A new autoinductive cascade employing benzoyl fluoride as a latent source of fluoride is reported for signal amplification and optical detection of fluoride. The autoinduction leads to a maximum ...4-fold signal enhancement for each fluoride generated, as well as a self-propagating cycle that generates three fluorophores for each single fluoride released. A two-step integrated protocol creates a more rapid autoinductive cascade than previously reported, as well as a highly sensitive diagnostic assay for the ultratrace quantitation of a phosphoryl fluoride nerve agent surrogate.
Dynamic covalent chemistry-based sensors have recently emerged as powerful tools to rapidly determine the enantiomeric excess of organic small molecules. While a bevy of sensors have been developed, ...those for flexible molecules with stereocenters remote to the functional group that binds the chiroptical sensor remain scarce. In this study, we develop an iterative, data-driven workflow to design and analyze a chiroptical sensor capable of assessing challenging acyclic γ-stereogenic alcohols. Following sensor optimization, the mechanism of sensing was probed with a combination of computational parametrization of the sensor molecules, statistical modeling, and high-level density functional theory (DFT) calculations. These were used to elucidate the mechanism of stereochemical recognition and revealed that competing attractive noncovalent interactions (NCIs) determine the overall performance of the sensor. It is anticipated that the data-driven workflows developed herein will be generally applicable to the development and understanding of dynamic covalent and supramolecular sensors.
Ricin toxin A-chain (RTA), a toxic protein from Ricinus communis, inactivates ribosomes to induce toxicity. The active site of RTA consists of two binding pockets. Many studies have focused on ...developing RTA inhibitors that can simultaneously bind to these critical pockets; however, almost all the inhibitors developed so far interact with only one pocket. In the present study, we discovered that pterin-7-carboxamides with aromatic l-amino acid pendants interacted with the active site of the enzyme in a 2-to-1 mode, where one inhibitor molecule bound to the primary pocket and the second one entered the secondary pocket in the active site of RTA. X-ray crystallographic analysis of inhibitor/RTA complexes revealed that the conformational changes of Tyr80 and Asn122 in RTA were critical for triggering the entry of inhibitor molecules into the secondary pocket of the RTA active site.
•Ricin toxin A chain (RTA) has two specific pockets in its active site.•No small molecular inhibitor was reported to bind to the secondary pocket of RTA.•Some pterin-7-carboxamides bind to the RTA active site in a 2-to-1 mode.•This is the first exaple of small molecules binding to the secondary pocket of RTA.•Movements of Tyr80 and Asn122 triggers the crucial binding of inhibitors to RTA.
A protocol for the rapid determination of the absolute configuration and enantiomeric excess (ee) of α‐chiral primary amines with potential applications in asymmetric reaction discovery has been ...developed. The protocol requires derivatization of α‐chiral primary amines through condensation with pyridine carboxaldehyde to quantitatively yield the corresponding imine. The CuI complex with 2,2′‐bis (diphenylphosphino)‐1,1′‐dinaphthyl (BINAPCuI) with the imine yields a metal‐to‐ligand charge‐transfer (MLCT) band in the visible region of the circular dichroism (CD) spectrum upon binding. Diastereomeric host–guest complexes give CD signals of the same signs but different amplitudes, allowing for differentiation of enantiomers. Processing the primary optical data from the CD spectrum with linear discriminant analysis (LDA) allows for the determination of the absolute configuration and identification of the amines, and processing with a supervised multilayer perceptron artificial neural network (MLP‐ANN) allows for the simultaneous determination of the ee and concentration. The primary optical data necessary to determine the ee of unknown samples is obtained in two minutes per sample. To demonstrate the utility of the protocol in asymmetric reaction discovery, the ee values and concentrations for an asymmetric metal‐catalyzed reaction are determined. The potential of the application of this protocol in high‐throughput screening (HTS) of ee is discussed.
New protocols: By employing pattern‐recognition techniques based on the monitorization of MLCT bands of simple receptors in the circular dichroism (CD) spectra, rapid and simultaneous ee and concentration determination of chiral amines was accomplished (see scheme). This protocol was also applied to determine the ee of the crude products of an asymmetric catalytic reaction by simple derivatization.
A critical step in repurposing the cellular translation machinery for the synthesis of polymeric products is the acylation of transfer RNA (tRNA) with unnatural monomers. Toward this goal, ...flexizymes, ribozymes capable of aminoacylation, have emerged as a uniquely adept tool for charging tRNA with ever increasingly diverse substrates. In this review, we present a library of monomer substrates that have been tested for tRNA acylation with the flexizyme system. From this mile-high view, we provide insights for understanding the chemical factors that influence flexizyme-mediated tRNA acylation. We conclude that flexizymes are primitive esterification catalysts that display a modest binding affinity to the monomer’s aromatic recognition element. Together, these robust, yet flexible, flexizyme systems provide researchers with unprecedented access for preparing unnatural acyl-tRNA and the opportunity to repurpose the translation machinery for the synthesis of novel biologically derived structures beyond native proteins and peptides.
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A critical hurdle to repurposing the translation machinery for the synthesis of unnatural polymeric products is the acylation of tRNA with unnatural monomers. Coronado et al. compile a comprehensive list of substrates that have been tested for flexizyme-mediated tRNA acylation and provide insight for understanding the factors that affect acylation.
The design of a sensor array that uses a single entity as both the host and the indicator (squaraine dye, SQ) to differentiate a series of metal ions and a series of thiols is reported. The metal ...ions and thiols act as both analytes and “modulators” of the squaraine response allowing pattern-based discrimination. Mercury(II), palladium(II), copper(II), iron(II), and nickel(II) can be discriminated when combining SQ with five thiols: propane thiol (PT), 3-mercaptopropionic acid (MPA), naphthalene-2-thiol (NT), 2,3-dimercaptopropanol (DMP), and 2-acetylamino-3-mercaptopropionic acid methyl ester (ACM). Likewise, the five thiols can be discriminated using SQ and the five metals. For example, SQ in combination with 2-acetylamino-3-mercaptopropionic acid methyl ester (ACM) afforded very good differentiation of all five metal ions. However, propanethiol, 3-mercaptopropionic acid, and naphthalene-2-thiol produced very similar differentiation of the considered metal ions. On the other hand, all metal ions considered in this study are able to discriminate 2,3-dimercaptopropanol (DMP) and 2-acetylamino-3-mercaptopropionic acid methyl ester (ACM) clearly and completely, both from one another and from the other three thiols (PT, NT, MPA). Importantly, mercury(II) is the only metal ion able to effect the discrimination of naphthalenethiol (NT) from PT and MPA, thus giving the best discrimination overall. The study shows that complex discrimination of widely diverse classes, metal ions and thiols, can be achieved via a single receptor/indicator.
Organic chemistry is replete with complex relationships: for example, how a reactant’s structure relates to the resulting product formed; how reaction conditions relate to yield; how a catalyst’s ...structure relates to enantioselectivity. Questions like these are at the foundation of understanding reactivity and developing novel and improved reactions. An approach to probing these questions that is both longstanding and contemporary is data-driven modeling. Here, we provide a synopsis of the history of data-driven modeling in organic chemistry and the terms used to describe these endeavors. We include a timeline of the steps that led to its current state. The case studies included highlight how, as a community, we have advanced physical organic chemistry tools with the aid of computers and data to augment the intuition of expert chemists and to facilitate the prediction of structure–activity and structure–property relationships.
Reversible covalent bonding is often used for the creation of novel supramolecular structures, multi-component assemblies and sensing ensembles. Despite the remarkable success of dynamic covalent ...systems, the reversible binding of a mono-alcohol with high strength is challenging. Here, we show that a strategy of carbonyl activation and hemiaminal ether stabilization can be embodied in a four-component reversible assembly that creates a tetradentate ligand and incorporates secondary alcohols with exceptionally high affinity. Evidence is presented that the intermediate leading to binding and exchange of alcohols is an iminium ion. To demonstrate the use of this assembly process we also explored chirality sensing and enantiomeric excess determinations. An induced twist in the ligand by a chiral mono-ol results in large Cotton effects in the circular dichroism spectra indicative of the handedness of the alcohol. The strategy revealed in this study should prove broadly applicable for the incorporation of alcohols into supramolecular architecture construction.
Asymmetric hydrogenation of unprotected NH imines catalyzed by rhodium/bis(phosphine)‐thiourea provided chiral amines with up to 97 % yield and 95 % ee. 1H NMR studies, coupled with control ...experiments, implied that catalytic chloride‐bound intermediates were involved in the mechanism through a dual hydrogen‐bonding interaction. Deuteration experiments proved that the hydrogenation proceeded through a pathway consistent with an imine.
In a bind: A bis(phosphine)‐thiourea ligand was successfully used in the rhodium‐catalyzed asymmetric hydrogenation of unprotected iminium salts. Control experiments and 1H NMR studies implied that the anion binding between the thiourea and chloride ions was involved in the mechanism. Deuteration experiments proved that the hydrogenation proceeded through a pathway consistent with an imine.
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