The comprehensive determination of the absolute configuration, enantiomeric ratio, and total amount of standard amino acids by optical methods adaptable to high-throughput screening with modern plate readers has remained a major challenge to date. We now present a small-molecular probe that smoothly reacts with amino acids and biothiols in aqueous solution and thereby generates distinct chiroptical responses to accomplish this task. The achiral sensor is readily available, inexpensive, and suitable for chiroptical analysis of each of the 19 standard amino acids, biothiols, aliphatic, and aromatic amines and amino alcohols. The sensing method is operationally simple, and data collection and processing are straightforward. The utility and practicality of the assay are demonstrated with the accurate analysis of 10 aspartic acid samples covering a wide concentration range and largely varying enantiomeric compositions. Accurate er sensing of 85 scalemic samples of Pro, Met, Cys, Ala, methylpyrrolidine, 1-(2-naphthyl)amine, and mixtures thereof is also presented.
The appearance of d-amino acids in mammals and humans has important implications in the life sciences. d/l-Amino acid mixtures play a key role in human physiology and pathology; thus, the introduction of artificial receptors for the real-time quantification of both the concentration and d/l composition of amino acids is very promising for the study of biological processes and for the diagnosis and treatment of diseases. We now report a sensing assay that is compatible with aqueous solutions and allows fast determination of the absolute configuration, enantiomeric composition, and overall amount of cysteine at micromolar concentrations. The method relies on fast UV and CD measurements, which provide accurate stereochemical information on samples covering a wide concentration range and drastically different d/l-cysteine ratios in simulated body fluids. Competition experiments show that other amino acids and biothiols do not interfere with the cysteine-targeted sensing.
Click reactions have become powerful synthetic tools with unique applications in the health and materials sciences. Despite the progress with optical sensors that exploit the principles of dynamic covalent chemistry, metal coordination or supramolecular assemblies, quantitative analysis of complex mixtures remains challenging. Herein, we report the use of a readily available coumarin conjugate acceptor for chiroptical click chirality sensing of the absolute configuration, concentration and enantiomeric excess of several compound classes. This method has several attractive features, including wide scope, fast substrate fixation without by-product formation or complicate equilibria often encountered in reversible substrate binding, excellent solvent compatibility, and tolerance of air and water. The ruggedness and practicality of this approach are demonstrated by comprehensive analysis of nonracemic monoamine samples and crude asymmetric imine hydrogenation mixtures without work-up. Click chemosensing addresses increasingly important time efficiency, cost, labor and chemical sustainability aspects and streamlines asymmetric reaction development at the mg scale.
Analytical methods that allow simultaneous determination of the concentration and enantiomeric composition of small sample amounts and are also compatible with highthroughput multi-well plate technology have received increasing attention in recent years. We now introduce a new class of broadly useful small-molecule probes and a relay sensing strategy that together accomplish these tasks with five classes of compounds including the challenging group of mono-alcohols-a scope that stands out among previously reported UV, fluorescence, and CD assays. Several chlorophosphite probes and aniline indicators have been evaluated and used for on-thefly CD/UV sensing following a continuous workflow. The wide application range of the readily available sensors is highlighted with almost 30 alcohols, diols, hydroxy acids, amines and amino alcohols, and the accuracy of the stereochemical analysis is showcased with samples covering a wide range of concentrations and enantiomeric ratios.
Practical chiroptical sensing with a small group of commercially available aromatic aldehydes is demonstrated. Schiff base formation between the electron‐deficient 2,4‐dinitrobenzaldehyde probe and either primary amines, diamines, or amino alcohols proceeds smoothly in chloroform at room temperature and is completed in the presence of molecular sieves within 2.5 hours. The substrate binding coincides with a distinct circular dichroism signal induction at approximately 330 nm, which can be correlated to the absolute configuration and enantiomeric composition of the analyte. The usefulness of this sensing method is highlighted with the successful sensing of 18 aliphatic and aromatic amines and amino alcohols and five examples showing quantitative %ee determination with good accuracy.
Asymmetric reaction development within ad ay or two has been ad ream of syntheticc hemists fors everal decades. We now show that such at ask is feasible with a highly efficients treamlined screening strategyu sing the asymmetric allylation of isatinsw ith ac hiral boronc omplex as ac ase study.O ur high-throughput screening (HTS) methodi sb ased on fast optical UV/CDa nalysis of minute amounts of crude reactionm ixtures ( % 3mgs cale) and it obviates product isolation and the general need for reference compounds which greatlyr educes preliminary work and analysis time. The setup, reactions creening, analysis and data processing for5 4asymmetric allylations of nine different isatinsi ns ix differents olvents was handled by a single operatori nl ess than 20 work hours.O ne could easily extend this HTS strategy to hundreds of reactions in roughly the same time frame and further reduce the labor with commerciallya vailable automated high-throughput experimentation equipment. The effectiveness of this asymmetric reaction development strategy is confirmed with the upscales ynthesis of two representative 3-allyl-3-hydroxyisatinsin9 8-99 %y ield and with 91-94% ee under optimized conditions. Asymmetric reaction developmenti sacentral task in the chemicala nd pharmaceutical sciences. Despite impressive advancesw ith high-throughput equipment, the optimization of the yield and the enantiomeric excess of ac hiral producto ften remains am ajor bottleneck that limits the overall progress and the workflow,e specially in highly collaborative settings where on-timed elivery of drug candidates for preclinical studies is critical. Such as cenariom ay arise, for example, at the early drug discovery stage where it is necessary to quickly select and establish as ynthetic methodt hat affords fast and reliable access to an urgently neededc ompoundand analoguest hereof for initial testing purposes.E xpectations of short response times to urgentc ompound requests generate operational constraintst hat can make this ad aunting challenge. As the major focus typically lies on time-efficiency and expeditious produc-tion of the target compound(s), the use of catalysts or reagents that are not commercially available and have to be prepared separately may not be acceptable. At the same time, analytical tools that allow determination of the conversion or yield when al arge number of miniaturized reactions are performed in parallel to identify optimal conditionsm ust be in place andr eady for use. Witht he help of high-throughput screening techniquesa nd automated equipment that have become routine in many laboratories, the development of a satisfactory synthetic route can often be accomplished fairly quickly when the goal is to prepare achiral compounds. [1] This may not be the case, however, when ac hiral product in high yield and enantiomeric excess (ee)i sn eeded. The determinationo fe ither conversiono ry ield and ee valueso ften involvest wo separatem ethods and elaborate purification steps prior to the analysis. The common use of chiralc ...
Das Auftreten von d‐Aminosäuren in Säugern und im Menschen ist von großer Bedeutung für die Lebenswissenschaften. d/l‐Aminosäuremischungen spielen eine Schlüsselrolle bei der menschlichen Physiologie und Pathologie; daher ist die Einführung künstlicher Rezeptoren für die Echtzeitquantifizierung der Konzentration und des d/l‐Verhältnisses von Aminosäuren vielversprechend für das Studium biologischer Prozesse und die Diagnose sowie Behandlung von Krankheiten. Die hier vorgestellte Detektionsmethode ist kompatibel mit wässrigen Lösungen und ermöglicht die rasche Bestimmung der absoluten Konfiguration, des ee‐Werts und der Gesamtmenge von Cystein bei mikromolaren Konzentrationen. Die Methode beruht auf schnellen UV‐ und CD‐Messungen, die akkurate stereochemische Informationen mit Proben über einen weiten Konzentrationsbereich und mit stark unterschiedlichen d/l‐Cysteinverhältnissen in simulierten Körperflüssigkeiten liefern. Konkurrenzexperimente zeigen, dass andere Aminosäuren und Biothiole die gezielte Cysteinanalyse nicht stören.
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