Development of Novel Chiral Biphenyl- Based Bis(Thiourea) Organocatalysts for Asymmetric Henry Reaction

Kód výsledku v IS VaVaI

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Výsledek na webu

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DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

Development of Novel Chiral Biphenyl- Based Bis(Thiourea) Organocatalysts for Asymmetric Henry Reaction

Popis výsledku v původním jazyce

In the first part of my Ph.D. research, I focused on syntheses of racemic compounds based on the aryloxy- aminopropanol and aralkyl-aminoethanol structural scaffolds. The samples of these compounds were provided to our collaborative partners for evaluation of the selected types of potential biological activity. All the amino alcohol-based compounds above bear at least one stereogenic center and both of their enantiomers can often largely differ in their biological effects. The biological testing of pure enantiomers together with the racemic samples is therefore highly justifiable and the development of procedures for their asymmetric syntheses has become our long-standing critical challenge. The asymmetric organocatalyzed Henry reaction can represent a powerful method to synthesize the aforementioned compounds in a substantially effective way. In the homogeneous organocatalyzed asymmetric Henry reaction, the chiral thiourea catalysts have proved their effectiveness and selectivity. However, the currently known thiourea organocatalysts for the enantioselective nitroaldol reaction of aromatic aldehydes are associated with limited possibilities of further functionalization of their structure, expensive resolution agents, difficult and low-yield syntheses involving precious transition-metal complexes with necessity of the subsequent chromatographic purification, cumbersome isolation of the final nitroaldol products from the reaction mixture, and none or low (predominantly anti) diastereoselectivities. In the second part of my Ph.D. work, I therefore concentrated on a simplification of the chiral backbone of the catalysts to the ?bare minimum?, and present the several novel C2-symmetric bis(thiourea) organocatalysts based on axially chiral biphenyls, which represent a tunable framework suitable for further functionalization in order to enhance enantio- or diastereoselectivity of the studied asymmetric reaction. Catalysts were prepared via high-yield and scalable syntheses avoiding transition-metal complexes and protecting groups using inexpensive resolution agents. Modifications of the chiral biphenyl backbone allowed to incorporate tertiary amine functionalities to the structure of the catalysts that eliminates the need for the auxiliary base during the reaction. The above organocatalysts were tested in the asymmetric Henry reaction of mainly aromatic and heterocyclic aldehydes with linear nitroalkanes. Under the thoroughly optimized reaction conditions, the excellent chemical yields (up to 99%), very good to excellent enantioselectivities (up to 97% ee), and remarkable syn-diastereoselectivities (up to 10:1) were observed. It is worth mentioning that for a number of electron-deficient aldehydes, an exceptionally good catalytic performance was reached with the highest enantiomeric excesses and syn-selectivities reported for the asymmetric organocatalyzed Henry reaction so far. The viability of the newly developed catalytic process, offering operationally simple isolation of the respective ?-nitroalcohols, was proved in total syntheses of enantiopure (S)-econazole and (R)-mirabegron a late-stage intermediate. The preliminary kinetic and spectroscopic experiments were conducted in order to establish a catalytic cycle of the above transformation and gain better insight into the reaction mechanism. Moreover, an interesting temperature and solvent effects were observed

Název v anglickém jazyce

Development of Novel Chiral Biphenyl- Based Bis(Thiourea) Organocatalysts for Asymmetric Henry Reaction

Popis výsledku anglicky

In the first part of my Ph.D. research, I focused on syntheses of racemic compounds based on the aryloxy- aminopropanol and aralkyl-aminoethanol structural scaffolds. The samples of these compounds were provided to our collaborative partners for evaluation of the selected types of potential biological activity. All the amino alcohol-based compounds above bear at least one stereogenic center and both of their enantiomers can often largely differ in their biological effects. The biological testing of pure enantiomers together with the racemic samples is therefore highly justifiable and the development of procedures for their asymmetric syntheses has become our long-standing critical challenge. The asymmetric organocatalyzed Henry reaction can represent a powerful method to synthesize the aforementioned compounds in a substantially effective way. In the homogeneous organocatalyzed asymmetric Henry reaction, the chiral thiourea catalysts have proved their effectiveness and selectivity. However, the currently known thiourea organocatalysts for the enantioselective nitroaldol reaction of aromatic aldehydes are associated with limited possibilities of further functionalization of their structure, expensive resolution agents, difficult and low-yield syntheses involving precious transition-metal complexes with necessity of the subsequent chromatographic purification, cumbersome isolation of the final nitroaldol products from the reaction mixture, and none or low (predominantly anti) diastereoselectivities. In the second part of my Ph.D. work, I therefore concentrated on a simplification of the chiral backbone of the catalysts to the ?bare minimum?, and present the several novel C2-symmetric bis(thiourea) organocatalysts based on axially chiral biphenyls, which represent a tunable framework suitable for further functionalization in order to enhance enantio- or diastereoselectivity of the studied asymmetric reaction. Catalysts were prepared via high-yield and scalable syntheses avoiding transition-metal complexes and protecting groups using inexpensive resolution agents. Modifications of the chiral biphenyl backbone allowed to incorporate tertiary amine functionalities to the structure of the catalysts that eliminates the need for the auxiliary base during the reaction. The above organocatalysts were tested in the asymmetric Henry reaction of mainly aromatic and heterocyclic aldehydes with linear nitroalkanes. Under the thoroughly optimized reaction conditions, the excellent chemical yields (up to 99%), very good to excellent enantioselectivities (up to 97% ee), and remarkable syn-diastereoselectivities (up to 10:1) were observed. It is worth mentioning that for a number of electron-deficient aldehydes, an exceptionally good catalytic performance was reached with the highest enantiomeric excesses and syn-selectivities reported for the asymmetric organocatalyzed Henry reaction so far. The viability of the newly developed catalytic process, offering operationally simple isolation of the respective ?-nitroalcohols, was proved in total syntheses of enantiopure (S)-econazole and (R)-mirabegron a late-stage intermediate. The preliminary kinetic and spectroscopic experiments were conducted in order to establish a catalytic cycle of the above transformation and gain better insight into the reaction mechanism. Moreover, an interesting temperature and solvent effects were observed

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

30107 - Medicinal chemistry

Projekt

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Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2018

Kód důvěrnosti údajů

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