Organometallic Chirality Sensing via "Click"-Like η6-Arene Coordination with an Achiral Cp*Ru(II) Piano Stool Complex.

Piano stool complexes have been studied over many years and found widespread applications in organic synthesis, catalysis, materials and drug development. We now report the first examples of quantitative chiroptical molecular recognition of chiral compounds through click-like η6-arene coordination with readily available half sandwich complexes. This conceptually new approach to chirality sensing is based on irreversible acetonitrile displacement of [Cp*Ru(CH3CN)3]PF6 by an aromatic target molecule, a process that is fast and complete within a few minutes at room temperature. The metal coordination coincides with characteristic circular dichroism inductions that can be easily correlated to the absolute configuration and enantiomeric ratio of the bound molecule. A relay assay that decouples the determination of the enantiomeric composition and of the total sample amount by a practical CD/UV measurement protocol was developed and successfully tested. The introduction of piano stool complexes to the chiroptical sensing realm is mechanistically unique and extends the scope of currently known methods with small-molecule probes that require the presence of amino, alcohol, carboxylate or other privileged functional groups for binding of the target compound. A broad application range including pharmaceutically relevant multifunctional molecules and the use in chromatography-free asymmetric reaction analysis are also demonstrated.

Selective chiroptical sensing of D/L-cysteine.

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.

Chiroptical sensing of homocysteine.

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.

Stereochemical analysis of chiral amines, diamines, and amino alcohols: Practical chiroptical sensing based on dynamic covalent chemistry.

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.

Quantitative Chirality and Concentration Sensing of Alcohols, Diols, Hydroxy Acids, Amines and Amino Alcohols using Chlorophosphite Sensors in a Relay Assay.

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.

Quantitative Chiroptical Sensing of Free Amino Acids, Biothiols, Amines, and Amino Alcohols with an Aryl Fluoride Probe.

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.

Streamlined Asymmetric Reaction Development: A Case Study with Isatins.

Asymmetric reaction development within a day or two has been a dream of synthetic chemists for several decades. We now show that such a task is feasible with a highly efficient streamlined screening strategy using the asymmetric allylation of isatins with a chiral boron complex as a case study. Our high-throughput screening (HTS) method is based on fast optical UV/CD analysis of minute amounts of crude reaction mixtures (≈3 mg scale) and it obviates product isolation and the general need for reference compounds which greatly reduces preliminary work and analysis time. The setup, reaction screening, analysis and data processing for 54 asymmetric allylations of nine different isatins in six different solvents was handled by a single operator in less than 20 work hours. One could easily extend this HTS strategy to hundreds of reactions in roughly the same time frame and further reduce the labor with commercially available automated high-throughput experimentation equipment. The effectiveness of this asymmetric reaction development strategy is confirmed with the upscale synthesis of two representative 3-allyl-3-hydroxyisatins in 98-99 % yield and with 91-94 % ee under optimized conditions.

Substrate-Specific Amino Acid Sensing Using a Molecular d/ l-Cysteine Probe for Comprehensive Stereochemical Analysis in Aqueous Solution.

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.

Selective Csp3-F Bond Functionalization with Lithium Iodide.

A highly efficient method for C-F bond functionalization of a broad variety of activated and unactivated aliphatic substrates with inexpensive lithium iodide is presented. Primary, secondary, tertiary, benzylic, propargylic and α-functionalized alkyl fluorides react in chlorinated or aromatic solvents at room temperature or upon heating to the corresponding iodides which are isolated in 91-99% yield. The reaction is selective for aliphatic monofluorides and can be coupled with in situ nucleophilic iodide replacements to install carbon-carbon, carbon-nitrogen and carbon-sulfur bonds with high yields. Alkyl difluorides, trifluorides, even in activated benzylic positions, are inert under the same conditions and aryl fluoride bonds are also tolerated.

Chemoselective bioconjugation based on modular click chemistry with 4-halocoumarins and aryl sulfonates.

We report chemoselective and modular peptide bioconjugation using stoichiometric amounts of 4-halocoumarin and arylsulfonate agents that undergo metal-free C(sp2)-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.

Click chemistry enables quantitative chiroptical sensing of chiral compounds in protic media and complex mixtures.

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.