Diastereomeric Mixture Research Articles

New Active Ingredients for Sustainable Modern Chemical Crop Protection in Agriculture.

Today, the agrochemical industry faces enormous challenges to ensure the sustainable supply of high-quality food, efficient water use, low environmental impact, and the growing world population. The shortage of agrochemicals due to consumer perception, changing needs of farmers and ever-changing regulatory requirements is higher than the number of active ingredients that are placed on the market. The introduction of halogen atoms into an active ingredient molecule offers the opportunity to optimize its physico-chemical properties such as molecular lipophilicity. As early as 2010, around four-fifths of modern agrochemicals on the market contained halogen atoms. In addition, it becomes clear that modern agrochemicals have increasingly complex molecular structures with one or more stereogenic centers in the molecule. Today, almost half of modern agrochemicals are chiral molecules (herbicides, insecticides/acaricides/nematicides ≪ fungicides) and most of them consist of mixtures such as racemic mixtures of enantiomers, followed by mixtures of diastereomers and mixtures of pure enantiomers. Therefore, it is important that halogen-containing substituents or stereogenic centers are considered in the structural optimization of the active ingredients to ultimately develop sustainable agrochemicals in terms of efficacy, ecotoxicology, ease of use and cost-effectiveness.

New Supramolecular Hydrogels Based on Diastereomeric Dehydrotripeptide Mixtures for Potential Drug Delivery Applications.

Self-assembly of peptide building blocks offers unique opportunities for bottom-up preparation of exquisite nanostructures, nanoarchitectures, and nanostructured bulk materials, namely hydrogels. In this work we describe the synthesis, characterization, gelation, and rheological properties of new dehydrotripeptides, Cbz-L-Lys(Cbz)-L,D-Asp-∆Phe-OH and (2-Naph)-L-Lys(2-Naph)-L,D-Asp-∆Phe-OH, containing a N-terminal lysine residue Nα,ε-bis-capped with carboxybenzyl (Cbz) and 2-Naphthylacetyl (2-Naph) aromatic moieties, an aspartic acid residue (Asp), and a C-terminal dehydrophenylalanine (∆Phe) residue. The dehydrotripeptides were obtained as diastereomeric mixtures (L,L,Z and L,D,Z), presumably via aspartimide chemistry. The dehydrotripeptides afforded hydrogels at exceedingly low concentrations (0.1 and 0.04 wt%). The hydrogels revealed exceptional elasticity (G' = 5.44 × 104 and 3.43 × 106 Pa) and self-healing properties. STEM studies showed that the diastereomers of the Cbz-capped peptide undergo co-assembly, generating a fibrillar 3D network, while the diastereomers of the 2-Naph-capped dehydropeptide seem to undergo self-sorting, originating a fibril network with embedded spheroidal nanostructures. The 2-Naph-capped hydrogel displayed full fast recovery following breakup by a mechanical stimulus. Spheroidal nanostructures are absent in the recovered hydrogel, as seen by STEM, suggesting that the mechanical stimulus triggers rearrangement of the spheroidal nanostructures into fibers. Overall, this study demonstrates that diastereomeric mixtures of peptides can be efficacious gelators. Importantly, these results suggest that the structure (size, aromaticity) of the capping group can have a directing effect on the self-assembly (co-assembly vs. self-sorting) of diastereomers. The cytotoxicity of the newly synthesized gelators was evaluated using human keratinocytes (HaCaT cell line). The results indicated that the two gelators exhibited some cytotoxicity, having a small impact on cell viability. In sustained release experiments, the influence of the charge on model drug compounds was assessed in relation to their release rate from the hydrogel matrix. The hydrogels demonstrated sustained release for methyl orange (anionic), while methylene blue (cationic) was retained within the network.

Synthesis of Diastereomeric 2,6-bis{[3-(2-Hydroxy-5-substitutedbenzyl)octahydro-1H-benzimidazol-1-yl]methyl}-4-substituted Phenols (R = Me, OMe) by Mannich-Type Tandem Reactions

The synthesis and characterization of two novel diastereomeric Mannich bases was carried out from the reaction of the cyclic aminal (2R,7R,11S,16S)-1,8,10,17-tetraazapentacyclo[8.8.1.1.8,170.2,70.11,16]icosane 1 and p-cresol 2a and 4-methoxyphenol 2b in a water/dioxane mixture. The title compounds (4a–b) are interesting because bearing two 3-(2-hydroxy-5-substitutedbenzyl)octahydro-1H-benzimidazol-1-yl]methyl} substituents joined to an arenol ring. The formation of these new Mannich bases in the reaction mixture can be explained by aminomethylation of previously reported di-Mannich base 2,2′-((hexahydro-1H-benzo[d]imidazole-1,3(2H)-diyl)bis(methylene))bis(4-substituentphenol) 3a–b. NMR analysis demonstrated that compounds 4a–b were formed as diastereomeric mixtures. Subsequent experiments revealed that at longer reaction times, the percentage yield of these new products increased considerably (yield percentages up to 22–27%), suggesting a nucleophilic competition between the p-substituted phenols and Mannich bases of type 3 for aminal 1.

Harnessing sulfur-binding domains to separate Sp and Rp isomers of phosphorothioate oligonucleotides

Chemical synthesis of phosphoromonothioate oligonucleotides (PS-ONs) is not stereo-specific and produces a mixture of Rp and Sp diastereomers, whose disparate reactivity can complicate applications. Although the current methods to separate these diastereomers which rely on chromatography are constantly improving, many Rp and Sp diastereomers are still co-eluted. Here, based on sulfur-binding domains that specifically recognize phosphorothioated DNA and RNA in Rp configuration, we developed a universal separation system for phosphorothioate oligonucleotide isomers using immobilized SBD (SPOIS). With the scalable SPOIS, His-tagged SBD is immobilized onto Ni-nitrilotriacetic acid-coated magnetic beads to form a beads/SBD complex, Rp isomers of the mixture can be completely bound by SBD and separated from Sp isomers unbound in liquid phase, then recovered through suitable elution approach. Using the phosphoromonothioate single-stranded DNA as a model, SPOIS separated PS-ON diastereomers of 4 nt to 50 nt in length at yields of 60–90% of the starting Rp isomers, with PS linkage not locating at 5’ or 3’ end. Within this length range, PS-ON diastereomers that co-eluted in HPLC could be separated by SPOIS at yields of 84% and 89% for Rp and Sp stereoisomers, respectively. Furthermore, as each Rp phosphorothioate linkage can be bound by SBD, SPOIS allowed the separation of stereoisomers with multiple uniform Sp configurations for multiple phosphorothioate modifications. A second generation of SPOIS was developed using the thermolabile and non-sequence-specific SBDPed, enabling fast and high-yield recovery of PS substrate stereoisomers for the DNAzyme Cd16 and further demonstrating the efficiency of this method.Key points• SPOIS allows isomer separations of the Rp and Sp isomers co-eluted on HPLC.• SPOIS can obtain Sp isomers with 5 min and Rp in 20 min from PS-ON diastereomers.• SPOIS was successfully applied to separate isomers of PS substrates of DNAzyme.Graphical

EDBD-3,6-Epidioxy-1,10-Bisaboladiene-An Endoperoxide Sesquiterpene Obtained from Drimys brasiliensis (Winteraceae) Exhibited Potent Preclinical Efficacy against Schistosoma mansoni Infection.

Schistosomiasis, a neglected tropical disease impacting over 250 million individuals globally, remains a major public health challenge due to its prevalence and significant impact on affected communities. Praziquantel, the sole available treatment, highlights the urgency of the need for novel anthelmintic agents to achieve the World Health Organization (WHO) goal of schistosomiasis elimination. Previous studies reported the promising antiparasitic activity of different terpenoids against Schistosoma mansoni Sambon (Diplostomida: Schistosomatidae). In the present work, the hexane extract from branches of Drimys brasiliensis afforded a diastereomeric mixture of endoperoxide sesquiterpenes, including 3,6-epidioxy-bisabola-1,10-diene (EDBD). This compound was evaluated in vitro and in vivo against S. mansoni. EDBD exhibited a significant reduction in S. mansoni viability in vitro, with an effective concentration (EC50) value of 4.1 µM. Additionally, EDBD demonstrated no toxicity to mammalian cells. In silico analysis predicted good drug-likeness properties, adhering to pharmaceutical industry standards, including favorable ADME profiles. Furthermore, oral treatment of S. mansoni-infected mice with EDBD (400 mg/kg) resulted in a remarkable egg burden reduction (98% and 99% in tissues and feces, respectively) surpassing praziquantel's efficacy. These findings suggest the promising potential of EDBD as a lead molecule for developing a novel schistosomiasis treatment.

7-Deazapurine and Pyrimidine Nucleoside and Oligonucleotide Cycloadducts Formed by Inverse Diels-Alder Reactions with 3,6-Di(pyrid-2-yl)-1,2,4,5-tetrazine: Ethynylated and Vinylated Nucleobases for Functionalization and Impact of Pyridazine Adducts on DNA Base Pair Stability and Mismatch Discrimination.

The manuscript reports on 7-deazapurine and pyrimidine nucleoside and oligonucleotide cycloadducts formed by the inverse electron demand Diels-Alder (iEDDA) reaction with 3,6-di(pyrid-2-yl)-1,2,4,5-tetrazine. Cycloadducts were constructed from ethynylated and vinylated nucleobases. Oligonucleotides were synthesized containing iEDDA modifications, and the impact on duplex stability was investigated. iEDDA reactions were performed on nucleoside triple bond side chains. Oxidation was not required in these cases as dihydropyridazine intermediates are not formed. In contrast, oxidation is necessary for reactions performed on alkenyl compounds. This was verified on 5-vinyl-2'-deoxyuridine. A diastereomeric mixture of 1,2-dihydropyridazine cycloadduct intermediates was isolated, characterized, and later oxidized. 12-mer oligonucleotides containing 1,2-pyridazine inverse Diels-Alder cycloadducts and their precursors were hybridized to short DNA duplexes. For that, a series of phosphoramidites was prepared. DNA duplexes with 7-functionalized 7-deazaadenines and 5-functionalized pyrimidines display high duplex stability when spacer units are present between nucleobases and pyridazine cycloadducts. A direct connectivity of the pyridazine moiety to nucleobases as reported for metabolic labeling of vinyl nucleosides reduced duplex stability strongly. Oligonucleotides bearing linkers with and without pyridazine cycloadducts attached to the 7-deazaadenine nucleobase significantly reduced mismatch formation with dC and dG.

3-Substituted 6-Azabicyclo[3.1.1]heptanes: Nonclassical Piperidine Isosteres for Drug Discovery.

Advanced analogs of piperidine and smaller homologues of tropane─3-substituted 6-azabicyclo[3.1.1]heptanes─were synthesized on a large scale using readily available bulk reagents. The key step of the approach involved the double alkylation reaction of malonate with cis-2,4-bis(mesyloxymethyl)azetidine-1-carboxylate, in turn easily prepared on up to 1 kg scale. After hydrolysis, N-Boc-6-azabicyclo[3.1.1]heptane-3,3-dicarboxylic acid was obtained (up to 400 g in a single run), which was used as a common intermediate for the preparation of all the title building blocks. In particular, Pb(OAc)4-mediated oxidative decarboxylation of this intermediate gave 2,6-methanopiperidone derivative (up to 400 g scale), while monodecarboxylation gave N-Boc-6-azabicyclo[3.1.1]heptane-3-carboxylic acids as an easily separatable mixture of cis and trans diastereomers (up to 100 g scale). Further functional group transformations gave diastereopure cis- and trans-N-Boc-monoprotected diamines and amino alcohols. Molecular structure analysis using exit vector parameters (EVP) revealed that cis isomers of 3-substituted 6-azabicyclo[3.1.1]heptanes are three-dimensional analogs of common 1,4-disubstituted piperidine chair conformer, whereas trans isomers can be considered as unusual "boat" piperidines.

Structural diversity in nudibranch chemistry: elucidation of norditerpenes with a dendrillane scaffold from the Australian nudibranch Goniobranchus coi

In addition to three known compounds (1–3), two new rearranged spongian diterpenes (4 and 5) with perhydroazulene and dioxabicyclooctane ring systems were isolated from the mantle and viscera of the Australian nudibranch Goniobranchus coi. The relative configuration of the major spiroepoxide 4 was explored by comparison with those of m-chloroperbenzoic acid oxidation products derived from dendrillolide A (1). Aldehydes 6 and 7 were identified as the ring-opened artefacts of the spiroepoxides 5 and 4 respectively, and yielded ketone 3 on storage. The relative configurations of lactols 8 and 9, isolated as an inseparable mixture of diastereomers, were deduced by molecular modelling and computational studies. Acetylation of the lactol mixture provided dendrillolide A (1), further confirming the structural assignments of 8 and 9. Dissection of animal tissue established that the norditerpenoid metabolites were present in both mantle and viscera tissues.

On the utility of the extracted ion chromatograms for assigning the conjugation sites and side reactions in bioconjugates synthesized by the maleimide-thiol chemistry

Maleimide-thiol chemistry is widely used in the synthesis of protein–protein conjugate vaccines. In this reaction, thiol and maleimide groups, either in the carrier protein or in the antigen molecules, are linked via a thiosuccinimide linker. The assignment of the conjugation sites is key and is usually done by LC-MS/MS analysis of the conjugate proteolytic digestion, resulting in a very complex mixture of linear peptides and cross-linked peptide pairs. During proteolysis, the thiosuccinimide linker is converted to its hydrolyzed and transcyclized forms. The set of MS/MS spectra assigned to cross-linked peptide pairs contains valuable information about the conjugation sites that must be validated using objective criteria for more reliable assignment. The extracted ion chromatograms (XICs) have not previously been considered for these validation purposes. In the LC-MS/MS analysis, linear peptides eluted with a single-peak XIC pattern, while the cross-linked peptide pairs with a transcyclized linker (consisting of a mixture of diastereomers) eluted with a two-peak XIC pattern in 68–100 % of cases. Cross-linked peptide pairs with the hydrolyzed linker were detected with a multi-peak XIC pattern consisting of two, three and four peaks in 77 %, 15 % and 8 % of cases, respectively. The four-peak XIC pattern corresponds to cross-linked peptide pairs with two positional isomers of the hydrolyzed linker containing a mixture of diastereomers. Tandem digestions increased the analytical value of the XICs by converting the large and hydrophobic cross-linked peptide pairs, that show a single-peak XIC pattern, to more hydrophilic species eluting in multi-peak XIC patterns. XICs are easily obtained in any LC-MS/MS analysis, contain valuable information about conjugation sites and side reaction detection, and are worthy of routine inclusion in bioconjugate characterization.

Ein‐Topf‐Synthese von 1,3‐Cyclohexadienen durch Birch‐Reduktion in Gegenwart von Carbonylverbindungen

Ein‐Topf‐Synthese von 1,3‐Cyclohexadienen durch Birch‐Reduktion in Gegenwart von Carbonylverbindungen

Two-dimensional sequential selective comprehensive chiral×reversed-phase liquid chromatography of synthetic phosphorothioate oligonucleotide diastereomers

In recent years, many nucleic acid-based pharmaceuticals have been approved and entered the market, and even a larger number are in late stage clinical trials. Conventional oligonucleotides are facing issues in vivo like fast renal clearance and nuclease degradation. Therefore, to increase their stability, phosphorothioation is a frequent modification of therapeutic oligonucleotides (ONs) which also leads to improved binding affinity facilitating cell internalization and intracellular distribution. At the same time, by replacing a phosphodiester linkage with a phosphorothioate group, a phosphorous stereogenic center is generated which causes the formation of Rp- and Sp-diastereomers. It increases the structural diversity. For example, with 15 of those phosphorothioate (PS) linkages, 32,768 different diastereomers are expected. Since the phosphorothioate is introduced non-stereoselectively, the molecular complexity of the resultant phosphorothioate ON products is tremendously increased impeding the chromatographic separation in the course of quality control. Since distinct phosphorothioate diastereomers have different bioactivities and pharmacological properties, there is increasing interest in implications of stereoisomerism of phosphorothiate oligonucleotides. From a quality and regulatory viewpoint, batch-to-batch reproducibility of the diastereomer profile may be of significant concern. In order to address this issue, this study investigates the stereoselectivity of LC methods for two phosphorothioate oligonucleotide (PSO) compounds differing in their molecular size and numbers of PS linkages. Diastereoselectivity of ion-pairing reversed-phase liquid chromatography (IP-RPLC), RPLC without ion-pairing agents and LC with chiral polysaccharide-based column were evaluated for model PSOs and an active pharmaceutical ingredient (API) of PSO with trivalent N-acetylgalactosamine (GalNAc) conjugate. Due to the structural complexity of PSOs, the separation power for the diastereomer mixture was increased by using sequential selective comprehensive two-dimensional chromatography with an amylose tris(α-methylbenzylcarbamate)-immobilized chiral stationary phase (CSP) in the first dimension and ion-pair RPLC with ethylammonium acetate in the second dimension. Improved diastereomer selectivity was obtained and a larger number of peaks could be separated.

Utilization of 13C NMR Carbon Shifts for the Attribution of Diastereomers in Methyl-Substituted Cyclohexanes.

In this report, we address the challenge of assigning diastereomers for methyl cyclohexanes, particularly those with quaternary centers, which remains nontrivial despite modern NMR techniques. By utilizing a HSQC NMR experiment to identify methyl-carbons coupled with a simple conformational analysis, we identified an effective and quite general method for assigning stereochemistry, even in cases where diastereomeric mixtures are inseparable.

Chiral Sulfoximine Mediated Cobalt-Catalyzed Atropselective C-H Annulation of Ynamides.

An achiral Cp*Co(III)-catalyzed enantioselective C-H activation/annulation of chiral sulfoximine-enabled thioamides with ynamides is presented herein. This method successfully synthesizes axially chiral five-membered 2-amidoindenones with good enantiocontrol. Interestingly, the annulation with chiral oxazolidone-containing ynamides could provide a separable mixture of diastereomers (up to ~10 : 1 dr). Moreover, enantiopure sulfoximines could be recovered with ~99 % purity, making this method practical. DFT studies show valuable insight into the mechanism and origin of asymmetric induction.

Quantum Mechanical Quantitative Nuclear Magnetic Resonance Enables Digital Reference Standards at All Magnetic Fields and Enhances qNMR Sustainability.

Quantum mechanics (QM)-driven 1H iterative functionalized spin analysis produces HifSA profiles, which encode the complete 1H spin parameters ("nuclear genotype") of analytes of interest. HifSA profiles enable the establishment of digital reference standards (dRS) that are portable, FAIR (findable - accessible - interoperable - reusable), and fit for the purpose of quantitative 1H NMR (qHNMR) analysis at any magnetic field. This approach enhances the sustainability of analytical standards. Moreover, the analyte-specific complete chemical shift and J-coupling information in HifSA-based dRS enable computational quantitation of substances in mixtures via QM-total-line-shape fitting (QM-qHNMR). We present the proof of concept for HifSA-based dRS by resolving the highly overlapping NMR resonances in the experimental spectra ("nuclear phenotypes") of the diastereomeric mixture of (2RS, 4RS)- and (2RS, 4SR)-difenoconazole (DFZ), a widely used antifouling food additive. The underlying 1H spin parameters are highly conserved in various solvents, are robust against variation in measurement temperature, and work across a wide range of magnetic fields. QM-qHNMR analysis of DFZ samples at 80, 400, 600, and 800 MHz showed high congruence with metrological reference values. Furthermore, this study introduces QM-qHNMR combined with chiral shift reagents for the analysis of all four DFZ stereoisomers: (2R, 4R)-, (2S, 4S)-, (2R, 4S)-, and (2S, 4R)-DFZ to perform chiral qHNMR measurements.

One-Pot Synthesis of 1,3-Cyclohexadienes by Birch Reduction in the Presence of Carbonyl Compounds.

Birch reductions are well-known transformations of arenes, applied for large scale synthesis of 1,4-cyclohexadienes. Herein, we describe first reactions of benzoic acids in the presence of carbonyl compounds, affording aldol products in moderate to high yields. Alkyl aldehydes give the expected nonconjugated dienes by reaction at the α-position. Interestingly, the intermediately formed enolate attacks aryl aldehydes and ketones from its γ-position, which can be explained by steric hindrance. This opens the door for the one-pot synthesis of 1,3-cyclohexadienes, which are not accessible by classical Birch reductions. Our method is applicable to benzoic, m- and p-toluic acid and various carbonyl compounds, and more than 25 new products were isolated in up to 93 % yield. Prochiral aryl aldehydes afford diastereomeric mixtures in ratios of about 4 : 1, but in the cyclohexadiene ring only trans isomers are formed with high selectivity. Finally, the 1,3-cyclohexadienes are suitable precursors for further transformations, which we have demonstrated in first examples. Thus, aromatization affords products of a formal meta selective Friedel-Crafts alkylation, and four new stereocenters were generated by cycloaddition of singlet oxygen with excellent selectivity.

Investigation of the intrinsic cannabinoid activity of hemp-derived and semisynthetic cannabinoids with β-arrestin2 recruitment assays-and how this matters for the harm potential of seized drugs.

Cultivation of industrial low-Δ9-tetrahydrocannabinol (Δ9-THC) hemp has created an oversupply of cannabidiol (CBD)-rich products. The fact that phytocannabinoids, including CBD, can be used as precursors to synthetically produce a range of THC variants-potentially located in a legal loophole-has led to a diversification of cannabis recreational drug markets. 'Hemp-compliant', 'hemp-derived' and 'semisynthetic' cannabinoid products are emerging and being advertised as (legal) alternatives for Δ9-THC. This study included a large panel (n = 30) of THC isomers, homologs, and analogs that might be derived via semisynthetic procedures. As a proxy for the abuse potential of these compounds, we assessed their potential to activate the CB1 cannabinoid receptor with a β-arrestin2 recruitment bioassay (picomolar-micromolar concentrations). Multiple THC homologs (tetrahydrocannabihexol, THCH; tetrahydrocannabiphorol, THCP; tetrahydrocannabinol-C8, THC-C8) and THC analogs (hexahydrocannabinol, HHC; hexahydrocannabiphorol, HHCP) were identified that showed higher potential for CB1 activation than Δ9-THC, based on either higher efficacy (Emax) or higher potency (EC50). Structure-activity relationships were assessed for Δ9-THC and Δ8-THC homologs encompassing elongated alkyl chains. Additionally, stereoisomer-specific differences in CB1 activity were established for various THC isomers (Δ7-THC, Δ10-THC) and analogs (HHC, HHCP). Evaluation of the relative abundance of 9(S)-HHC and 9(R)-HHC epimers in seized drug material revealed varying epimeric compositions between batches. Increased abundance of the less active 9(S)-HHC epimer empirically resulted in decreased potency, but sustained efficacy for the resulting diastereomeric mixture. In conclusion, monitoring of semisynthetic cannabinoids is encouraged as the dosing and the relative composition of stereoisomers can impact the harm potential of these drugs, relative to Δ9-THC products.

Chloro(η2,η2-cycloocta-1,5-diene){1-[(2-[(S)-1-(hydroxymethyl)-3-methylbutyl]amino)-2-oxoethyl]-3-(1-naphthalenylmethyl)benzimidazol-2-ylidene}rhodium(I)

Commercially available and air- and moisture-stable rhodium complex [Rh(OH)(cod)]2 (2) was utilized in the synthesis of [RhX(cod)(NHC)] (3). The presence of an OH group in complex 2 serves as an internal base, facilitating the deprotonation of the C–H bond of the azolium ring in the hydroxyamide-substituted benzimidazolium salt 1. This reaction between 1 and 2 proceeded in THF at room temperature without temperature control, affording the desired NHC/Rh complex 3 in excellent yield. The characterization of complex 3 was accomplished through NMR and HRMS analyses, revealing its existence as a diastereomeric mixture of two NHC/Rh complexes. Furthermore, its catalytic performance was briefly evaluated in the reaction between 2-naphthaldehyde (5) and phenylboronic acid (6).

A CuI6L4 Cage Dynamically Reconfigures to Form Suit[4]anes and Selectively Bind Fluorinated Steroids.

Simple organic ligands can self-assemble with metal ions to generate metal-organic cages, whose cavities bind guests selectively. This binding may enable new methods of chemical separation or sensing, among other useful functions. Here we report the preparation of a CuI6L4 pseudo-octahedral metal-organic cage, the ligands of which self-assemble from simple organic building blocks. Temperature, solvent, and the presence of different guests governed which structure predominated from a dynamic mixture of cage diastereomers with different arrangements of right- or left-handed metal vertices. Dissolution in dimethyl sulfoxide or the binding of tetrahedral guests led to a chiral tetrahedral T-symmetric framework, whereas low temperatures favored the achiral S4-symmetric diastereomer. Tetrahedral guests with long arms were encapsulated to form mechanically bonded suit[4]anes, with guest arms protruding out through host windows. The cage was also observed to bind fluorinated steroids, an important class of drug molecules, but not non-fluorinated steroids, providing the basis for new separation processes.

Online-Monitoring of the Enantiomeric Ratio in Microfluidic Chip Reactors Using Chiral Selector Ion Vibrational Spectroscopy.

A novel experimental approach for the rapid online monitoring of the enantiomeric ratio of chiral analytes in solution is presented. The charged analyte is transferred to the gas phase by electrospray. Diastereomeric complexes are formed with a volatile chiral selector in a buffer-gas-filled ion guide held at room temperature, mass-selected, and subsequently spectrally differentiated by cryogenic ion trap vibrational spectroscopy. Based on the spectra of the pure complexes in a small diastereomer-specific spectral range, the composition of diastereomeric mixtures is characterized using the cosine similarity score, from which the enantiomeric ratio in the solution is determined. The method is demonstrated for acidified alanine solutions and using three different chiral selectors (2-butanol, 1-phenylethanol, 1-amino-2-propanol). Among these, 2-butanol is the best choice as a selector for protonated alanine, also because the formation ratio of the corresponding diastereomeric complexes is found to be independent of the nature of the enantiomer. Subsequently, a microfluidic chip is implemented to mix enantiomerically pure alanine solutions continuously and determine the enantiomeric ratio online with minimal sample consumption within one minute and with competitive accuracy.

Atropisomeric N‐Heterocyclic Carbene‐Palladium(II) Complexes: Influence of the Backbone Substitution

AbstractIn order to facilitate the synthesis of NHC precursors as well as to incorporate new moieties, the influence of the NHC backbone substitution was investigated within the concept of atropisomeric NHC‐metal complexes. A series of NHC precursors was prepared from new anilines and used to synthesize the corresponding Pd(allyl)Cl(NHC) complexes, most of the time as a mixture of diastereomers (meso and chiral). Chiral HPLC at preparative scale enabled to obtain enantiopure complexes in low to excellent yields. These complexes displayed good activity in the intramolecular α‐arylation of amides and, as a function of the structure of the chiral catalyst, excellent enantioselectivities were reached (up to 96 % ee).