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

Abstract

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.

Keywords: asymmetric organocatalysis; castagnolli–cushman reaction; chiral thiourea-BiMAH catalysts; isoinversion temperature; pinder reaction.

Scheme 1

The established reactions of Pinder and Castagnoli–Cushman.

Scheme 2

Natural products and drug molecules containing the scaffold of Pinder and Castagnoli–Cushman reaction products.

Scheme 3

Previously reported and presently described chiral organocatalysts for the asymmetric Pinder reaction.

Scheme 4

Model Pinder reaction for exploring conditions of maximum and minimum conversion.

Scheme 5

Pinder reaction with various substituted aldehydes under the optimized conditions for the racemic reaction (THF, DIPEA, rt, 18 h).

Scheme 6

HPLC and ¹H NMR of crude product 13 demonstrating consistent assessment of cis/trans isomer ratios.

Scheme 7

Esterification attempts of the Pinder acid products for analytical purposes.

Scheme 8

Types of chiral organocatalysts designed for the asymmetric Pinder reaction bearing a Lewis acid and a nucleophilic/basic domain.

Scheme 9

Screening of different types of dual BIMAH-based organocatalysts in the Pinder reaction.

Scheme 10

Aniline variation in the isobutyl-BIMAH/thiourea catalysts.

Scheme 11

Effect of the steric and electronic properties of aldehyde substrates on the stereochemistry of the Pinder reaction catalyzed by 26aS. The ee’s were determined either directly for the acids (6, 8, 9) or the Me-ester derivatives prepared with TMSCHN₂ in MeOH as described earlier.

Scheme 12

Partial mechanistic hypothesis based on solvent, additive and electrophilic substrates.

Scheme 13

Partial mechanistic hypothesis based on solvent, additive and electron rich substrates.

Scheme 14

Equilibration between cis and trans aldehyde-catalyst complexes leading to competing endo and exo transition states and ultimately to opposite enantiomers.

Scheme 15

Equilibration between cis and trans aldehyde-catalyst complexes leading to competing endo and exo transition states and ultimately to opposite enantiomers.

Scheme 16

Newman projection of the transition state leading to the trans-substituted lactone product.