Recognition of enantiomers with chiral molecular tweezers derived from (+)- or (−)-usnic acid

doi:10.1016/j.tetasy.2010.03.016

Tetrahedron: Asymmetry

Volume 21, Issues 9–10, 17 May 2010, Pages 1307-1310

Dedicated to Professor Henri Kagan on the occasion of his 80th birthday

https://doi.org/10.1016/j.tetasy.2010.03.016 Get rights and content

Abstract

The synthesis of four stereoisomers of a chiral molecular tweezer using trans-1,2-diaminocyclohexane as spacer and two molecules of usnic acid as pincers is reported. The behavior of these chiral tweezers as chiral complexing agents was evaluated in NMR with various chiral esters containing an electron-poor aromatic ring to allow non-covalent aromatic–aromatic interactions.

Graphical abstract

Introduction

The process of molecular recognition of guest molecules by synthetic host is of great interest in supramolecular chemistry and depends on the nature of the intermolecular interactions. For this reason the study and characterization of these intermolecular interactions has experienced enormous growth in recent years. Among the different intermolecular forces, non-covalent aromatic interactions are of particular relevance. The π–π-stacked aromatic interactions have been found to govern diverse molecular organizations in both solution and the solid state. They control the vertical base–base stacking in DNA, the tertiary structures of proteins and also play a major role in the assembly and crystallization of many natural and synthetic molecules.¹ Aromatic interactions have been also used in template-directed synthesis to control the enantioselectivity of reactions in asymmetric syntheses.² Whitlock first reported the synthesis of molecular tweezers and their use as suitable models to bind aromatic guests.³ Molecular tweezers are simple molecular hosts that can be described by the presence of two pincers tethered by a more or less rigid spacer. With a distance between electron rich or deficient aromatic pincers of about 7 Å, molecular tweezers appear to be an ideal model to study non-covalent aromatic interactions.⁴

Among the various molecular tweezers synthesized, some chiral tweezers were prepared either from Kagan’s ethers^4b or from Tröger’s bases.⁵ In most cases the synthesis of these compounds requires several tedious steps and their uses in chiral recognition are rare. For example, it has been shown that Tröger’s base analogue could be used in NMR as a chiral solvating agent (CSA) to differentiate the enantiomers of chiral secondary or tertiary alcohols via the formation of diastereomeric salts.⁶ Virgili et al. also reported the synthesis of an enantiopure muconate derivative used as CSA.⁷ The presence of two anthracene moieties as pincers could allow π–π-stacked aromatic interactions with chiral aromatic guests. Although no thermodynamic difference between diastereomeric host–guest complexes was found, this twezeer was efficient to determine the enantiomeric excess of chiral compounds with the help of ¹H and ¹³C NMR. Further work was devoted to the preparation of other kind of chiral molecular tweezers and their use as agents for complexation of chiral derivatives. It seemed that the intermolecular interactions between the host and guest were often due to several non-covalent interactions such as attractive or repulsive electrostatic interactions, hydrogen bonding, repulsive steric interactions and more rarely π–π-interactions.⁸

Recently a new chiral molecular tweezer 1 (Fig. 1) was synthesized in our laboratory with (1R,2R)-1,2-diaminocyclohexane as a spacer and two molecules of (+)-usnic acid, an abundant natural lichen compound, as pincers.⁹ The ability of this molecular tweezer to bind various electron-poor aromatic compounds such as 2,4,7-trinitrofluorenone (TNF) has been studied. For example a charge transfer complex was formed in which TNF is sandwiched between the two usnic acid units (2, Fig. 1). This molecular tweezer 1 and its host–guest chiral complex 2 were fully characterized and both substrates afforded crystals suitable for X-ray diffraction analysis. The association constant for the complex 2 has been determined by ¹H NMR following two different methods¹⁰ and indicates a value about 55 M⁻¹ at 298 K. With this chiral molecular tweezer 1 in hand, we believed that 1 might be a good tool for chiral recognition and quantification of enantiomeric excess in solution. Therefore, we now report herein the preparation of each of the stereoisomers of the tweezer from (1R,2R)- and (1S,2S)-1,2-diaminocyclohexane and (+)- and (−)-usnic acid and our first results in the field of the chiral recognition process.

Section snippets

Synthesis of each of the stereoisomer of chiral tweezer 1

Based on the described synthesis of 1,⁹ its stereoisomers have been prepared by combining 1 equiv of (1R,2R)- or (1S,2S)-1,2-diaminocyclohexane with 2 equiv of (+)- or (−)-usnic acid¹¹ in THF/EtOH (1/4) at reflux for 4–8 h (Scheme 1). The resulting solids were recrystallized from ethanol to give the tweezers in acceptable yields (60–86%).

Crystal of the chiral molecular tweezer 3 suitable for X-ray diffraction analysis was obtained by slow evaporation of dichloromethane at room temperature from

Conclusion

In conclusion, we have successfully prepared four stereoisomers of potential chiral molecular tweezers from trans-1,2-diaminocyclohexane as a spacer and two molecules of usnic acid. Only the combinations (R,R)-(+) 1 and (S,S)-(-) 5 lead to the formation of molecular tweezers. The X-ray structure analysis of 3 showed that the two usnic acids have an unfavorable spatial arrangement to form a tweezer. The behavior of 1 as a chiral complexing agent was evaluated with chiral esters. These first

Acknowledgments

This work was supported by the Université de Rennes 1, the Région Bretagne and Rennes Métropole. We gratefully acknowledge Loic Toupet (Institut de Physique de Rennes) for X-ray crystallographic data.

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Recognition of enantiomers with chiral molecular tweezers derived from (+)- or (−)-usnic acid

Abstract

Graphical abstract

Introduction

Section snippets

Synthesis of each of the stereoisomer of chiral tweezer 1

Conclusion

Acknowledgments

J. Am. Chem. Soc.

Acc. Chem. Res.

Acc. Chem. Res.

Org. Lett.

Perkin Trans. 2

Angew. Chem., Int. Ed.

Bioorg. Med. Chem.

Tetrahedron

Helv. Chim. Acta

Adv. Heterocylc. Chem.

J. Org. Chem.

J. Org. Chem.