Enantioselective hydroxymethylation of isoindolinones using
bench-stable formaldehyde surrogates

k 2023

Enantioselective hydroxymethylation of isoindolinones using bench-stable formaldehyde surrogates

ŠVESTKA, David, Pavel BOBÁĽ, Mario WASER and Jan OTEVŘEL

Basic information

Original name

Enantioselective hydroxymethylation of isoindolinones using bench-stable formaldehyde surrogates

Authors

ŠVESTKA, David (203 Czech Republic, belonging to the institution), Pavel BOBÁĽ (703 Slovakia, belonging to the institution), Mario WASER (40 Austria) and Jan OTEVŘEL (203 Czech Republic, belonging to the institution)

Edition

XXIInd INTERDISCIPLINARY MEETING OF YOUNG LIFE SCIENTISTS, 2023

Other information

Language

English

Type of outcome

Prezentace na konferencích

Field of Study

30104 Pharmacology and pharmacy

Country of publisher

Czech Republic

Confidentiality degree

není předmětem státního či obchodního tajemství

RIV identification code

RIV/00216224:14160/23:00131465

Organization unit

Faculty of Pharmacy

Keywords in English

Enantioselective organocatalysis; isoindolinone; Takemoto catalyst

Abstract

V originále

The asymmetric cross-aldol reaction with formaldehyde is one of the most efficient carbon chain extension methods. However, performing this type of reaction is far from straightforward. Formalin solutions may cause incompatibility issues with many catalytic systems due to the water presence. On the other hand, the polymeric precursors thereof (para- or metaformaldehyde) are poorly soluble in many organic solvents causing the slow release of the reactive monomer and overall reaction slowdown. For these reasons, research on bench-stable, soluble, and reactive formaldehyde surrogates (“H2C=O cans”) for catalytic reactions is highly desired. 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. 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 h in the very good enantiomeric ratios (e.r.~95:5). Compared to the prior methodologies,this protocol constitutes a steep advance in the efficacy and stereoselectivity of the organocatalytic process.

Links

EF19_073/0016943, research and development project

Name: Interní grantová agentura Masarykovy univerzity

MUNI/IGA/0916/2021, interní kód MU

Name: Asymmetric organocatalyzed hydroxymethylation of isoindolinones

Investor: Masaryk University

Citovat

ŠVESTKA, David, Pavel BOBÁĽ, Mario WASER and Jan OTEVŘEL. Enantioselective hydroxymethylation of isoindolinones using bench-stable formaldehyde surrogates. In XXIInd INTERDISCIPLINARY MEETING OF YOUNG LIFE SCIENTISTS. 2023.

@proceedings{2303494,
   author = {Švestka, David and Bobáľ, Pavel and Waser, Mario and Otevřel, Jan},
   booktitle = {XXIInd INTERDISCIPLINARY MEETING OF YOUNG LIFE SCIENTISTS},
   keywords = {Enantioselective organocatalysis; isoindolinone; Takemoto catalyst},
   language = {eng},
   title = {Enantioselective hydroxymethylation of isoindolinones using bench-stable formaldehyde surrogates},
   year = {2023}
}

TY  - CONF
ID  - 2303494
AU  - Švestka, David - Bobáľ, Pavel - Waser, Mario - Otevřel, Jan
PY  - 2023
TI  - Enantioselective hydroxymethylation of isoindolinones using bench-stable formaldehyde surrogates
KW  - Enantioselective organocatalysis
KW  - isoindolinone
KW  - Takemoto catalyst
N2  - The asymmetric cross-aldol reaction with formaldehyde is one of the most efficient carbon chain extension methods. However, performing this type of reaction is far from straightforward. Formalin solutions may cause incompatibility issues with many catalytic systems due to the water presence. On the other hand, the polymeric precursors thereof (para- or metaformaldehyde) are poorly soluble in many organic solvents causing the slow release of the reactive monomer and overall reaction slowdown. For these reasons, research on bench-stable, soluble, and reactive formaldehyde surrogates (“H2C=O cans”) for catalytic reactions is highly desired. 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. 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 h in the very good enantiomeric ratios (e.r.~95:5). Compared to the prior methodologies,this protocol constitutes a steep advance in the efficacy and stereoselectivity of the organocatalytic process.
ER  -

ŠVESTKA, David, Pavel BOBÁĽ, Mario WASER and Jan OTEVŘEL. Enantioselective hydroxymethylation of isoindolinones using bench-stable formaldehyde surrogates. In \textit{XXIInd INTERDISCIPLINARY MEETING OF YOUNG LIFE SCIENTISTS}. 2023.

Detailed Information on Publication Record