Chirality imprinting and direct asymmetric reaction screening using a stereodynamic Brønsted/Lewis acid receptor

Abstract

Molecular recognition, activation and dynamic self-assembly with Brønsted and Lewis acids play a central role across the chemical sciences including catalysis, crystal engineering, supramolecular architectures and drug design. Despite this general advance, the utilization of the corresponding binding motifs for fast and robust quantitative chemosensing of chiral compounds in a complicate matrix has remained challenging. Here we show that a stereodynamic probe carrying complementary boronic acid and urea units achieves this goal with hydroxy carboxylic acids. Synergistic dual-site binding and instantaneous chirality imprinting result in characteristic ultraviolet and CD readouts that allow instantaneous determination of the absolute configuration, enantiomeric excess and concentration of the target compound even in complex mixtures. The robustness and practicality of this strategy for high-throughput screening purposes is demonstrated. Comprehensive sensing of only 0.5 mg of a crude reaction mixture of an asymmetric reduction eliminates cumbersome work-up protocols and minimizes analysis time, labour and waste production.

Macroscopic helical chirality and self-motion of hierarchical self-assemblies induced by enantiomeric small molecules

“…Discrimination of enantiomers, such as amines 49 , 50 , diamines 51 , alcohols 52 , 53 , amino alcohols 54 , 55 , amino acids 56 , and the like that closely related to pharmaceutical, chemical, biotechnology and bio-safety, environment, and food industries, is one of core research fields in analytical and catalytic chemistry 57 – 60 . With hierarchical chirality, the macrostripes demonstrated unique helical self-motion behaviours when enantiomeric amines are employed as target species to study their enantioselective discrimination ability in THF solvent (Fig.…”

Streamlined Asymmetric Reaction Development: A Case Study with Isatins

“…First, a test reaction in a small vial was conducted with isatin 1 b , which was selected as a representative example. Quenching of the reaction with NaOH/H 2 O 2 followed by addition of HCl produces homogeneous reaction mixtures with stable chiroptical signals . We then collected the UV spectrum of 1 b and the UV and CD spectra of the quenched crude reaction mixture containing the corresponding allylic alcohol 2 b .…”

The In Situ Enzymatic Screening (ISES) Approach to Reaction Discovery and Catalyst Identification

“…Here, the screening technology revolves around the development of a suitable array of sensors for each type of product analyte. There are many examples for each of these methods of detection useful for amines, alcohols, and carboxylates (Bentley et al., ; Bentley, Zhang, & Wolf, ; De los Santos & Wolf, ; Jo et al., ; Leung & Anslyn, ; Leung et al., ; Leung, Folmer‐Andersen, Lynch, & Anslyn, ; Mei & Wolf, ; Shabbir et al., ). These methods can often be carried out in 96‐well plates leading to throughput comparable to the colorimetric ISES techniques described herein.…”

“…More open‐ended screens for ‘serendipitous chemistry’ have also drawn significant attention in recent years (McNally, Prier, & MacMillan, ; Robbins & Hartwig, ). Among the analytical tools being harnessed to provide information on the reactions being screened are mass spectrometry (Ebner, Muller, Markert, & Pfaltz, ; Isenegger, Baechle, & Pfaltz, ; Lichtor & Miller, ; Montavon, Li, Cabrera‐Pardo, Mrksich, & Kozmin, ; Mueller, Markert, Teichert, & Pfaltz, ), IR thermography (Loskyll, Stoewe, & Maier, ; Reetz, Becker, Liebl, & Fürstner, ; Taylor & Morken, ), and circular dichroism (Bentley, Proano, & Wolf, ; De los Santos & Wolf, ; Lin et al., ) with microfluidic technologies and miniaturization (Buitrago Santanilla et al., ; Goodell et al., ; Treece, Goodell, Vander Velde, Porco, & Aube, ) being explored to increase throughput. Generally, these methods are performed after taking aliquots or otherwise stopping or working up the reaction.…”