Asymmetric Hydroxymethylation of Isoindolinones Using Bench-Stable Formaldehyde Surrogates

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14160%2F23%3A00132383" target="_blank" >RIV/00216224:14160/23:00132383 - isvavai.cz</a>

Výsledek na webu

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DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

Asymmetric Hydroxymethylation of Isoindolinones Using Bench-Stable Formaldehyde Surrogates

Popis výsledku v původním jazyce

The asymmetric cross-aldol reaction with formaldehyde is one of the most efficient carbon chain extension methods. Various sources of formaldehyde, such as paraformaldehyde, trioxane, and aqueous formaldehyde, are commonly used for homologation reactions. However, performing this type of reaction is far from straightforward.1 Formalin solutions may cause incompatibility issues with catalytic systems due to the presence of water. On the other hand, the polymeric precursors thereof are poorly soluble in many organic solvents and have relatively low reactivity. Alternatively, anhydrous formaldehyde is generated in situ from its precursors under the alkaline conditions.2 Since the formaldehyde releasers have never been systematically investigated, we synthesized and evaluated more than 20 formaldehyde surrogates in a model asymmetric methylolation of isoindolinones. A thorough screening of our catalyst library revealed that the bifunctional molecules containing basic moieties (i.e., Takemoto-type catalysts) provided the best enantioselective outcomes. Next, a series of optimizations was performed to establish the most suitable reaction conditions. A combination of the above catalysts with the triazole-based formaldehyde surrogates furnished the hydroxymethylated products within 24–48 h in very good enantiomeric ratios (e.r.~95:5). Compared to the prior methodologies,3 this protocol constitutes a steep advance in the efficacy and stereoselectivity of the organocatalytic process. Additionally, several stereoretentive transformations of obtained products were accomplished.

Název v anglickém jazyce

Asymmetric Hydroxymethylation of Isoindolinones Using Bench-Stable Formaldehyde Surrogates

Popis výsledku anglicky

The asymmetric cross-aldol reaction with formaldehyde is one of the most efficient carbon chain extension methods. Various sources of formaldehyde, such as paraformaldehyde, trioxane, and aqueous formaldehyde, are commonly used for homologation reactions. However, performing this type of reaction is far from straightforward.1 Formalin solutions may cause incompatibility issues with catalytic systems due to the presence of water. On the other hand, the polymeric precursors thereof are poorly soluble in many organic solvents and have relatively low reactivity. Alternatively, anhydrous formaldehyde is generated in situ from its precursors under the alkaline conditions.2 Since the formaldehyde releasers have never been systematically investigated, we synthesized and evaluated more than 20 formaldehyde surrogates in a model asymmetric methylolation of isoindolinones. A thorough screening of our catalyst library revealed that the bifunctional molecules containing basic moieties (i.e., Takemoto-type catalysts) provided the best enantioselective outcomes. Next, a series of optimizations was performed to establish the most suitable reaction conditions. A combination of the above catalysts with the triazole-based formaldehyde surrogates furnished the hydroxymethylated products within 24–48 h in very good enantiomeric ratios (e.r.~95:5). Compared to the prior methodologies,3 this protocol constitutes a steep advance in the efficacy and stereoselectivity of the organocatalytic process. Additionally, several stereoretentive transformations of obtained products were accomplished.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

<a href="/cs/project/LM2018127" target="_blank" >LM2018127: Česká infrastruktura pro integrativní strukturní biologii</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>S - Specificky vyzkum na vysokych skolach<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2023

Kód důvěrnosti údajů

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