New Enantiopure Receptors Family for Selective Recognition of Chiral Anions in Aqueous media: Strong ECD Response Expected – EnaRecAnions

1. Description of experimental methods

- Multi-step organic synthesis.

- Reaction setup, processing and purification of reaction mixtures.

- Purification by recrystallization or column chromatography (stationary phase: silica gel).

- Complete characterization of reaction intermediates and the final molecule by 1D and 2D NMR spectroscopy (1H and 13C nuclei).

- Solid-state characterization of the molecular cage by single-crystal X-ray diffraction.

- Resolution of the two enantiomers by chiral liquid chromatography (chiral HPLC).

- Study of chiroptical properties by polarimetry, electronic circular dichroism (ECD) and vibrational dichroism (VCD).

2. General strategies and approaches

- Divergent synthesis route based on a “template” approach, where TBTQ and CTB units are prepared separately in two distinct steps.

- Systematic verification of the reproducibility of each synthesis step at different scales, from tens of milligrams to grams.

- Optimization of the “template” synthesis route, in which the CTB unit is formed in a second step, by varying a single parameter at a time (nature of the acid, solvent, reaction time, speed of precursor addition to the reaction medium, etc.).

- A synthetic route whose initial precursor is a chiral TBTQ unit with C3 symmetry, whose structure has already been described in the literature.

- Use of the team's know-how to form the skeleton of the cage molecule.

- Chiral resolution of the two enantiomers of the cage with a chiral stationary phase (chiral HPLC).

3. Specific equipment

- 300 and 400 MHz NMR spectrometers.

- Digital polarimeter (for mercury line wavelengths).

- UV-visible spectrophotometer, electronic circular dichroism (ECD) and vibrational dichroism (VCD) spectrophotometers.

- Exact mass spectrometry analyses were performed on a hybrid quadrupole time-of-flight mass spectrometer (microTOF-Q II), equipped with an electrospray ionization (ESI) source.

- A suitable single crystal was selected and mounted on an Xcalibur Gemini diffractometer (kappa geometry), equipped with an Atlas CCD detector and a molybdenum X-ray source (λ = 0.71073 Å).

We have developed a synthetic route to a new family of chiral cages with C3 symmetry, achieving perfect control of diastereoselectivity. This host molecule features a cyclotribenzylene (CTB) unit as well as a more rigid tribenzotriquinacene (TBTQ) unit. Our synthetic approach relies on the so-called "template" method, using a pre-functionalized TBTQ derivative as a key intermediate. Only the diastereoisomer with relative anti configuration was obtained during this synthesis. A resolution process of the racemic mixture of the cage was performed by high-performance liquid chromatography (HPLC). The cage was fully characterized in solution by ¹H and ¹³C NMR spectroscopies. The relative and absolute configurations were successfully determined through a combination of X-ray crystallographic analysis and chiroptical properties such as polarimetry, ECD, and VCD spectroscopies. Although the preparation of such cages with small cavities remains a significant synthetic challenge, these results open the way to the design of new cryptophanes bearing a rigid TBTQ-type unit via irreversible bond-forming synthesis.

Our work has paved the way for the design of new chiral cages containing both a tribenzotriquinacene (TBTQ) unit and a cyclotribenzylene (CTB) unit.

This novel strategy relies on the formation of irreversible carbon–carbon bonds during the key steps of this synthesis.

Further studies will be needed to determine whether the limitations observed for cages with short arms persist with longer arms.

Increasing the π-acidity of the cage, as well as introducing hydrosolubilizing groups, could allow a full evaluation of the enantioselective encapsulation properties of chiral anions over a wide pH range.

The design of molecular receptors for selective anion binding is of great importance in several fields such as biochemistry, environment and medical areas. However, anion complexation by synthetic receptors in water remains challenging with respect to organic solvents.The EnaRecAnions project deals with the synthesis and study of a novel family of chiral cages for chiral anion binding in organic media and water. Strong modification of electronic circular dichroism spectra (ECD) of enantiopure molecular receptors are expected upon complexation. If such phenomena are reversible, these features may be promising tools for the development of chiroptical detectors.