Vibrational Circular Dichroism of a Chiral Triplet Nitrene Investigated Under Matrix-Isolation Conditions in Parahydrogen.

Vibrational circular dichroism (VCD) spectra of chiral high-spin organic radicals are expected to show a strong intensity enhancement and are thought to be difficult to predict using state-of-the-art theoretical methods. Herein we show that the chiral triplet nitrene obtained from photochemical cleavage of N2 from enantiopure 2-azido-9H-fluorenol does not feature extraordinarily strong intensities and that the experimental spectra match nicely with calculated ones. Thereby, this study demonstrates the general feasibility of studies on chiral high-spin organics by matrix-isolation VCD.

Vibrational circular dichroism spectra of proline in water at different pH values.

Recording VCD spectra of aqueous solution poses a particular challenge as water is a strong infrared absorber. Likewise, the computational analysis of VCD spectra by means of DFT-based spectral calculations requires the consideration of explicit solvent molecules, thus posing an even greater challenge. Several studies suggested that by modeling the solvent environment with a few water molecules in a micro-solvation approach would be sufficient to describe experimental spectra. For example, using proline at different pH values, we herein show that a change in the relative spatial orientation of a single water molecule in five-fold solvated structures strongly affects the computed VCD spectral signatures and that Boltzmann-weighted spectra do not correctly reproduce the experiment. We thus explored an approach based on molecular dynamics and subsequent DFT-calculations, in which we considered 30 water molecules (about 1.5 solvation shells). Once again, it was found that the Boltzmann-weighted spectra obtained on the basis of several hundred structures did not correctly reproduce experimental signatures, and a simple averaging scheme resulted in well-matching spectra with comparable bandwidths. The rationale behind the procedure was that sampling the configurational space of the solvent molecules is as equally important as the conformational sampling of the solute. For conformationally more flexible molecules, it is assumed that a much larger set of structures will have to be computed in order to properly sample the conformational space of both solute and solvent.

Enantioconvergent and Site-Selective Etherification of Carbohydrate Polyols through Chiral Copper Radical Catalysis.

Going beyond currently reported two electron transformations that formed the core backdrop of asymmetric catalytic site-selective carbohydrate polyol functionalizations, we herein report a seminal demonstration of an enantioconvergent copper catalyzed site-selective etherification of minimally protected saccharides through a single-electron radical pathway. Further, this strategy paves a rare strategy, through which a carboxamide scaffold that is present in some glycomimetics of pharmacological relevance, can be selectively introduced. In light of the burgeoning interest in chiral radical catalysis, and the virtual absence of such stereocontrol broadly in carbohydrate synthesis, our strategy showcased the unknown capability of chiral radical copper catalysis as a contemporary tool to address the formidable site-selectivity challenge on a remarkable palette of naturally occurring saccharides. When reducing sugars were employed, a further dynamic kinetic resolution type glycosylation can be activated by the catalytic system to selectively generate the challenging ß-O-glycosides.

Intermolecular Enantioselective Amination Reactions Mediated by Visible Light and a Chiral Iron Porphyrin Complex.

In the presence of 1 mol % of a chiral iron porphyrin catalyst, various 3-arylmethyl-substituted 2-quinolones and 2-pyridones underwent an enantioselective amination reaction (20 examples; 93-99 % ee). The substrates were used as the limiting reagents, and fluorinated aryl azides (1.5 equivalents) served as nitrene precursors. The reaction is triggered by visible light which allows a facile dediazotation at ambient temperature. The selectivity of the reaction is governed by a two-point hydrogen bond interaction between the ligand of the iron catalyst and the substrate. Hydrogen bonding directs the amination to a specific hydrogen atom within the substrate that is displaced by the nitrogen substituent either in a concerted fashion or by a rebound mechanism.

Enantioselective, Intermolecular [π2+σ2] Photocycloaddition Reactions of 2(1H)-Quinolones and Bicyclo[1.1.0]butanes.

1-Substituted bicyclo[1.1.0]butanes add enantioselectively to 2(1H)-quinolones upon irradiation (λ = 366 nm) in the presence of a chiral complexing agent. A two-point hydrogen bond between the quinolone and the template is responsible for stereocontrol in the photocycloaddition reaction. The reaction leads to the formation of products with a chiral bicyclo[2.1.1]hexane skeleton in high enantiomeric excess (91-99% ee). The chiral template can be almost quantitatively (97%) recovered and used in another reaction. A triplet reaction pathway is likely, and sensitization is a suitable tool if the reaction is to be performed with visible light (λ = 420 nm).

Synthesis and VCD Spectroscopic Characterization of a Series of Azacryptands from a Chiral Valine-Based Derivative of Tris(2-aminoethyl)amine (TREN).

Utilizing experimental and computational vibrational circular dichroism (VCD) spectroscopy, we explored the conformational preferences of a series of chiral C3 -symmetric octaazacryptands with tris(2-aminoethyl)-amine head groups derived from valine. While the spectra of the smallest azacryptand with p-phenyl linkers and its elongated derivative with p-biphenyls linker were found to match well with the computed spectra, the computed conformational preferences of the m-biphenyl-based azacryptand did not seem to reflect the conformations dominating in chloroform solution. A detailed analysis revealed that structural changes resulting in a collapsed cage structure gave a notably better match with the experiment. It could subsequently be concluded from the VCD analysis, that the octaazacryptands prefer a collapsed structure, which is not predicted by density functional theory (DFT) calculations as the global minimum structures. These findings are expected to have consequences also for future studies on inclusion complexes of such azacryptands.

Synthesis, Stereochemical Determination, and Antimicrobial Evaluation of Myxocoumarin A.

The myxobacterial natural product myxocoumarin A from Stigmatella aurantiaca MYX-030 has remarkable antifungal activity against agriculturally relevant pathogens. To broaden the initial evaluation of its biological potential, we herein completed the first total synthesis of myxocoumarin A. This synthetic access facilitated stereochemical investigations on the natural product structure, revealing its (R)-configuration. Biological activity profiling showed a lack of activity against Candida spp. and Gram-negative bacteria but revealed strong antibiotic activities against Bacillus subtilis and Staphylococcus aureus, including MRSA.

Diastereoselective, Lewis acid-mediated Diels-Alder reactions of allenoic acid derivatives and 1,3-cyclopentadienes.

Allenes with different substituents at their terminal carbon atom display axial chirality and can be obtained in enantiopure form by a photochemical deracemization protocol. It has now been studied under which conditions allenoic acid derivatives undergo a Diels-Alder reaction with 1,3-cyclopentadienes and which products result. Cyclic derivatives (lactams, lactones) underwent an exo-selective reaction catalyzed by the Lewis acid Eu(fod)3, while acyclic derivatives yielded with high preference the endo-products (EtAlCl2 as the preferred Lewis acid). The exocyclic double bond forms with exquisite diastereoselectivity and the chirality transfer is close to perfect. The method was applied to the synthesis of the sesquiterpenes ß-santalol (1) and 10(E)-ß-santalic acid (13).

Modelling solute-solvent interactions in VCD spectra analysis with the micro-solvation approach.

Vibrational circular dichroism (VCD) spectroscopy has become an important part of the (stereo-)chemists' toolbox as a reliable method for the determination of absolute configurations. Being the chiroptical version of infrared spectroscopy, it has also been recognized as being very sensitive to conformational changes and intermolecular interactions. This sensitivity originates from the fact that the VCD spectra of individual conformers are often more different than their IR spectra, so that changes in conformational distributions or band positions and intensities become more pronounced. What is an advantage for studies focussing on intermolecular interactions can, however, quickly turn into a major obstacle during AC determinations: solute-solvent interactions can have a strong influence on spectral signatures and they must be accurately treated when simulating VCD and IR spectra. In this perspective, we showcase selected examples which exhibit particularly pronounced solvent effects. It is demonstrated that it is typically sufficient to model solute-solvent interactions by placing single solvent molecules near hydrogen bonding sites of the solute and subsequently use the optimized structures for spectra simulations. This micro-solvation approach works reasonably well for medium-sized, not too conformationally flexible molecules. We thus also discuss its limitations and outline the next steps that method development needs to take in order to further improve the workflows for VCD spectra predictions.

Solvation of serine-based model peptides and the role of the intramolecular OH·O hydrogen bond in interpreting VCD spectra.

Infrared and vibrational circular dichroism (VCD) spectra are occasionally very sensitive to solute-solvent interactions and show distinct spectral changes when strong solute-solvent hydrogen bonds give rise to conformational changes. In this regard, small peptides are ideal model systems to investigate such solvent effects on IR and VCD spectra as they possess several hydrogen bonding donor sites. In the present study, we investigate serine and serine-phenylalanine, which both are N-protected with Boc and C-capped with n-propylamine. Compared to previously studied model peptides, the serine residue introduces a strong hydrogen bonding site that competes with the amides for intra- and intermolecular interactions. For both compounds, we computationally found that the intramolecular OH·O interactions are preferentially broken by DMSO, but it was not sufficient to model only this particular interaction. Instead, depending on the conformer family, it was necessary to consider different numbers of solvent molecules in the computed structures and the experimental spectra were found to be best described by assuming mixed solvation states. Our analyses show that the IR and VCD spectra of molecules with multiple hydrogen bonding cannot be simulated by simply solvating all donor sites as this would neglect the presence of important conformer families. In turn, these results stresss the need for novel routines to account for solvation in IR and VCD spectra, that help estimating the contributions of different solvations states to the conformational distribution.

Matrix-isolation vibrational circular dichroism (VCD) spectroscopy of chiral 1-phenyl-1-propanol.

Matrix Isolation IR and VCD spectroscopy is used to characterize the self-aggregation of the title compound. It is shown that only the IR spectral region of the OH-/CH-stretching modes is sensitive to hydrogen bonding interactions and that the fingerprint region is not notably affected. In contrast, some characteristic VCD spectral features can be identified in the fingerprint region.

Matrix-isolation and cryosolution-VCD spectra of α-pinene as benchmark for anharmonic vibrational spectra calculations.

The inclusion of anharmonicity in vibrational spectral analyis remains associated to small molecular systems with up to a dozen of atoms, with half a dozen of non-hydrogen atoms, typically thesize of propylene oxide. One may see two reasons for this: first of all, larger systems are often thought to be computationally too demanding (high computational costs) for a full anharmonic vibrational analysis. Second, the identification of resonances and their correction is often considered something only expert theoreticians could address because of the lack of unequivocal criteria. In this contribution, we illustrate that resonances can indeed become a complex problem, which can be handled almost transparently thanks to recent advances in vibrational perturbation theory (VPT2). The study also emphasizes the importance and the central role played by experiment in benchmarking novel theoretical approaches. In fact, we herein provide the currently highest resolution VCD spectra available for α- and ß-pinene obtained under matrix-isolation conditions and in liquid Xenon as solvent. They are interpreted by VPT2 with novel tests for the identification of resonances. Hence, the study demonstrates the mutual stimulation of advances in both experimental techniques and computational models.

Matrix effects in MI-VCD spectra of two chiral oxiranes and their potential microscopic origin.

Combining vibrational circular dichroism (VCD) spectroscopy with the matrix isolation (MI) technique opens up interesting possibilities to study chiral molecules. MI involves the isolation of guest species in inert solid matrices at cryogenic temperatures. Hence, MI-VCD measures are solid-state VCD measurements, and as such, can suffer from mostly birefringance-related artefacts in the same way as common solid-state VCD measurements. In this contribution, we demonstrate that the sample preparation condition have tremendous impact on the quality and reliability of the recorded MI-VCD spectra. While MI-IR spectra are basically blind to these artefacts, the variation of deposition temperatures and host flow rates seem to control whether high quality MI-VCD spectra are obtained or if depolarization effects lead to completely obscured spectra. For two selected examples, styrene oxide (SO) and 1-phenyl propylene oxide (PPO), we discuss how the various experimental conditions may lead to the aforementioned effects and give a microscopic description of their origin.

Simultaneous observation of halogen-lone pair and halogen-π interactions of ferrocene derivatives under cryogenic conditions.

Contrasting cryosolutions and matrix isolation infrared spectroscopy, we investigate weak intermolecular interactions in complexes of iodo trifluoroethene (C2F3I) and N,N-dimethyl ferrocenyl amine as well as the parent ferrocene. In liquid xenon, solely the C-I⋯N halogen bond can be observed, while the confined environment in solid argon allows for the characterization of C-I⋯π and π⋯π bonded complexes.

Enantioselective Synthesis of Arylglycines via Pd-Catalyzed Coupling of Schöllkopf Bis-Lactim Ethers with Aryl Chlorides.

Arylglycines are important pharmacophores present in several top-selling drugs. This compound class has now been made accessible from abundant aryl chlorides by a Pd-catalyzed Schöllkopf-type amino acid synthesis. In the presence of the catalyst methylnaphthyl(XPhos)-palladium bromide, the base lithium 2,2,6,6-tetramethylpyrrolidide and the additive ZnCl2 , tert-leucine-derived bis-lactim ethers were efficiently arylated at room temperature, reaching yields of 95 % and diastereoselectivities of 98 : 2. Hydrolysis gave the corresponding arylglycines in high enantiomeric excess.

Morphological Profiling Identifies the Motor Protein Eg5 as Cellular Target of Spirooxindoles.

Oxindoles and iso-oxindoles are natural product-derived scaffolds that provide inspiration for the design and synthesis of novel biologically relevant compound classes. Notably, the spirocyclic connection of oxindoles with iso-oxindoles has not been explored by nature but promises to provide structurally related compounds endowed with novel bioactivity. Therefore, methods for their efficient synthesis and the conclusive discovery of their cellular targets are highly desirable. We describe a selective RhIII -catalyzed scaffold-divergent synthesis of spirooxindole-isooxindoles and spirooxindole-oxindoles from differently protected diazooxindoles and N-pivaloyloxy aryl amides which includes a functional group-controlled Lossen rearrangement as key step. Unbiased morphological profiling of a corresponding compound collection in the Cell Painting assay efficiently identified the mitotic kinesin Eg5 as the cellular target of the spirooxindoles, defining a unique Eg5 inhibitor chemotype.

Inducing Propeller Chirality in Triaryl Boranes with Chiral Amines.

Stabilization of chiral propeller conformations in triaryl compounds is challenging due to generally low racemization barriers. Nonetheless, it was recently found that chiral conformational preferences can be induced to triaryl boranes by incorporating point-chiral alkylether chains to the aryl blades and subsequently locking the structure with ammonia. A four-point interaction, meaning that the cooperative effects of Lewis-adduct formation and three hydrogen bonds, was proposed as stabilizing mechanism. Herein, it was shown that three such strong interactions suffice to introduce a preferential propeller handedness. Although DFT calculations predict no noteworthy preferences for either P- or M-chiral propellers for some of the investigated triarylborane-amine adducts that were prepared with chiral primary amines, vibrational circular dichroism (VCD) spectroscopic characterizations revealed that there is indeed a measurable excess of one propeller handedness. Furthermore, the steric demand of the amine was found to play a key role in the induction process and especially in preventing blade rotations.

Catalytic Atroposelective C7 Functionalisation of Indolines and Indoles.

Axially chiral atropisomeric compounds are widely applied in asymmetric catalysis and medicinal chemistry. In particular, axially chiral indole- and indoline-based frameworks have been recognised as important heterobiaryl classes because they are the core units of bioactive natural alkaloids, chiral ligands and bioactive compounds. Among them, the synthesis of C7-substituted indole biaryls and the analogous indoline derivatives is particularly challenging, and methods for their efficient synthesis are in high demand. Transition-metal catalysis is considered one of the most efficient methods to construct atropisomers. Here, we report the enantioselective synthesis of C7-indolino- and C7-indolo biaryl atropisomers by means of C-H functionalisation catalysed by chiral RhJasCp complexes.

Dynamic Stereochemistry of a Biphenyl-Bisprolineamide Model Catalyst and its Imidazolidinone Intermediates.

In this study, we characterize the dynamic stereochemistry of a biphenyl-2,2'-bis(proline amide) catalyst in chloroform and DMSO as representative weakly and strongly hydrogen bonding solvents. Using vibrational circular dichroism (VCD) spectroscopy and density functional theory (DFT) based spectra calculations, we show that the preferred axial stereochemistry of the catalyst is determined by solute-solvent interactions. Explicitly considering solvation with DMSO molecules is found to be essential to correctly predict the conformational preferences of the catalyst. Furthermore, we investigate the stereochemistry of the corresponding enamines and imidazolidinones that are formed upon reaction with isovaleraldehyde. The enamines are found to rapidly convert to endo-imidazolidinones and the thermodynamically favored exo-imidazolidinones are formed only slowly. The present study demonstrates that the stereochemistry of these imidazolidinones can be deduced directly from the VCD spectra analysis without any further detailed analysis of NMR spectra. Hence, we herein exemplify the use of VCD spectroscopy for an in situ characterization of intermediates relevant in asymmetric catalysts.

Solvation of the Boc-Val-Phe-nPr peptide characterized by VCD spectroscopy and DFT calculations.

The conformational preferences of peptides are strongly determined by hydrogen bonding interactions. Intermolecular solute-solvent interactions compete with intramolecular interactions, which typically stabilize the secondary structure of the peptide. The analysis of vibrational circular dichroism (VCD) spectra can give insights into solvation-induced changes in the conformational distribution of small peptides. Here we describe the VCD spectroscopic characterization of the model peptide Boc-Val-Phe-nPr in chloroform as representative for a weakly interacting solvent and dimethyl sulfoxide (DMSO-d6) as a strongly hydrogen bonding solvent. We show that the conformational preferences of the peptide in chloroform are well-described by the computationally predicted distribution of the isolated molecule assuming only implicit solvation effects through a continuum solvation model. In order to simulate the spectra recorded in DMSO-d6, solvation was accounted for explicitly by computed microsolvated structures containing one to three solvent molecules. A good match of the computed spectra with the experimental data is obtained by this method. Comparing the conformational distributions in deuterated chloroform-d1 and DMSO-d6, structures with intramolecular hydrogen bonds such as the (δ,δ)-conformer family contribute to the conformational distribution only when there is no strong interaction with the solvent. This is in contrast to the results for the related Boc-Pro-Phe-nPr studied before, for which the intramolecular interaction was found to persist in DMSO-d6. Furthermore, we discuss the influence of hydrogen bonding to different numbers of solvent molecules on the spectral signatures and show that the structure of the peptide in DMSO-d6 is best described as a mixture of twofold-solvated (δ,ß)- and threefold-solvated (ß,ß)-conformers.