Recommended Tests for the Self-Disproportionation of Enantiomers (SDE) to Ensure Accurate Reporting of the Stereochemical Outcome of Enantioselective Reactions

The purpose of this review is to highlight the necessity of conducting tests to gauge the magnitude of the self-disproportionation of enantiomers (SDE) phenomenon to ensure the veracity of reported enantiomeric excess (ee) values for scalemic samples obtained from enantioselective reactions, natural products isolation, etc. The SDE always occurs to some degree whenever any scalemic sample is subjected to physicochemical processes concomitant with the fractionation of the sample, thus leading to erroneous reporting of the true ee of the sample if due care is not taken to either preclude the effects of the SDE by measurement of the ee prior to the application of physicochemical processes, suppressing the SDE, or evaluating all obtained fractions of the sample. Or even avoiding fractionation altogether if possible. There is a clear necessity to conduct tests to assess the magnitude of the SDE for the processes applied to samples and the updated and improved recommendations described herein cover chromatography and processes involving gas-phase transformations such as evaporation or sublimation

Mechanistic study of asymmetric amplification in the Soai autocatalytic reaction

Soai’s discovery of chiral amplification in the autocatalytic alkylation of pyrimidine-5-carbaldehyde with diisopropylzinc is one of the most noteworthy findings of the last decade of the 20th century. This is the first experimental confirmation of an early theoretical rationalisation of autocatalysis as a mechanism for the evolution of biological homochirality from a racemic environment (Frank, 1953). This thesis describes kinetic and spectroscopic investigations that were conducted with the aim of better understanding the mechanism under which chiral amplification is achieved in the Soai system. The methodology used to perform the kinetic studies that are presented in this thesis focuses on the use of reaction calorimetry as in-situ tool coupled with the appropriate analytical technique for enantiomeric excess measurements. Observations of an unusual temperature effect on the reaction rate and a profound induction period are reported together with extensive kinetic investigations. Kinetic experiments were designed and carried out following Reaction Progress Kinetic Analysis methodology, which is described in detail. These experiments were carried out in order to ascertain the concentration dependence of the substrates and the reaction product, and revealed a 1.6 order in pyrimidyl aldehyde, a zero order in diisopropylzinc and a first order in the reaction product. Meticulous NMR studies of the alkoxide product at low temperature demonstrated its tendency to form tetrameric complexes, which could be either directly involved in the autocatalysis or be the precursors of the active catalytic species. Possible mechanisms that involve tetramers formation are proposed and supported by simulations carried out using COPASI simulation software. This thesis also includes a separate Chapter on the MIB mediated alkylation of benzaldehyde with diethylzinc, a system characterised by a marked nonlinear effect. Kinetic studies demonstrate how the high degree of chiral amplification comes at the expense of the reaction rate

Spontaneous chiral symmetry breaking in early molecular networks

Background: An important facet of early biological evolution is the selection of chiral enantiomers for molecules such as amino acids and sugars. The origin of this symmetry breaking is a long-standing question in molecular evolution. Previous models addressing this question include particular kinetic properties such as autocatalysis or negative cross catalysis. Results: We propose here a more general kinetic formalism for early enantioselection, based on our previously described Graded Autocatalysis Replication Domain (GARD) model for prebiotic evolution in molecular assemblies. This model is adapted here to the case of chiral molecules by applying symmetry constraints to mutual molecular recognition within the assembly. The ensuing dynamics shows spontaneous chiral symmetry breaking, with transitions towards stationary compositional states (composomes) enriched with one of the two enantiomers for some of the constituent molecule types. Furthermore, one or the other of the two antipodal compositional states of the assembly also shows time-dependent selection. Conclusion: It follows that chiral selection may be an emergent consequence of early catalytic molecular networks rather than a prerequisite for the initiation of primeval life processes. Elaborations of this model could help explain the prevalent chiral homogeneity in present-day living cells. Reviewers: This article was reviewed by Boris Rubinstein (nominated by Arcady Mushegian), Arcady Mushegian, Meir Lahav (nominated by Yitzhak Pilpel) and Sergei Maslov

Estimation of Enantiomeric Excess Based on Rapid Host–Guest Exchange

Chiral molecules possess enantiomers that have non-superimposable chemical structures but exhibit identical nuclear magnetic resonance (NMR) spectra. This feature prevents the use of NMR spectroscopic methods for the determination of enantiomeric excesses (ee) of chiral molecules, using simple mixtures of their enantiomers. Recently, however, it was reported that the addition of a symmetrical prochiral molecule (a reporter or host) into a solution of chiral analyte can lead to estimation of ee through interactions involving rapid exchange of the chiral analyte (guest) in the formed host–guest complex. This is due to the ee-dependent splitting of NMR resonances of the prochiral host molecule based on averaging the chemical shift non-equivalency caused by the presence of a chiral guest. The mechanism is not dependent on diastereomer formation, and 1:1 host–guest complexes can also show ee-dependent NMR peak splitting. Prochiral molecules capable of ee sensing using the NMR technique are now referred to as so-called prochiral solvating agents (pro-CSAs). pro-CSAs represent a family of reagents distinct from the commonly used NMR chiral derivatizing reagents (where chiral auxiliaries are used to derivatize enantiomers to diastereomers) or chiral solvating agents (where chiral auxiliaries interact in an asymmetric manner with analyte enantiomers). pro-CSA methods are unique since neither pro-CSA nor NMR contains chiral factors, making the technique neutral with respect to chirality. Here, we review our recent work on this matter involving several different nominally achiral receptor molecules whose unique guest binding properties and solution characteristics (especially with regard to NMR spectroscopy) allow for the estimation of ee in the corresponding chiral guests

Insights in Homochiral Metal-Organic Frameworks: From Their Synthesis to Enantioselective Applications

A través de la reacció d'un derivat d'aminoàcid i Cu(II) s'ha obtingut la xarxa metaloorgànica (MOF) quiral anomenada TAMOF-1. Per tal de ser utilitzada en la investigació de processos enantioselectius, la síntesi del TAMOF-1 s'ha optimitzat en termes de mida de partícula i superfície porosa, donat que aquests paràmetres són crucials de cara a la seva aplicabilitat. La porositat d'aquest material ens ha permès utilitzar-ho com a catalitzador heterogeni per a processos de resolució cinètica, i com a rebliment de columnes cromatogràfiques per a separacions quirals en fase líquida, tant en columnes cromatogràfiques preparatives, com en columnes analítiques i semipreparatives en HPLC. De fet, s'ha aconseguit separar mescles de regioisòmers no quirals difícils de separar industrialment amb aquestes mateixes columnes, que tenen una vida útil de més de dos anys. Amb l'objectiu d'obtenir anàlegs de TAMOF-1, s'han dissenyat i sintetitzat nous lligands derivats d'aminoàcids anàlegs al lligand original, però amb distàncies més grans entre els grups coordinants. Posteriorment, aquests lligands s'han utilitzat en l'estudi de la formació de nous MOFs quirals, i les estructures obtingudes s'han caracteritzat per raigs X, difracció de pols i adsorció/desorció de nitrogen, entre d'altres tècniques.A través de la reacción de un derivado de aminoácido y Cu(II) se ha obtenido la red metaloorgánica (MOF) quiral llamada TAMOF-1. Con el fin de ser utilizada en la investigación de procesos enantioselectivos, la síntesis de TAMOF-1 se ha optimizado en términos de tamaño de partícula y superficie porosa, ya que estos parámetros son cruciales para controlar su aplicabilidad. La porosidad de este material nos ha permitido utilizarlo como catalizador heterogéneo para procesos de resolución cinética, y como relleno de columnas cromatográficas para separaciones quirales en fase líquida, tanto en columnas cromatográficas preparativas, como en columnas analíticas y semipreparativas en HPLC. De hecho, se ha logrado separar mezclas de regioisómeros no quirales difíciles de separar industrialmente con estas mismas columnas, que tienen una vida útil de más de dos años. Con el objetivo de obtener análogos de TAMOF-1, se han diseñado y sintetizado nuevos ligandos derivados de aminoácidos análogos al ligando original, pero con mayores distancias entre los grupos coordinantes. Posteriormente, estos ligandos se han utilizado para estudiar la formación de nuevos MOFs quirales, y las estructuras obtenidas se han caracterizado por rayos X, difracción de polvo y adsorción/desorción de nitrógeno, entre otras técnicas.Through the reaction of an amino acid derivative and Cu(II), the chiral metal-organic framework (MOF) called TAMOF-1 was obtained. In order to be used in the investigation of enantioselective processes, the synthesis of TAMOF-1 was optimised in terms of particle size and the porous surface, as these parameters are crucial to controlling its applicability. The porosity of this material has allowed us to use it as a heterogeneous catalyst for kinetic resolution processes, and as a stationary phase for chromatographic columns for chiral separation in liquid phase, both in preparative chromatographic columns and in analytical and semi-preparative HPLC columns. In fact, it has been possible to separate mixtures of achiral regioisomers that are difficult to separate industrially with these same columns, which have a lifespan of more than two years. To obtain analogues of TAMOF-1, new ligands derived from amino acids analogous to the original ligand but with greater distances between the coordinating groups have been designed and synthesised. Subsequently, these ligands have been used to study the formation of new chiral MOFs, and the structures obtained have been characterised by single crystal and powder X-ray diffraction and nitrogen adsorption/desorption, among other techniques

Insights into the self-assembly of pi-conjugated systems

In Chapter 1 supramolecular polymerization of small molecules is introduced and exemplified. The self-assembly of these single component systems, for example by hydrogen bonding and p-p interactions, has reached a high level of understanding. However for the fabrication of complex architectures with specific properties, a perfect organization of multiple components in the aggregates needs to be achieved. In order to arrive at such complex architectures more insight into the specificities of the self- assembly of p-conjugated systems is a necessity, which is the subject of this thesis. A covalent strategy for the spatial organization of p-conjugated components by placement on a foldameric scaffold is discussed in Chapter 2. Although the synthesis of these foldamers was successful, the 30 synthetic steps make the synthesis of a specific foldamer a lengthy process while only achieving relatively small structures. It was found that placing the chromophores in a defined three dimensional environment hampered a uniform description of the charge transfer characteristics within the current theoretical models. Furthermore, the level of complexity in these synthetic systems pales in comparison with the examples found in Nature. A more promising approach could be the self-assembly of molecules. Supramolecular polymerization via the cooperative mechanism is generally observed for the examples discussed in this thesis. Cooperative mechanisms have a nucleation event preceding the formation of the selfassembled structures. The evidence presented in Chapter 3 showed that the nucleation of oligothiophenes can be either homogeneous or heterogeneous in nature, depending on sample purity. Especially when the supramolecular interactions are counterbalancing each other, heterogeneous nucleation is likely to be present. By changing the self-assembly protocol, e.g. altering the cooling rate and method, the outcome of the self-assembly was remarkably different. This showed that the oligothiophenes were able to self-assemble into multiple different structures thereby displaying the presence of a complex energy landscape in analogy to polymorphism in the crystallization of molecules and to protein folding. At higher concentration the internal structure of the oligothiophene assemblies was resolved by using a combination of small-angle X-ray scattering and linear birefringence on magnetically aligned assemblies as discussed in Chapter 4. Optical and chiroptical studies showed that the cooperative nature of the self-assembly at this higher concentration was maintained. Cylindrical assemblies were observed, where the thiophene molecules were radially organized and p-p stacking was in a tangential direction. Chapter 5 discusses the use of circular dichroism (CD) spectroscopy to monitor the coassembly of multiple components. For the achiral oligo(p-phenylene vinylene) ureidotriazine systems, artificial CD effects are observed for the self-assembled structures in dodecane that are a result of unwanted linear dichroic (LD) effects as a consequence of flow induced alignment in the cuvette. These LD artifacts interfere with the CD measurements. By using methylcyclohexane (MCH) the LD effects are absent and the observed CD effects can be considered as a result of exciton coupling between the chromophores. The influence of two preparation methods on the organization of mixed assemblies consisting of achiral and chiral OPV derivatives with different oligomeric length is studied with CD spectroscopy in MCH. The first preparation method allows the molecules to be fully mixed at high temperature, while subsequent cooling shows chiral amplification of the achiral longer oligomer by the shorter chiral oligomer. The study indicates the formation of enriched clusters of one of the two components either within one stack, or as separate stacks. The second method is based on the addition of the shorter oligomer at a temperature, where the assemblies of the achiral oligomer are already present and kinetically inert. In this case the chiral amplification is reduced, indicating the formation of more enriched clusters of compounds. However, to arrive at an unambiguous assignment of the internal structure of the assemblies, the CD data should be combined with complementary techniques. In Chapter 6 the influence of reduced dynamics on the self-assembly of p-conjugated star shaped molecules is discussed. Two different types of aggregates, A1 and A2, are distinguished for the selfassembly in MCH, where a transition from A1 to A2 occurs, thereby showing the increased thermodynamic stability of the A2 aggregate. The addition of a good solvent enhances the rate of the transition. SEC in these alkane solvents shows that the A1 state in the solvent mixture (4:1MCH/toluene) was far more dynamic than in pure MCH. Furthermore, it reveals an unusually high monomer content of 15 mol% in the solvent mixture, which is confirmed by 1H NMR. As expected, in pure MCH the monomer content is much lower and for that reason it could not be detected. In order to investigate the origin of the A1–A2 transition, the two enantiomers are mixed and chiral amplification in the form of the Majority Rules effect is shown to occur in MCH, while it is only weakly present in the solvent mixture. The presence of the other enantiomer significantly slows down the kinetics of the transition from A1 to A2, where the transition only occurred in the solvent mixture. Quite remarkably, chiral amplification is absent in the A2 state in the solvent mixture. The combined results suggest that the A1–A2 transition is related to a tightening of the internal structure, where the transition is facilitated by the presence of an enantiomerically pure cluster. In general the research described in this thesis reveals some important parameters that determine the self-assembly process and its outcome. Reflection on these parameters and their implication on the design and synthesis of complex multicomponent supramolecular architectures is given in an epilogue to this thesis

Chiral Auxiliaries and Chirogenesis

This Reprint Book highlights and overviews the most important and novel aspects of chiral auxiliary and chirogenesis in different natural/physical sciences and in modern technologies. In particular, some newly emerging classes of molecules used for these purposes are described. This book consists of four review articles and one research paper and is of interest for general chemistry readership, including graduate and postgraduate students, and for researchers specializing in the fields of chirality and stereochemistr

Chiral Auxiliaries and Chirogenesis II

This Reprint Book highlights and overviews the most important and novel aspects of chiral auxiliary and chirogenesis in different natural/physical sciences and in modern technologies. In particular, some newly emerging classes of molecules used for these purposes have been described. Furthermore, some important experimental and theoretical issues associated with the chirality field have been addressed. This book consists of one review article and six research papers and is of interest for general chemistry readership, including graduate and post-graduate students, and for researchers specializing in the fields of chirality and stereochemistr

Enantiospecificity Of Polyclonal Antibodies Raised Against Racemic And Pure Enantiomers Of Salbutamol And The Implications Of Their Use In Enzyme Immunoassay

Salbutamol (albuterol) adalah agonis β2-adrenergik yang popular digunakan dalam rawatan asma dan gangguan obstruktif pulmonari kronik (COPD). Salbutamol (albuterol) is a β2-adrenergic agonist popularly used in the treatment of asthma and chronic obstructive pulmonary disorder (COPD), and is also commonly abused as a performance enhancer in sports as well as an effective growth promoter in livestock