Regioconvergent Nucleophilic Substitutions with Morita-Baylis-Hillman Fluorides.

Lithium iodide enables regioconvergent C-F bond functionalization of isomeric Morita-Baylis-Hillman fluorides with carbon, sulfur, and nitrogen nucleophiles. The defluorinative carbon-carbon and carbon-heteroatom bond formations give multifunctional compounds in excellent yields and with good to high diastereoselectivities at room temperature. The possibility of catalytic enantioselective allylation is also discussed.

Optical Relay Sensing of Cryptochiral Alcohols Displaying α-, ß-, γ- and δ-Stereocenters or Chirality by Virtue of Isotopic Substitution.

A reaction-based optical relay sensing strategy that enables accurate determination of the concentration and enantiomeric ratio (er) of challenging chiral alcohols exhibiting stereocenters at the α-, ß-, γ- or even δ-position or hard-to-detect cryptochirality arising from H/D substitution is described. This unmatched application scope is achieved with a conceptually new sensing approach by which the alcohol moiety is replaced with an optimized achiral sulfonamide chromophore to minimize the distance between the covalently attached chiroptical reporter unit and the stereogenic center in the substrate. The result is a remarkably strong, red-shifted CD induction that increases linearly with the sample er. The CD sensing part of the tandem assay is seamlessly coupled to a redox reaction with a quinone molecule to generate a characteristic UV response that is independent of the enantiopurity of the alcohol and thus allows determination of the total analyte concentration. The robustness and utility of the CD/UV relay are further verified by chromatography-free asymmetric reaction analysis with small aliquots of crude product mixtures, paving the way toward high-throughput chiral compound screening workflows which is a highly sought-after goal in the pharmaceutical industry.

Circular Dichroism Sensing: Strategies and Applications.

The analysis of the absolute configuration, enantiomeric composition, and concentration of chiral compounds are frequently encountered tasks across the chemical and health sciences. Chiroptical sensing methods can streamline this work and allow high-throughput screening with remarkable reduction of operational time and cost. During the last few years, significant methodological advances with innovative chirality sensing systems, the use of computer-generated calibration curves, machine learning assistance, and chemometric data processing, to name a few, have emerged and are now matched with commercially available multi-well plate CD readers. These developments have reframed the chirality sensing space and provide new opportunities that are of interest to a large group of chemists. This review will discuss chirality sensing strategies and applications with representative small-molecule CD sensors. Emphasis will be given to important milestones and recent advances that accelerate chiral compound analysis by outperforming traditional methods, conquer new directions, and pioneering efforts that lie at the forefront of chiroptical high-throughput screening developments. The goal is to provide the reader with a thorough understanding of the current state and a perspective of future directions of this rapidly emerging field.

Chiroptical Switching and Quantitative Chirality Sensing with (Pseudo)halogenated Quinones.

(Pseudo)halogenated quinones react smoothly with chiral amines, amino alcohols, and amino acids toward push-pull conjugates with optical sensing and switching applications. The chiroptically active conjugates serve as redox switches between two reversibly interconverting states with remarkably different UV and CD signatures. Addition of sodium borohydride generates a hydroquinone derivative that is quantitatively re-oxidized to the original quinone upon exposure to air. This chiroptical quinone/hydroquinone redox switch system combines several attractive features such as simple set-up, use of inexpensive chemicals, short response time, and thermal and photochemical stability. A conceptually new sensing approach that is based on integrated chiroptical amplification and redox switching enables on-the-fly deconvolution of otherwise overlapping CD spectra and is used for quantitative er analysis of challenging samples containing constitutional isomers in varying enantiomeric compositions.

Optical Enantiodifferentiation of Chiral Nitriles.

Chiroptical sensing of nitriles is achieved with excellent functional group tolerance by hydrozirconation and subsequent transmetalation of the corresponding iminate to a chromophoric palladium complex. A one-pot workflow that uses the Schwartz reagent and [(η3-1-tert-butylindenyl)(µ-Cl)Pd]2 as sensor generates a palladium complex displaying red-shifted CD inductions and characteristic UV changes. These chiroptical responses are accurately correlated to the enantiomeric ratio and total concentration of the original nitrile.

Chemometric sensing of stereoisomeric compound mixtures with a redox-responsive optical probe.

The analysis of mixtures of chiral compounds is a common task in academic and industrial laboratories typically achieved by laborious and time-consuming physical separation of the individual stereoisomers to allow interference-free quantification, for example using chiral chromatography coupled with UV detection. Current practice thus impedes high-throughput and slows down progress in countless chiral compound development projects. Here we describe a chemometric solution to this problem using a redox-responsive naphthoquinone that enables chromatography-free click chemistry sensing of challenging mixtures. The achiral probe covalently binds amino alcohols within a few minutes at room temperature and generates characteristic UVA and CDA spectra that are intentionally altered via sodium borohydride reduction to provide a second, strikingly different chiroptical data set (UVB and CDB). Chemometric partial least squares processing of the chiroptical outputs then enables spectral deconvolution and accurate determination of individual analyte concentrations. The success of this approach is demonstrated with 35 samples covering considerably varied total analyte amounts and stereoisomeric ratios. All chemicals and machine learning algorithms are readily available and can be immediately adapted by any laboratory.

Rapid organocatalytic chirality analysis of amines, amino acids, alcohols, amino alcohols and diols with achiral iso(thio)cyanate probes.

The widespread occurrence and significance of chiral compounds does not only require new methods for their enantioselective synthesis but also efficient tools that allow rapid determination of the absolute configuration, enantiomeric composition and overall concentration of nonracemic mixtures. Although chiral analysis is a frequently encountered challenge in the chemical, environmental, materials and health sciences it is typically addressed with slow and laborious chromatographic or NMR spectroscopic techniques. We now show with almost 40 analytes representing 5 different compound classes, including mono-alcohols which are particularly challenging sensing targets, that this task can be solved very quickly by chiroptical sensing with a single, readily available arylisocyanate probe. The probe reacts smoothly and irreversibly with amino and alcohol groups when an organocatalyst is used at room temperature toward urea or carbamate products exhibiting characteristic UV and CD signals above 300 nm. The UV signal induction is not enantioselective and correlated to the total concentration of both enantiomers, the concomitant generation of a CD band allows determination of the enantiomeric composition from the same sample, and the sense of the induced Cotton effect reveals the absolute configuration by comparison with a reference. This approach eliminates complications that can arise when enantiomerically impure NMR derivatizing agents are used and it outperforms time-consuming HPLC protocols. The generation of distinct UV and CD signals at high wavelengths overcomes issues with insufficient resolution of overlapping signals often encountered with chiral NMR solvating agents that rely on weak binding forces. The broad solvent compatibility is another noteworthy and important characteristic of this assay. It addresses frequently encountered problems with insufficient solubility of polar analytes, for example pharmaceuticals, in standard mobile phase mixtures required for chiral HPLC analysis. We anticipate that the broad application spectrum, ruggedness and practicality of organocatalytic chiroptical sensing with aryliso(thio)cyanate probes together with the availability of automated CD multi-well plate readers carry exceptional promise to accelerate chiral compound development projects at reduced cost and with less waste production.