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Title: Development of α-amylase Catalysed Organic Transformations
Authors: Dutt, Sunil
Supervisor: Tyagi, Vikas
Keywords: α-Amylase;Biocatalytic;Aza-Michael Addition;Chemo-enzymatic;Cascade;Quinolines
Issue Date: 29-Mar-2023
Abstract: Enzymes and whole cells are examples of biocatalysts that really can speed up and begin biochemical processes. In particular, enzymes are globular proteins formed by relatively tiny microbes that facilitate the modification of organic compounds into usable products. In addition, applying enzymes as a catalyst for unnatural reactions has been established as a valuable and environmentally sustainable method for synthetic chemistry. Besides, they provide high enantioselectivity, regioselectivity, and chemoselectivity, which could help to accelerate chemical reactions quite successfully and decrease the possibility of unwanted side reactions like racemization, decomposition, rearrangements, and isomerization. The selectivity and specificity of enzymes as a biocatalyst are also enhanced by genetic engineering to create efficient and environmentally friendly catalysts. Consequently, a critical challenge in the field of bioprocesses is the investigation of an enzyme that could facilitate a non-natural reaction. Further, enzymes have been categorized into different classes such as lyases, isomerases, ligases, oxidoreductases, transferases as well as hydrolases. Among different hydrolases, α- amylase have been used to catalyze a broad range of organic transformations. In nature, α- amylase catalyzes the hydrolysis of 1,4-glycosidic bonds in starch which leads to the formation of glucose, maltose, and dextrin. However, in the last decade, various α-amylase catalyzed nonnatural organic transformations have been reported. A crucial transformation in organic synthesis is the Michael addition of amines to enones to develop β-amino carbonyls. The Michael addition of aromatic amines to enones has been catalysed in the presence of a number of catalysts, but, no enzyme was available to catalyze this process. We first time found that α-amylase from Aspergillus oryzae has a superior catalytic efficiency (63-83% yield) whenever it was used to facilitate the Michael addition of various aryl (hetero) amines to methyl vinyl ketone. Additionally, in order to understand the key interactions of the substrates with the amino acid residues close to the active site as well as the most likely reaction mechanism, molecular docking, and molecular dynamics (MD) simulations were investigated. The above studies showed the significance of Glu230 and Asn295 in the substrate activation process. We continued to expand our research beyond and developed the derivatives of substituted quinolines. The quinoline ring system, which is widely spread in pharmaceutical drugs is essential for the growth of new drugs. The biological activities of quinoline derivatives such as antimalaria, anticancer, antiviral, antifungal, and anti-tuberculosis make them highly interesting scaffolds in medicinal chemistry. A few catalysts have previously been made accessible for the synthesis of modified quinolines. Herein, we displayed a one-pot domino Abstract of the thesis ix aza-Michael/Aldol/aromatization reaction catalyzed by α-amylase for the formation of modified quinolines. It was also found that the α-amylase enzyme from Aspergillus oryzae has high catalytic efficiency (56-86% yield) in the cascade reaction of various 2-amino benzaldehydes with, α,β-unsaturated carbonyls. Further, we find the application of α-amylase in chemo-enzymatic synthesis. The field of using an enzyme as well as transition metals to facilitate a series of chemical reactions in a singlepot has grown significantly in recent years. In this context, we developed a one-pot synthesis and functionalization of β-aminocarbonyls using α-amylase enzyme and a Pd-based catalyst. When isocyanide has been used in the reaction, the chemo-enzymatic approach produces substituted indole derivatives with a broad variety of substitutions. Further, phenylboronic acid was used in the place of isocyanide, which provided a decent yield for the modified amino biaryls. Besides, the one-pot chemo-enzymatic method worked well when substituted 2-bromo aniline and isocyanide/phenylboronic acid were used in the reaction, and it generates the corresponding products in an isolated yield of 56–84%. All the synthesized compounds were characterized by 1H NMR and 13CNMR.
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