzyme–mediator systems generate radical intermediates that abstract hydrogen atoms under mild conditions. These systems have been employed extensively for alcohol oxidation, primarily in biomass degradation, but they are underexplored for direct activation of C(sp3)–H bonds in alkyl groups. Here, we combine horseradish peroxidase (HRP), H2O2, and redox mediator N-hydroxyphthalimide (NHPI) for C(sp3)–H functionalization of alkylbenzene-type substrates. The HRP–NHPI system is >10-fold more active than existing enzyme–mediator systems in converting alkylbenzenes to ketones and aldehydes under air, and it operates from 0–50 °C and in numerous aqueous–organic solvent mixtures. The benzylic substrate radical can be trapped through a reaction with NHPI, demonstrating the formation of benzylic products beyond ketones. Furthermore, we demonstrate a one-pot, two-step enzymatic cascade for converting alkylbenzenes to benzylic amines. Overall, the HRP–NHPI system enables the selective benzylic C–H functionalization of diverse substrates under mild conditions using a straightforward procedure.

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confidence: 84%

A Horseradish Peroxidase–Mediator System for Benzylic C–H Activation

2022

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“…The types of enzymatic reactions predicted correctly by the Enzymatic Transformer are well illustrated by selected cases from the enantiomeric resolutions in the test set for two lipases, 31,32 two alcohol dehydrogenases, 33,34 and one example each of a synthase, 35 reductase, [36][37][38] transaminase 39,40 and peroxygenase (reaction (1) to (8), Figure 4). 41,42 Considering that none of the products of these reactions have been seen by the model during training, the ability of the Enzymatic Transformer model to correctly predict not only the correct reaction product but also the correct stereochemical outcome of the enantiomeric resolution reactions is remarkable. On the other hand, analyzing unsuccessful predictions by the Enzymatic Transformer returns a differentiated picture ( Figure 5).…”

Section: Examples Of Correct and Incorrect Predictions By The Enzymatmentioning

confidence: 99%

Predicting Enzymatic Reactions with a Molecular Transformer

Kreutter¹,

Schwaller²,

Reymond

2021

Preprint

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The use of enzymes for organic synthesis allows for simplified, more economical and selective synthetic routes not accessible to conventional reagents. However, predicting whether a particular molecule might undergo a specific enzyme transformation is very difficult. Here we exploited recent advances in computer assisted synthetic planning (CASP) by considering the Molecular Transformer, which is a sequence-to-sequence machine learning model that can be trained to predict the products of organic transformations, including their stereochemistry, from the structure of reactants and reagents. We used multi-task transfer learning to train the Molecular Transformer with one million reactions from the US Patent Office (USPTO) database as a source of general chemistry knowledge combined with 32,000 enzymatic transformations, each one annotated with a text description of the enzyme. We show that the resulting Enzymatic Transformer model predicts the products formed from a given substrate and enzyme with remarkable accuracy, including typical kinetic resolution processes.

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“…2-HAP can be produced using chemical and biocatalytic methods. The chemical synthesis methods mainly include photocatalytic oxidation of phenethyl alcohol, photocatalytic decarboxylative carbonylation of carboxylic acid, , oxidation of phenylglycol or terminal olefin by metal and nanometal catalysis, , and/or dehalogenation of bromoacetophenone catalyzed by microwave radiation . Unfortunately, chemical methods include disadvantages such as harsh reaction conditions, high-priced substrates and catalysts, and technical challenges (such as catalyst stability and heavy metal recovery).…”

Section: Introductionmentioning

confidence: 99%

One-Pot Enzymatic–Chemical Cascade Route for Synthesizing Aromatic α-Hydroxy Ketones

et al. 2021

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2-Hydroxyacetophenone (2-HAP) is an important building block for the production of a series of natural products and pharmaceuticals; however, there is no safe, efficient, and economical method for 2-HAP synthesis. Here, a one-pot enzymatic-chemical cascade route was designed for synthesizing 2-HAP based on retrosynthetic analysis. First, a spontaneous proton-transfer reaction was designed using a computational simulation that enabled 2-HAP synthesis from the isomer 2-hydroxy-2-phenylacetaldehyde. A route for 2-hydroxy-2-phenylacetaldehyde synthesis was then constructed by introducing the unnatural substrate glyoxylic acid into a C–C ligation reaction catalyzed by Candida tropicalis pyruvate decarboxylase. Assembly and optimization of this enzymatic–chemical cascade route resulted in a final yield of 92.7%. Furthermore, stereospecific carbonyl reductases were introduced to construct a synthetic application platform that enabled further transformation of 2-HAP into (S)- and (R)-1-phenyl-1,2-ethanediol. This method of cascading spontaneous chemical and enzymatic reactions to synthesize chemicals offers insight into avenues for synthesizing other valuable chemicals.

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Enantiocomplementary C–H Bond Hydroxylation Combining Photo‐Catalysis and Whole‐Cell Biocatalysis in a One‐Pot Cascade Process

Cited by 23 publications

References 58 publications

A Horseradish Peroxidase–Mediator System for Benzylic C–H Activation

A Horseradish Peroxidase–Mediator System for Benzylic C–H Activation

Predicting Enzymatic Reactions with a Molecular Transformer

One-Pot Enzymatic–Chemical Cascade Route for Synthesizing Aromatic α-Hydroxy Ketones

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