The uses of supramolecular chemistry in synthetic methodology development
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Enantioselective indicator displacement assays (eIDAs), was transitioned to a high-throughput screening protocols, for the rapid determination of concentration and enantioselectivity (ee) of chiral diols and α-hydroxycarboxylic acid. To improve the design of our previously established receptor based on o-(N,N-dialkylaminomethyl)arylboronate scaffolds for eIDAs. The rigidity of the receptor, which pertinent from the formation of an intramolecular N-B dative bond was investigated. o-(Pyrrolidinylmethyl)phenylboronic acid its complexes with bifunctional substrates such as catechol, [alpha]-hydroxyisobutyric acid, and hydrobenzoin was studied in detail by x-ray crystallography and ¹¹B NMR. Our structural study predicts that the formation of an N-B dative bond, and/or solvolysis to afford a tetrahedral boronate anion, depends on the solvent and the complexing substrate present. To simplify the operation of eIDAs, we introduced an analytical method, which utilize a dual-chamber quartz cuvette, which reduces the number of spectroscopic measurements from two to one and introduced artificial neural networks (ANNs) which simplifies data analysis. In a second example a high-throughtput screening protocol for hydrobenzoin was developed. The method involves the sequential utilization of what we define herein as screening, training, and analysis plates. Several enantioselective boronic-acid based receptors were screened using 96-well plates, both for their ability to discriminate the enantiomers of hydrobenzoin and to find their optimal pairing with indicators resulting in the largest optical responses. The best receptor/indicator combination was then used to train an ANN to determine concentration and ee. To prove the practicality of the developed protocol, analysis plates were created containing true unknown samples of hydrobenzoin generated by established Sharpless asymmetric dihydroxylation reactions, and the best ligand was correctly identified. The system was extended to pattern recognition for the rapid determination of identity, concentration, and ee of chiral vicinal diols. A diverse enantioselective sensor array was generated with three chiral boronic acid receptors and pH indicators. The optical response produced by the sensor array, was analyzed by two pattern recognition algorithms: principal component analysis (PCA) and ANNs. The PCA plot demonstrated good chemoselective and enantioselective separation of the analytes, and ANNs was used to accurately determine the concentration and ee of five unknown samples.