Leo A. Joyce

The uses of supramolecular chemistry in synthetic methodology development: examples of anion and neutral molecular recognition

The principles of supramolecular chemistry have successfully permeated through a broad range of organic chemistry subdisciplines. One subdiscipline that is not routinely associated with supramolecular chemistry is that of organic synthetic methodology. Though sometimes indiscernible, non-bonded and bonding supramolecular interactions play a large role in chemical reactions and catalysis. Many synthetic methods hinge on the creation of anionic charge, albeit just partial, at some step during this process, and hence are prime targets for molecular recognition interactions. Examples are artificial enzymes, biomimetic catalysis, organocatalysis, and many of the catalysts that are derived from a combinatorial screen. Further, supramolecular chemistry is playing an increasingly large role in high-throughput analytical techniques. This tutorial review ties together supramolecular approaches to methodology creation, combinatorial screening, and analytical protocols. The goal is to show, and further predict, that supramolecular chemistry will continually increase its impact in organic synthetic methodology development.

A simple method for the determination of enantiomeric excess and identity of chiral carboxylic acids.

The association between an achiral copper(II) host (1) and chiral carboxylate guests was studied using exciton-coupled circular dichroism (ECCD). Enantiomeric complexes were created upon binding of the enantiomers of the carboxylate guests to the host, and the sign of the resultant CD signal allowed for determination of the configuration of the studied guest. The difference in magnitudes and shapes of the CD signals, in conjunction with linear discriminant analysis (LDA), allowed for the identity of the guest to be determined successfully. A model was created for the host-guest complexes which successfully predicts the sign of the observed CD signal. Further, Taft parameters were used in the model, leading to rationalization of the observed magnitudes of the CD signals. Finally, the enantiomeric excess (ee) of unknown samples of three chiral carboxylic acid guests was determined with an average absolute error of ±3.0%.

Pattern-based recognition for the rapid determination of identity, concentration, and enantiomeric excess of subtly different threo diols.

A pattern-based recognition approach for the rapid determination of the identity, concentration, and enantiomeric excess of chiral vicinal diols, specifically threo diols, has been developed. A diverse enantioselective sensor array was generated using three chiral boronic acid receptors and three pH indicators. The optical response produced by the sensor array was analyzed by two pattern-recognition algorithms: principal component analysis and artificial neural networks. Principal component analysis demonstrated good chemoselective and enantioselective separation of the analytes, and an artificial neural network was used to accurately determine the concentrations and enantiomeric excesses of five unknown samples with an average absolute error of +/-0.08 mM in concentration and 3.6% in enantiomeric excess. The speed of the analysis was enhanced by using a 96-well plate format, portending applications in high-throughput screening for asymmetric-catalyst discovery. X-ray crystallography and (11)B NMR spectroscopy was utilized to study the enantioselective nature of the boronic acid host 2.

A Mechanically Controlled Indicator Displacement Assay

Detection and quantification of biologically active analytes is of paramount importance. These substances, whether therapeutic or harmful, are routinely evaluated for a range of properties, such as pharmaceutical activity and chemical toxicity. Such analyses are routinely performed in a variety of scientific disciplines, including drug discovery, environmental pollution monitoring, medical testing, and food safety evaluation. To this end, many studies aim to control the selectivity of a binding event such that the energy of binding between a receptor and an analyte is maximized. To translate binding into detection and quantification, colorimetric or fluorescent molecular sensors are regarded as a very promising approach. One sensing strategy is the indicator displacement assay (IDA). This approach uses a competitive binding event, between an indicator and a guest, to a complimentary site on a host. This method allows the determination of total guest (or analyte) concentration accurately, leading to the broad use of this approach for developing multicomponent optical sensors and enantioselective assays. To further develop the IDA strategy, we sought methods to increase the binding between host and guest molecules. The high effective concentration observed for molecular interfaces allows accentuated binding events, as compared to similar solution-based studies. The binding that occurs between a host in one layer and a guest in another layer provides a conceptual mimic to the binding that occurs in living cells. One promising interfacial sensing environment is the air– water interface. Here, the position between the host and guest in the two-phase boundary facilitates and enhances binding. Furthermore, a variety of monolayer assemblies have been prepared in an attempt to facilitate molecular recognition of biologically important substances. One of the more promising strategies is mechanically controlled molecular recognition at interfaces, which enables facile control of molecular conformation. This control has allowed for reversible capture and release of guests, enantioselective binding of amino acids, and discrimination of nucleobases differing only by a single methyl group, all by using a simple and versatile stimulus, namely mechanical force. Herein, we introduce what we call a mechanically controlled indicator displacement assay (MC-IDA). This strategy utilizes a deformable monolayer assembly of fluorescently tagged host molecules formed at the air–water interface. This monolayer acts as a mechanically controllable signal-emission unit. External compression and expansion of monolayers in lateral directions can alter molecular conformations, resulting in control of molecular recognition (Scheme 1). We demonstrate that the fluorescent signaling between a host and an indicator can be switched on by surface compression, and the displacement of this indicator in response to an analyte can be enhanced to give very sensitive molecular sensing. The goal of the present study was to demonstrate the application of mechanically controlled molecular recognition at interfaces to create novel applications of the IDA. For this task, we designed and synthesized an amphiphilic dilysine peptide host 1 (Figure 1a; see the Supporting Information for details of the synthesis). The host was designed to contain three important motifs: a phenylboronic acid, a cholesterol moiety, and a carboxyfluorescein indicator at the N-terminus of the peptide. The phenylboronic acid was chosen because it allows for reversible covalent bond formation with vicinal diols, as found in carbohydrates, glycopeptides, and ahydroxycarboxylic acids. The cholesterol group provides a hydrophobic functionality, imparting compatibility with organic media. The carboxyfluorescein was chosen as a fluo-

Enantio‐ and Chemoselective Differentiation of Protected α‐Amino Acids and β‐Homoamino Acids with a Single Copper(II) Host

The association between an achiral copper(II)-containing host 1 and chiral carboxylates has been expanded beyond previous studies to new chiral carboxylate guests, both α-amino acids and β-homoamino acids. The observed exciton-coupled circular dichroism (ECCD) signals for the enantiomers of each carboxylate were equal and opposite, and these signals differed in size and shape between the individual amino acids. Linear discriminant analysis (LDA) was applied as a statistical analysis technique to differentiate the amino acids, both enantioselectively and chemoselectively, giving the absolute configuration and identity of the amino acid. The identity of each of the α-amino acids and β-homoamino acids were determined independently by LDA, and then the two were considered together. Each of these analyses showed good differentiation of the amino acid guests with the use of only one host molecule.

Homodecoupled 1,1‐ and 1,n‐ADEQUATE: Pivotal NMR Experiments for the Structure Revision of Cryptospirolepine

Cryptospirolepine is the most structurally complex alkaloid discovered and characterized thus far from any Cryptolepis specie. Characterization of several degradants of the original, sealed NMR sample a decade after the initial report called the validity of the originally proposed structure in question. We now report the development of improved, homodecoupled variants of the 1,1- and 1,n-ADEQUATE (HD-ADEQUATE) NMR experiments; utilization of these techniques was critical to successfully resolving long-standing structural questions associated with crytospirolepine.

Chromatographic Separation and Assignment of Absolute Configuration of Hydroxywarfarin Isomers

The absolute configuration of several hydroxywarfarin isomers was assigned using a comparison of elution order on chiral stationary phases, optical rotation, and circular dichroism (CD) spectra, with confirmation of assignments made by comparison between experimental and calculated CD spectra and selective synthesis of hydroxywarfarin isomers from enantiopure warfarin using human liver microsomes.

Imine-based chiroptical sensing for analysis of chiral amines: from method design to synthetic application

Imine-bond formation between a chiral amine analyte and 3-hydroxypyridine-2-carboxaldehyde (HCA) was used to create a fast and robust method for enantiopurity analysis. This approach showed good universality, and was applied to a variety of different classes of chiral amines. The sign of the measured CD signal was enantiospecific across the range of amines tested, allowing some confidence in absolute configuration determination. This technique was transitioned to an HPLC-CD detector to allow for rapid and automated sample introduction, while maintaining the level of accuracy noted for the standalone CD spectrophotometer. Finally, the enantiomeric purity of a series of crude reaction mixtures of synthetic amines produced by biocatalytic transamination was accurately determined using this approach.

Tricyclic 1,5-naphthyridinone oxabicyclooctane-linked novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents-SAR of left-hand-side moiety (Part-2).

Novel bacterial topoisomerase inhibitors (NBTIs) represent a new class of broad-spectrum antibacterial agents targeting bacterial Gyrase A and ParC and have potential utility in combating antibiotic resistance. A series of novel oxabicyclooctane-linked NBTIs with new tricyclic-1,5-naphthyridinone left hand side moieties have been described. Compounds with a (R)-hydroxy-1,5-naphthyridinone moiety (7) showed potent antibacterial activity (e.g., Staphylococcus aureus MIC 0.25 μg/mL), acceptable Gram-positive and Gram-negative spectrum with rapidly bactericidal activity. The compound 7 showed intravenous and oral efficacy (ED50) at 3.2 and 27 mg/kg doses, respectively, in a murine model of bacteremia. Most importantly they showed significant attenuation of functional hERG activity (IC50 >170 μM). In general, lower logD attenuated hERG activity but also reduced Gram-negative activity. The co-crystal structure of a hydroxy-tricyclic NBTI bound to a DNA-gyrase complex exhibited a binding mode that show enantiomeric preference for R isomer and explains the activity and SAR. The discovery, synthesis, SAR and X-ray crystal structure of the left-hand-side tricyclic 1,5-naphthyridinone based oxabicyclooctane linked NBTIs are described.

Detection of dehalogenation impurities in organohalogenated pharmaceuticals by UHPLC–DAD–HRESIMS

The presence of dehalogenated impurities is often observed in halogen-containing pharmaceuticals, and can present a difficult analytical challenge, as the chromatographic behavior of the halogenated drug and the hydrogen-containing analog can be quite similar. In this study we describe the chromatographic separation and unambiguous identification of dehalogenation impurities or associated isomers in organohalogenated pharmaceuticals using UHPLC with a pentafluorophenyl column coupled with diode-array and high resolution electrospray ionization mass spectrometry detection (UHPLC-DAD-HRESIMS).