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A chromophoric bifunctional probe design that allows selective chiroptical sensing of cysteine in aqueous solution is introduced. The common need for chiral HPLC separation is eliminated which expedites and simplifies the sample analysis while reducing solvent waste. Screening of the reaction between six phenacyl bromides and the enantiomers of cysteine showed that cyclization to an unsaturated thiomorpholine scaffold coincides with characteristic UV and CD effects, in particular when the reagent carries a proximate auxochromic nitro group. The UV changes and CD inductions were successfully used for determination of the absolute configuration, enantiomeric composition and total concentration of 18 test samples. This assay is highly selective for free cysteine while other amino acids, cysteine derived small peptides and biothiols do not interfere with the chiroptical signal generation. 

We report chemoselective and modular peptide bioconjugation using stoichiometric amounts of 4-halocoumarin and arylsulfonate agents that undergo metal-free C(sp 2 )-heteroatom bond formation at micromolar concentrations. The underlying ipso -substitution click chemistry is irreversible and generates stable and inherently fluorescent bioconjugates, and the broad selection of coumarin tags offers high labeling flexibility and versatility. Different coumarins and arylsulfonates can be selectively attached to amino and thiol groups in the small peptides glutathione and ornipressin, and both free as well as latent thiols captured in disulfide bridges can be targeted if desired. The broad utility, ease of use, storage, and preparation of 4-halocoumarins and arylsulfonates are very attractive features that extend currently available dual bioconjugation capabilities. 

The cyclization reaction between ortho -phthalaldehyde and l -homocysteine coincides with the generation of a pronounced positive CD signal at approximately 335 nm. Under identical conditions, other amino acids including cysteine produce very weak CD responses. This unusual substrate specificity allows accurate chiroptical analysis of the enantiomeric composition of homocysteine samples in the presence of cysteine without the need for time-consuming chromatographic separation. This significantly simplifies and speeds up ee determination at reduced solvent waste production. 

Abstract Analytical methods that allow simultaneous determination of the concentration and enantiomeric composition of small sample amounts and are also compatible with high‐throughput 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‐the‐fly 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.