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The oxidative aromatization of aliphatic N-heterocycles is a fundamental organic transformation for the preparation of a diverse array of heteroaromatic compounds. Despite many attempts to improve the efficiency and practicality of this transformation, most synthetic methodologies still require toxic and expensive reagents as well as harsh conditio...
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... and 2-quinolones are privileged scaffolds present in many drugs such as lenvatinib, brexpiprazole, bosutinib, and indacaterol ( Figure 1a), and consequently, several methodologies have been reported to date for their synthesis. However, the functionalization of these N-heterocycles is a challenge due to the low reactivity of their π-electron-deficient skeleton. ...
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... Thus, the development of practical and mild transformations that allow the synthesis of these aromatic rings from readily available starting materials is highly desirable. From a retrosynthetic standpoint, the oxidation of 1,2,3,4-tetrahydroquinolines (THQs) is the straightforward way to obtain aromatic quinolines (Figure 1b). 10 Such an approach enables the synthesis of these heteroaromatic compounds with substitution patterns and/or functional groups that are otherwise difficult to insert via traditional aromatic functionalization reactions. ...
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... Nevertheless, such methods show drawbacks in terms of reaction yields and, not less important, the costs of the catalysts. Herein, we describe a new, milder, and more sustainable route to quinolines via the oxidative aromatization of THQs by MAO-N biocatalysts (Figure 1b). Although this transformation operates well for N-unsubstituted THQs, it was found that the presence of alkyl substituents on the THQs nitrogen posed hurdles toward the formation of quinolinium derivatives and in turn to 2-quinolone frameworks through further oxidation (Figure 1b). ...
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... we describe a new, milder, and more sustainable route to quinolines via the oxidative aromatization of THQs by MAO-N biocatalysts (Figure 1b). Although this transformation operates well for N-unsubstituted THQs, it was found that the presence of alkyl substituents on the THQs nitrogen posed hurdles toward the formation of quinolinium derivatives and in turn to 2-quinolone frameworks through further oxidation (Figure 1b). 15 A different biocatalytic strategy was therefore investigated to access N-alkylquinolinium compounds, namely, the oxidative cyclization/aromatization of N-cyclopropyl-N-alkylanilines (NCAs) using horseradish peroxidase (HRP). ...
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... the other hand, no formation of 4a was achieved with oxone and mCPBA (Table 3, entries 8−9). Importantly, no desired product 4a was detected in the absence of H 2 O 2 , thus suggesting that the reaction is catalyzed by the HRP activated by the peroxide (Table 3, entry 10). Furthermore, when the biocatalytic cyclization/aromatization reaction was carried out without HRP and in the presence of sole H 2 O 2 , only a low amount of the desired product 4a was The reaction was carried out under N 2 . ...
Citations
... [19] Since not only the position of substituents, but also electronic factors can affect the conversion rates of biocatalytic reactions, substituents with different electronic properties were introduced into the aniline backbone to examine their effect on the efficiency of the aminolysis reaction. [20] Electron-donating substituents in para-position (1 d, 1 g, 1 h and 1 i) result in high conversion rates (up to~73 %), whereas electron-withdrawing ones are far less efficient. The three halogenated derivatives 1 j-1 l have conversion rates less than 30 %, while the trifluoromethyl (1 m), cyano (1 n) and nitro (1 o) substitutions abolish catalytic activity. ...
... Similar observations were reported for the enzyme monoamine oxidase, which catalyzes the oxidative aromatization of 1,2,3,4-tetrahydroquinolines (THQs); here, electron-donating substituents also favor the aromatization of THQs resulting in good conversion rates, while THQs derivatives with halogen substituents on the aromatic ring are poor substrates. [20] The aminolytic activity of Ndbn was further investigated on amines with a polycyclic aromatic hydrocarbon structure. Ndbn was highly active against 1 p (41.03 % conversion) and 1 q (64.94 % conversion), whereas no activity was recoded with 1 r. ...
The formation of amide bonds via aminolysis of esters by lipases generates a diverse range of amide frameworks in biosynthetic chemistry. Few lipases have satisfactory activity towards bulky aromatic amines despite numerous attempts to improve the efficiency of this transformation. Here, we report the discovery of a new intracellular lipase (Ndbn) with a broad substrate scope. Ndbn turns over a range of esters and aromatic amines in the presence of water (2 %; v/v), producing a high yield of multiple valuable amides. Remarkably, a higher conversion rate was observed for the synthesis of amides from substrates with aromatic amine rather than aliphatic amines. Molecular dynamics (MD) and quantum mechanical/molecular mechanical (QM/MM) studies showcase the mechanism for the preference for aromatic amines, including a more suitable orientation, shorter catalytic distances in the active site pocket and a lower reaction barrier for aromatic than for aliphatic amines. This unique lipase is thus a promising biocatalyst for the efficient synthesis of aromatic amides.
... In the last years, Horseradish Peroxidase (HRP) received a great attention as an effective and selective catalyst in synthetic transformations. [1][2][3] The enzyme is activated by heterolytic cleavage of H 2 O 2 with the concomitant formation of the ferryl intermediate, which is in turn converted to the resting state by oxygen atom transfer to substrate. [4][5][6] When H 2 O 2 accumulates in the reaction medium, HRP is inhibited due to undesired overoxidation of the iron atom in the prosthetic group. ...
... All reaction products were dried under high vacuum (10 À 3 mbar) before the spectroscopic and spectrometric analyses. 1 13 C NMR data and original spectra of the reaction products are reported in supporting information respectively SI#4 and SI#5. The crude product was purified by flash chromatography column using Hexane: EtOAc as eluent (5 : 1 for 1 a, 2 a, 3 a and 1 b, 2 b and 3 b, and 6 : 2 for 3 a, 3 b). ...
Pummerer's ketones resembling the tricyclic scaffold of bioactive natural substances were synthesized by blue‐LED driven Horseradish Peroxidase oxidative coupling of substituted phenols in 2‐methyltetrahydrofuran by using meso‐tetraphenylporphyrin as photosensitizer and dioxygen as primary oxidant. The application of functionalized lignin nanoparticles as a renewable and efficient platform for the immobilization of the enzyme extended the effectiveness of the overall process to heterogeneous catalysis under buffer limiting conditions.
Enzymes have gained their unique efficiency and catalytic activity through billions of years of evolution, perfecting their active site to a desired reaction. Inspired by nature, a novel enzyme‐mimicking platform is designed based on stable protein 1 (SP1) to create a nano‐compartment that mimics peroxidase activity. The biohybrid reveals enhanced activity over the hemin cofactor alone and improved stability in organic solvents in comparison to native peroxidase. Furthermore, the utilization of the obtained biohybrid in an optical glucose biosensing platform is shown. The biohybrid crystallographic structure is solved, indicating that the SP1 structure is not affected by the hemin coordination. This work opens the path for developing new cofactor binding centers in engineered protein scaffolds for various artificial catalytic processes.
A practical, efficient approach for the synthesis of C4‐arylated 2‐quinolones from propargylic chlorides and anilines has been developed. The synthesis process involves subsequent oxidations of the initial products, tetrahydroquinolines and quinolinium ions, eventually leading to desired quinolones. A mechanism for the transformation is proposed based on a meticulous examination of intermediates and comprehensive control experiments. With a thorough understanding of the reaction mechanism, the applicability of the reaction scope is expanded.
The fabrication of novel systems where enzymatic and metallic actives sites directly interact represents an elegant strategy for sustainable processes. One of the new strategies involves the in situ formation of metal nanoparticles on a protein network as scaffold. This biological entity is the key element because it conserves the biological catalytic efficiency and induces the final metallic nanoparticles generation on the structure. This method allows to obtain bifunctional enzyme‐metallic catalysts with excellent versatility and efficiency in a different reaction and experimental conditions. In this concept article, the relevant aspects in terms of fabrication of enzyme‐metal nanoparticles hybrids and recently reported examples of successful application in cascade processes will be described.
