A Novel Dual Organocatalyst for the Asymmetric Pinder Reaction and a Mechanistic Proposal Consistent with the Isoinversion Effect Thereof

In general, the Pinder reaction concerns the reaction between an enolisable anhydride and an aldehyde proceeding initially through a Knoevenagel reaction followed by the ring closing process generating lactones with at least two chiral centers. These scaffolds are frequently present in natural produ...

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Autores principales:	Fotini Moschona, Athena Vagena, Veroniki P. Vidali, Gerasimos Rassias
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	pinder reaction castagnolli–cushman reaction asymmetric organocatalysis chiral thiourea-BiMAH catalysts isoinversion temperature Organic chemistry QD241-441
Acceso en línea:	https://doaj.org/article/422c33c1310849f8bc9c15f31cd7f9e7
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id	oai:doaj.org-article:422c33c1310849f8bc9c15f31cd7f9e7
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spelling	oai:doaj.org-article:422c33c1310849f8bc9c15f31cd7f9e72021-11-11T18:25:16ZA Novel Dual Organocatalyst for the Asymmetric Pinder Reaction and a Mechanistic Proposal Consistent with the Isoinversion Effect Thereof10.3390/molecules262163981420-3049https://doaj.org/article/422c33c1310849f8bc9c15f31cd7f9e72021-10-01T00:00:00Zhttps://www.mdpi.com/1420-3049/26/21/6398https://doaj.org/toc/1420-3049In general, the Pinder reaction concerns the reaction between an enolisable anhydride and an aldehyde proceeding initially through a Knoevenagel reaction followed by the ring closing process generating lactones with at least two chiral centers. These scaffolds are frequently present in natural products and synthetic bioactive molecules, hence it has attracted intense interest in organic synthesis and medicinal chemistry, particularly with respect to controlling the diastereo- and enantioselectivity. To the best of our knowledge, there has been only one attempt prior to this work towards the development of a catalytic enantioselective Pinder reaction. In our approach, we designed, synthesized, and tested dual chiral organocatalysts by combining BIMAH amines, (2-(α-(alkyl)methanamine)-1H-benzimidazoles, and a Lewis acid motif, such as squaramides, ureas and thioureas. The optimum catalyst was the derivative of isopropyl BIMAH bearing a bis(3,5-trifluoromethyl) thiourea, which afforded the Pinder products from various aromatic aldehydes with diastereomeric ratio >98:2 and enatioselectivity up to 92 ee%. Interestingly, the enantioselectivity of this catalyzed process is increased at higher concentrations and exhibits an isoinversion effect, namely an inverted "U" shaped dependency with respect to the temperature. Mechanistically, these features, point to a transition state involving an entropy-favored heterodimer interaction between a catalyst/anhydride and a catalyst/aldehyde complex when all other processes leading to this are much faster in comparison above the isoinversion temperature.Fotini MoschonaAthena VagenaVeroniki P. VidaliGerasimos RassiasMDPI AGarticlepinder reactioncastagnolli–cushman reactionasymmetric organocatalysischiral thiourea-BiMAH catalystsisoinversion temperatureOrganic chemistryQD241-441ENMolecules, Vol 26, Iss 6398, p 6398 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	pinder reaction castagnolli–cushman reaction asymmetric organocatalysis chiral thiourea-BiMAH catalysts isoinversion temperature Organic chemistry QD241-441
spellingShingle	pinder reaction castagnolli–cushman reaction asymmetric organocatalysis chiral thiourea-BiMAH catalysts isoinversion temperature Organic chemistry QD241-441 Fotini Moschona Athena Vagena Veroniki P. Vidali Gerasimos Rassias A Novel Dual Organocatalyst for the Asymmetric Pinder Reaction and a Mechanistic Proposal Consistent with the Isoinversion Effect Thereof
description	In general, the Pinder reaction concerns the reaction between an enolisable anhydride and an aldehyde proceeding initially through a Knoevenagel reaction followed by the ring closing process generating lactones with at least two chiral centers. These scaffolds are frequently present in natural products and synthetic bioactive molecules, hence it has attracted intense interest in organic synthesis and medicinal chemistry, particularly with respect to controlling the diastereo- and enantioselectivity. To the best of our knowledge, there has been only one attempt prior to this work towards the development of a catalytic enantioselective Pinder reaction. In our approach, we designed, synthesized, and tested dual chiral organocatalysts by combining BIMAH amines, (2-(α-(alkyl)methanamine)-1H-benzimidazoles, and a Lewis acid motif, such as squaramides, ureas and thioureas. The optimum catalyst was the derivative of isopropyl BIMAH bearing a bis(3,5-trifluoromethyl) thiourea, which afforded the Pinder products from various aromatic aldehydes with diastereomeric ratio >98:2 and enatioselectivity up to 92 ee%. Interestingly, the enantioselectivity of this catalyzed process is increased at higher concentrations and exhibits an isoinversion effect, namely an inverted "U" shaped dependency with respect to the temperature. Mechanistically, these features, point to a transition state involving an entropy-favored heterodimer interaction between a catalyst/anhydride and a catalyst/aldehyde complex when all other processes leading to this are much faster in comparison above the isoinversion temperature.
format	article
author	Fotini Moschona Athena Vagena Veroniki P. Vidali Gerasimos Rassias
author_facet	Fotini Moschona Athena Vagena Veroniki P. Vidali Gerasimos Rassias
author_sort	Fotini Moschona
title	A Novel Dual Organocatalyst for the Asymmetric Pinder Reaction and a Mechanistic Proposal Consistent with the Isoinversion Effect Thereof
title_short	A Novel Dual Organocatalyst for the Asymmetric Pinder Reaction and a Mechanistic Proposal Consistent with the Isoinversion Effect Thereof
title_full	A Novel Dual Organocatalyst for the Asymmetric Pinder Reaction and a Mechanistic Proposal Consistent with the Isoinversion Effect Thereof
title_fullStr	A Novel Dual Organocatalyst for the Asymmetric Pinder Reaction and a Mechanistic Proposal Consistent with the Isoinversion Effect Thereof
title_full_unstemmed	A Novel Dual Organocatalyst for the Asymmetric Pinder Reaction and a Mechanistic Proposal Consistent with the Isoinversion Effect Thereof
title_sort	novel dual organocatalyst for the asymmetric pinder reaction and a mechanistic proposal consistent with the isoinversion effect thereof
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/422c33c1310849f8bc9c15f31cd7f9e7
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A Novel Dual Organocatalyst for the Asymmetric Pinder Reaction and a Mechanistic Proposal Consistent with the Isoinversion Effect Thereof

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