Biocatalytic Friedel–Crafts Alkylation Using a Promiscuous Biosynthetic Enzyme

Schultz, Erica E.; Braffman, Nathaniel R.; Luescher, Michael U.; Hager, Harry H.; Balskus, Emily P.

doi:10.1002/anie.201814016

Cited by 49 publications

(78 citation statements)

References 34 publications

(17 reference statements)

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“…We set out to investigate whether BrtB, the only enzyme in the brt gene cluster with no ascribed function, could be responsible for ester formation. Following the protocol reported by Schultz et al 15 , we expressed and purified a Strep-Tag©-recombinant version of BrtB (NStrep-BrtB) in Escherichia coli BL21 DE3 Rosetta cells and tested its ability to convert 1 and 2 into 3 in vitro. We found that adding NStrep-BrtB to a reaction mixture composed of 1, 2 and Ca 2+ and Mg 2+ -containing buffer 12,15 was necessary and sufficient to generate diester 3 as well as monoester(s) 6a and/or 6b (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…However, the role played by the brt-encoded CylK homolog (BrtB) has remained unclear. The reasons for this are twofold: first, the action of a CylK homolog is not necessary to explain the biosynthesis of currently known bartolosides 13,14 ; second, CylK requires a free C-2 resorcinol as a nucleophile 12,15 , a position that is unavailable (it is alkylated) in the bartolosides. Here, we show that BrtB is an O-alkylating enzyme that catalyzes the esterification of free (non-activated) fatty acids with the chlorinated positions found in the bartolosides, generating a diversity of fatty acid-bartoloside esters (Fig.…”

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confidence: 99%

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BrtB is an O-alkylating enzyme that generates fatty acid-bartoloside esters

et al. 2020

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Esterification reactions are central to many aspects of industrial and biological chemistry. The formation of carboxyesters typically occurs through nucleophilic attack of an alcohol onto the carboxylate carbon. Under certain conditions employed in organic synthesis, the carboxylate nucleophile can be alkylated to generate esters from alkyl halides, but this reaction has only been observed transiently in enzymatic chemistry. Here, we report a carboxylate alkylating enzyme-BrtBthat catalyzes O-C bond formation between free fatty acids of varying chain length and the secondary alkyl halide moieties found in the bartolosides. Guided by this reactivity, we uncovered a variety of natural fatty acid-bartoloside esters, previously unrecognized products of the bartoloside biosynthetic gene cluster.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

BrtB is an O-alkylating enzyme that generates fatty acid-bartoloside esters

et al. 2020

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“…Enzymes are potent biocatalysts that are able to carry out numerous chemical transformations with remarkable chemo‐, regio‐ and stereo‐selectivity . The intrinsic sustainability of enzymatic processes along with the use of green reaction conditions such as absence of potentially toxic solvents, and activation with non‐conventional sources of energy has expanded the use of biocatalysis in both chemical industries and in academic institutions, focusing in drug discovery and in the synthesis of molecules with relevant biological activity .…”

Section: Introductionmentioning

confidence: 99%

“…Enzymes are potent biocatalysts that are able to carry out numerous chemical transformations with remarkable chemo-, regio-and stereo-selectivity. [1][2][3][4][5] The intrinsic sustainability of enzymatic processes along with the use of green reaction conditions such as absence of potentially toxic solvents, and activation with non-conventional sources of energy has expanded the use of biocatalysis in both chemical industries and in academic institutions, focusing in drug discovery and in the synthesis of molecules with relevant biological activity. [6][7][8] Recent developments in protein engineering and enzyme directed evolution, [9,10] together with the availability of efficient methods for the production of recombinant molecules, have led to rapidly expanding new fields in biocatalysis.…”

Section: Introductionmentioning

confidence: 99%

Thermal and Mechanical Stability of Immobilized Candida antarctica Lipase B: an Approximation to Mechanochemical Energetics in Enzyme Catalysis.

Pérez‐Venegas¹,

Tellez-Cruz²,

Solorza‐Feria³

et al. 2019

ChemCatChem

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Very recently, several successful enzymatic processes performed with mechanical activation have been disclosed; that is, despite the mechanical stress caused by High-Speed Ball-Milling, immobilized enzymes can retain activity. In the present study, the effect of thermal and mechanical stress was examined as potential inducers of enzymatic denaturation, when using either free, immobilized, or ground immobilized enzyme. The recorded observations show a remarkable stability of ground immobilized enzyme. Moreover, ground biocatalyst turns out to exhibit an increase of one order of magnitude in the efficiency of the catalytic process, maintaining excellent enantiodiscrimination, without significant activity loss even after four milling cycles. These observations rule out enzyme inactivation as direct consequence of the milling process. Additionally, boosted enzyme efficiency was used to optimize a relatively inefficient chiral amine resolution reaction, achieving a 25 % faster biotransformation (in 45 min) and yielding essentially enantiopure products (ee > 99%, E > 500). E N435 = 595 and E 80°C = 317), leading to highly enantiopure compounds, higher than 99 % for both (S)-3 and (R)-4), and corroborating the aforementioned increase in ΔΔG � when ground N435 is used (Figure 9). 4 5 6 7 8

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“…Friedel-Crafts alkylation has been an important method for preparing substituted aromatics from the past to the present days [1][2][3]. Among these classical, but practical alkylation reactions, the homogeneous benzylation of aromatic hydrocarbons by benzyl alcohol (BzOH) or benzyl chloride (BzCl) is one of the significant reaction processes for the preparation of diphenylmethane (DPM) and its substituted derivatives (Scheme 1).…”

Section: Introductionmentioning

confidence: 99%

The Steric Effect in Green Benzylation of Arenes with Benzyl Alcohol Catalyzed by Hierarchical H-beta Zeolite

Liu

Wang

et al. 2019

Catalysts

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For decades the steric effect was still ambiguously understood in catalytic benzylation reactions of arenes with benzyl alcohol, which limited the green synthesis of phenylmethane derivates in industrial scale. This research applies a series of silica–alumina beta zeolites to systematically evaluate factors like catalyst porosity, reactants molecule size, and reaction temperature on catalytic benzylation. First, a suitable hierarchical beta zeolite catalyst was screened out by X-ray powder diffraction, N2 adsorption−desorption, and probe benzylation with p-xylene. In the following substrates expanding study, for a typical benzylation of benzene, it showed extraordinary performance among literature reported ones that the conversion was 98% while selectivity was 90% at 353 K only after 10 min. The steric effect of aromatics with different molecular sizes on benzylation was observed. The reaction activities of four different aromatics followed the order: benzene > toluene > p-xylene > mesitylene. Combined with macroscopic kinetic analysis, this comprehensive study points out for the first time that the nature of this steric effect was dominated by the relative adsorption efficiency of different guest aromatic molecules on the host zeolite surface.

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Biocatalytic Friedel–Crafts Alkylation Using a Promiscuous Biosynthetic Enzyme

Abstract: This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record.

Cited by 49 publications

References 34 publications

BrtB is an O-alkylating enzyme that generates fatty acid-bartoloside esters

BrtB is an O-alkylating enzyme that generates fatty acid-bartoloside esters

Thermal and Mechanical Stability of Immobilized Candida antarctica Lipase B: an Approximation to Mechanochemical Energetics in Enzyme Catalysis.

The Steric Effect in Green Benzylation of Arenes with Benzyl Alcohol Catalyzed by Hierarchical H-beta Zeolite

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