Síntesis biocatalíticas concurrentes de compuestos quirales multifuncionales. Cascadas de aldosas con transaminasas o cetoreductasas
[eng] Concurrent or consecutive enzymatic cascade reactions have received special attention in the development of synthetic strategies for complex molecules. The advantage of these strategies is that they eliminate the need to purify the intermediate compounds, making the synthetic process more effi...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/202965 |
| Acceso en línea: | https://hdl.handle.net/2445/202965 http://hdl.handle.net/10803/689164 |
| Access Level: | acceso abierto |
| Palabra clave: | Biocatàlisi Enzims Quiralitat Deshidrogenases Biocatalysis Enzymes Chirality Dehydrogenases |
| Sumario: | [eng] Concurrent or consecutive enzymatic cascade reactions have received special attention in the development of synthetic strategies for complex molecules. The advantage of these strategies is that they eliminate the need to purify the intermediate compounds, making the synthetic process more efficient. In this thesis, we study the design of biocatalytic routes for the synthesis of chiral compounds from simple precursors, in which each enzymatic reaction contributes to increase the degree of complexity of the final molecules. With this approach, derivatives of γ-hydroxy-α-amino acids, 2- hydroxy-4-butyrolactones and 2-hydroxy-4-arylbut-3-enoic acid were synthesized. The γ-hydroxy-α- amino acids are relevant in the pharmaceutical industry due to their biological properties. For example, (2S,3R,4S)-4-hydroxyisoleucine, 4-hydroxy-L -norvaline and 4-hydroxypipecolic acid are used in the treatment of diabetes mellitus. In addition, these compounds are chiral precursors of bioactive molecules such as antibiotics, fungicides and herbicides, such as α-amino-γ-butyrolactones, 4,5- dihydroxynorvaline or 4-hydroxypyroglutamic acid and its derivatives. In this sense, in chapter 3.1 we approached the diastereoselective synthesis of γ-hydroxy-α-amino acids through consecutive enzymatic reactions coupling an aldolase and several transamination systems with excellent enantioselectivity. The γ-hydroxy-α-amino acids were chemically transformed into α-amino-γ- butyrolactones (12 compounds). On the other hand, 2-hydroxy acid derivatives and 2-hydroxy-4- butyrolactones are relevant synthons for the synthesis of biologically active molecules, both natural and synthetic, as well as chiral auxiliaries in asymmetric organic synthesis. To obtain these molecules, several synthesis methods have been developed, such as asymmetric reduction with metal complexes, stereoselective aldol reactions with metal or organocatalysis, and enzymatic reduction, among others. Chapter 3.2 deals with the diastereoselective synthesis of 2-hydroxy-4-butyrolactones by aldol reactions catalyzed by a stereoselective aldolase, followed by reduction of the carbonyl group of the aldol products using stereocomplemetal dehydrogenases. In total 29 products were synthesized: the enantiomers of 2-hydroxy-4-butyrolactone (>99% ee), 2-hydroxy-3-alkyl-4-butyrolactones with (2R,3S), (2S,3S), (2R,3R), or (2S,3R) configuration with diastereomeric ratios between 60:40 to 98:2. and 2-hydroxy-4-alkyl-4-butyrolactones with (2S,4R) configuration with 87:13 to 98:2 diastereomeric ratio. Finally, 2-hydroxy-4-arylbut-3-enoic acid derivatives are relevant precursors in the synthesis of angiotensin-converting enzyme inhibitors (e.g. Enalapril, lisinopril, Cilapril or Benazepril) used in the treatment of blood pressure lowering. In chapter 3.3, the promiscuous activity of the enzyme 1- piperidine-2-carboxylate/Δ(1)-pyrroline-2-carboxylate reductase from Pseudomonas syringae pv. tomato DSM 50315 (DpkA) is exploited to achieve the stereoselective synthesis of 2-hydroxy-4- arylbut-3-enoic acids. The synthetic strategy consisted of consecutive enzymatic reactions between HBPA aldolase, which catalyzed aldol condensation reactions between pyruvate and aromatic aldehydes, followed by stereoselective reduction catalysed by DpkA. In total, 9 2-hydroxy-4-arylbut- 3-enoic acid derivatives with (S,E)-configuration and 87-99% enantiomeric purity were obtained. |
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