Development of atropisomeric organocatalysts for asymmetric Henry reaction

Kód výsledku v IS VaVaI

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RIV/62157124:16370/19:43878097

Výsledek na webu

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DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

Development of atropisomeric organocatalysts for asymmetric Henry reaction

Popis výsledku v původním jazyce

Our department has been interested in compounds affecting adrenergic receptors for a long period. These compounds often share the structure derived from aryl- aminoethanol or aryloxy-aminopropanol skeleton. Neverthe- less, the amino alcohol-based compounds are not important only in this particular group of therapeutics but occur ubiquitously among bioactive substances of natural or synthetic origin. Many of these molecules have developed an important role in clinical practice and appear also on a list of the best-selling active pharmaceutical ingredients. The amino alcohol unit introduces the promising pharmacophoric properties, which can be largely affected by its stereoisomeric configuration. The asymmetric organocata- lyzed Henry reaction can represent a powerful method to synthesize the above compounds in a substantially effective way. In the catalytic asymmetric Henry reaction, the chiral bifunctional organocatalysts have proved their effectiveness and selectivity, however, many of them also suffer from serious practical disadvantages such as narrow substrate scope, relatively high catalyst loading, long reaction times, necessity of the very low reaction temperatures, and low stereoselective outcome, which provide us enough room for improvements. Therefore we have concentrated on the identification of the novel axially chiral backbones for the organocatalysts, which represent the tunable C2-symmetric frameworks that can help to address at least some of the aforementioned issues. In order to find the most active and selective molecules, a large screening including 24 chiral scaffolds and 31 catalysts has been performed. Under the thoroughly optimized reaction conditions, the excellent chemical yields (up to 99%), very good to excellent enantioselectivities (up to 97% ee), and remarkable diastereoselectivities (up to 10:1) were observed. It is worth mentioning that for a number of substrates, an exceptionally good catalytic performance was reached with the highest enantiomeric excesses and diastereoselectivities reported for the asymmetric organocatalyzed Henry reaction so far. The preliminary kinetic and spectroscopic experiments were conducted in order to propose a catalytic cycle of the above transformation and gain better insight into the reaction mechanism. Moreover, interesting temperature and solvent effects were observed. The robustness of the newly developed catalytic processes was proved in a larger scale total syntheses of enantiopure (S)-econazole, the late-stage intermediate of (R)- mirabegron, and CF3-appended (R)-halostachine.

Název v anglickém jazyce

Development of atropisomeric organocatalysts for asymmetric Henry reaction

Popis výsledku anglicky

Our department has been interested in compounds affecting adrenergic receptors for a long period. These compounds often share the structure derived from aryl- aminoethanol or aryloxy-aminopropanol skeleton. Neverthe- less, the amino alcohol-based compounds are not important only in this particular group of therapeutics but occur ubiquitously among bioactive substances of natural or synthetic origin. Many of these molecules have developed an important role in clinical practice and appear also on a list of the best-selling active pharmaceutical ingredients. The amino alcohol unit introduces the promising pharmacophoric properties, which can be largely affected by its stereoisomeric configuration. The asymmetric organocata- lyzed Henry reaction can represent a powerful method to synthesize the above compounds in a substantially effective way. In the catalytic asymmetric Henry reaction, the chiral bifunctional organocatalysts have proved their effectiveness and selectivity, however, many of them also suffer from serious practical disadvantages such as narrow substrate scope, relatively high catalyst loading, long reaction times, necessity of the very low reaction temperatures, and low stereoselective outcome, which provide us enough room for improvements. Therefore we have concentrated on the identification of the novel axially chiral backbones for the organocatalysts, which represent the tunable C2-symmetric frameworks that can help to address at least some of the aforementioned issues. In order to find the most active and selective molecules, a large screening including 24 chiral scaffolds and 31 catalysts has been performed. Under the thoroughly optimized reaction conditions, the excellent chemical yields (up to 99%), very good to excellent enantioselectivities (up to 97% ee), and remarkable diastereoselectivities (up to 10:1) were observed. It is worth mentioning that for a number of substrates, an exceptionally good catalytic performance was reached with the highest enantiomeric excesses and diastereoselectivities reported for the asymmetric organocatalyzed Henry reaction so far. The preliminary kinetic and spectroscopic experiments were conducted in order to propose a catalytic cycle of the above transformation and gain better insight into the reaction mechanism. Moreover, interesting temperature and solvent effects were observed. The robustness of the newly developed catalytic processes was proved in a larger scale total syntheses of enantiopure (S)-econazole, the late-stage intermediate of (R)- mirabegron, and CF3-appended (R)-halostachine.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

30107 - Medicinal chemistry

Projekt

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Návaznosti

S - Specificky vyzkum na vysokych skolach

Rok uplatnění

2019

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů