Asymmetric Hydroxymethylation of Isoindolinones Using
Bench-Stable Formaldehyde Surrogates

k 2023

Asymmetric Hydroxymethylation of Isoindolinones Using Bench-Stable Formaldehyde Surrogates

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

Basic information

Original name

Asymmetric 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

57th Conference: Advances in Organic, Bioorganic and Pharmaceutical Chemistry – Liblice 2023, 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/00216224:14160/23:00132383

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. 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.

Links

LM2018127, research and development project

Name: Česká infrastruktura pro integrativní strukturní biologii (Acronym: CIISB)

Investor: Ministry of Education, Youth and Sports of the CR

MUNI/A/1096/2022, interní kód MU

Name: Vývoj asymetrické Mannichovy reakce 2-sukcinimidyl, 2-glutarimidyl karboxylátů a příbuzných sloučenin

Investor: Masaryk University

Citovat

ŠVESTKA, David, Pavel BOBÁĽ, Mario WASER and Jan OTEVŘEL. Asymmetric Hydroxymethylation of Isoindolinones Using Bench-Stable Formaldehyde Surrogates. In 57th Conference: Advances in Organic, Bioorganic and Pharmaceutical Chemistry – Liblice 2023. 2023.

@proceedings{2344720,
   author = {Švestka, David and Bobáľ, Pavel and Waser, Mario and Otevřel, Jan},
   booktitle = {57th Conference: Advances in Organic, Bioorganic and Pharmaceutical Chemistry – Liblice 2023},
   keywords = {Enantioselective organocatalysis; isoindolinone; Takemoto catalyst},
   language = {eng},
   title = {Asymmetric Hydroxymethylation of Isoindolinones Using Bench-Stable Formaldehyde Surrogates},
   year = {2023}
}

TY  - CONF
ID  - 2344720
AU  - Švestka, David - Bobáľ, Pavel - Waser, Mario - Otevřel, Jan
PY  - 2023
TI  - Asymmetric 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. 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.
ER  -

ŠVESTKA, David, Pavel BOBÁĽ, Mario WASER and Jan OTEVŘEL. Asymmetric Hydroxymethylation of Isoindolinones Using Bench-Stable Formaldehyde Surrogates. In \textit{57th Conference: Advances in Organic, Bioorganic and Pharmaceutical Chemistry – Liblice 2023}. 2023.

Detailed Information on Publication Record