Asymmetric Organocatalytic Transfer Hydroxymethylation of Isoindolinones Using Formaldehyde Surrogates

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14160%2F24%3A00138096" target="_blank" >RIV/00216224:14160/24:00138096 - 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 Organocatalytic Transfer Hydroxymethylation of Isoindolinones Using Formaldehyde Surrogates

Popis výsledku v původním jazyce

The cross-aldol reaction with formaldehyde is a highly efficient method for extending carbon chains that is greatly rewarding in terms of atom economy and increased molecular complexity. Various sources of formaldehyde, such as paraformaldehyde, trioxane, and aqueous formaldehyde, are commonly used for this homologation reaction. Nevertheless, their use has several disadvantages – paraformaldehyde is poorly soluble in organic solvents and has relatively slow chain unzipping, trioxane requires activation with acid, and formalin may cause incompatibilities in catalytic systems owing to the water and methanol presence. Alternatively, anhydrous formaldehyde can be generated in situ from its precursors under the basic conditions. These formaldehyde surrogates have never been systematically investigated and used in enantioselective reactions. To test their superiority over other formaldehyde sources, a challenging asymmetric hydroxymethylation of isoindolinones, which was first reported by Massa et al. in 2018, was utterly reoptimized. By employing a combination of the piperidine-based Takemoto-type catalyst and our bench-stable surrogate, we were able to dramatically improve all reaction parameters and expand its scope from 2 to 34 isoindolinone derivatives. A scale-up experiment, enantioselective downstream transformations and preliminary mechanistic elucidations were also carried out.

Název v anglickém jazyce

Asymmetric Organocatalytic Transfer Hydroxymethylation of Isoindolinones Using Formaldehyde Surrogates

Popis výsledku anglicky

The cross-aldol reaction with formaldehyde is a highly efficient method for extending carbon chains that is greatly rewarding in terms of atom economy and increased molecular complexity. Various sources of formaldehyde, such as paraformaldehyde, trioxane, and aqueous formaldehyde, are commonly used for this homologation reaction. Nevertheless, their use has several disadvantages – paraformaldehyde is poorly soluble in organic solvents and has relatively slow chain unzipping, trioxane requires activation with acid, and formalin may cause incompatibilities in catalytic systems owing to the water and methanol presence. Alternatively, anhydrous formaldehyde can be generated in situ from its precursors under the basic conditions. These formaldehyde surrogates have never been systematically investigated and used in enantioselective reactions. To test their superiority over other formaldehyde sources, a challenging asymmetric hydroxymethylation of isoindolinones, which was first reported by Massa et al. in 2018, was utterly reoptimized. By employing a combination of the piperidine-based Takemoto-type catalyst and our bench-stable surrogate, we were able to dramatically improve all reaction parameters and expand its scope from 2 to 34 isoindolinone derivatives. A scale-up experiment, enantioselective downstream transformations and preliminary mechanistic elucidations were also carried out.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

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Návaznosti

S - Specificky vyzkum na vysokych skolach<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2024

Kód důvěrnosti údajů

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