Matthias Brauser

Chiral induction in helical supramolecular assemblies of two benzenetricarboxamide-based alignment media is investigated using residual dipolar couplings. High enantiodiscrimination is achieved and made scalable by a sergeant-and-soldier approach.

Modern nuclear magnetic resonance (NMR) methods like carbon relaxation dispersion in the rotating frame ( ¹³ C−R _1ρ ) and proton chemical exchange saturation transfer ( ¹ H‐CEST) are key methods to investigate molecular recognition in biomacromolecules and to detect molecular motions on the μs to s timescale, revealing transient conformational states. Changes in kinetics can be linked to binding, folding, or catalytic events. Here, we investigated whether these methods allow detection of changes in the dynamics of a small, highly selective peptide catalyst during recognition of its enantiomeric substrates. The flexible tetrapeptide Boc‐ l ‐(π‐Me)−His− ^A Gly‐ l −Cha− l ‐Phe−OMe, used for the monoacetylation of cycloalkane‐diols, is probed at natural abundance using ¹³ C‐R _1ρ and ¹ H‐CEST. Indeed, we detected differences in dynamics of the peptide upon interaction with the diol. Importantly, these differ depending on the enantiomer of the substrate used. These enantiospecific influences of the substrates on the dynamics of the peptide are rationalized using computational techniques. We find that even though one enantiomer reacts faster, as confirmed by reaction monitoring, the other is more tightly bound in DCM (as confirmed by ¹ H‐saturation transfer difference (STD) measurements). These findings provide insights into the recognition of the substrates and explain the selectivity differences observed between the solvents toluene and DCM.

Modern nuclear magnetic resonance (NMR) methods like carbon relaxation dispersion in the rotating frame ( ¹³ C−R _1ρ ) and proton chemical exchange saturation transfer ( ¹ H‐CEST) are key methods to investigate molecular recognition in biomacromolecules and to detect molecular motions on the μs to s timescale, revealing transient conformational states. Changes in kinetics can be linked to binding, folding, or catalytic events. Here, we investigated whether these methods allow detection of changes in the dynamics of a small, highly selective peptide catalyst during recognition of its enantiomeric substrates. The flexible tetrapeptide Boc‐ l ‐(π‐Me)−His− ^A Gly‐ l −Cha− l ‐Phe−OMe, used for the monoacetylation of cycloalkane‐diols, is probed at natural abundance using ¹³ C‐R _1ρ and ¹ H‐CEST. Indeed, we detected differences in dynamics of the peptide upon interaction with the diol. Importantly, these differ depending on the enantiomer of the substrate used. These enantiospecific influences of the substrates on the dynamics of the peptide are rationalized using computational techniques. We find that even though one enantiomer reacts faster, as confirmed by reaction monitoring, the other is more tightly bound in DCM (as confirmed by ¹ H‐saturation transfer difference (STD) measurements). These findings provide insights into the recognition of the substrates and explain the selectivity differences observed between the solvents toluene and DCM.

Nuclear magnetic resonance (NMR) is a key method to investigate molecular recognition in biomacromolecules and to detect molecular motions on the µs to s timescale revealing transient conformational states. Changes in kinetics of interconversions between those states can be linked to binding, folding or catalytic events. Here, we investigated whether these methods allow detection of changes in the dynamics of a small, highly selective peptide catalyst during recognition of its enantiomeric substrates. The flexible tetrapeptide Boc-L-(π-Me)-His-AGly-L-Cha-L-Phe-OMe, used for the monoacetylation of cycloalkane-diols, is probed at natural abundance using carbon relaxation dispersion in the rotating frame (13C-R1ρ) and proton chemical exchange saturation transfer (1H-CEST). Indeed, we detected differences in dynamics of the peptide upon interaction with the diol. Importantly, these differ depending on the enantiomer of the substrate used providing insights into the recognition of the substrates. These enantiospecific influences of the substrates on the dynamics of the peptide catalyst revealed are rationalized using. computational techniques. Moreover, findings obtained are supported by experimental reaction monitoring of the acetylation reaction.

The investigation of reaction mechanisms is a complex task that usually requires the use of several techniques. To obtain as much information as possible on the reaction and any intermediates – possibly invisible to one technique – the combination of techniques is a solution. In this work we present a new setup for combined UV/Vis and NMR spectroscopy and compare it to an established alternative. The presented approach allows a versatile usage of different commercially‐available components like mirrors and fiber bundles as well as different fixed pathlengths according to double transmission or single transmission measurements. While a previous approach is based on a dip‐probe setup for conventional NMR probes, the new one is based on a micro‐Helmholtz coil array (LiquidVoxel™). This makes the use of rectangular cuvettes possible, which ensure well‐defined pathlengths allowing for quantification of species. Additionally, very low quantities of compound can be analyzed due to the microfabrication and small cuvette size used. As proof‐of‐principle this new setup for combined UV/Vis and NMR spectroscopy is used to examine a well‐studied photochromic system of the dithienylethene compound class. A thorough comparison of the pros and cons of the two setups for combined UV/Vis and NMR measurements is performed.

The kinetic resolution of trans-cyclohexane-1,2-diol with a lipophilic oligopeptide catalyst shows extraordinary selectivities. To improve our understanding of the factors governing selectivity, we quantified the Gibbs free energies of interactions of the peptide with both enantiomers of trans-cyclohexane-1,2-diol using nuclear magnetic resonance (NMR) spectroscopy. For this, we use advanced methods such as transverse relaxation (R₂), diffusion measurements, saturation transfer difference (STD), and chemical shift (δ) analysis of peptide-diol mixtures upon varying their composition (NMR titrations). The methods employed give comparable and consistent results. The molecular recognition by the catalyst is approximately 3 kJ mol^-1 in favor of the preferentially acetylated (R,R)-enantiomer in the temperature range studied. Interestingly, the difference of 3 kJ mol^-1 is also confirmed by results from reaction monitoring of the acylation step under catalytic conditions, indicating that this finding is true regardless of whether the investigation is performed on the acetylated species or on the free catalyst. To arrive at these conclusions, the self-association of both the catalyst and the substrate in toluene was found to play an important role and thus needs to be taken into account in reaction screening.

The Pd-catalyzed allylic alkylation of 3,4-disubstituted, racemic cyclobutene electrophiles exhibits a highly unusual stereoselectivity that allows for controlling diastereo- and enantioselectivity only by the choice of ligand and independent of the configuration of the substrate. In order to shed light on the origin of stereoinduction, we performed a systematic mechanistic investigation, including preparation of various putative Pd-allyl intermediates, ¹H/³¹P NMR reaction monitoring, ²H-labeling studies, ESI-HRMS and ³¹P NMR analysis of reaction mixtures, and DFT structural computations. The mechanism disclosed exhibits several steps with stereospecificities deviating from the commonly accepted "double inversion rule": oxidative addition was found to follow a stereoconvergent course, giving anti-configured η¹-Pd-cyclobutene species as detectable on-cycle intermediates irrespective of the configuration of starting material, while the subsequent nucleophilic attack features a stereodivergent behavior. In stark contrast to their highly reactive anti-analogues, syn-Pd-cyclobutene complexes that can be formed as side products are rendered entirely unreactive by strong internal Pd-O chelation, preventing the formation of undesired product diastereomers.

The kinetic resolution of trans-cyclohexane-1,2-diol with a lipophilic oligopeptide catalyst shows extraordinary selectivities. To improve our understanding of the factors governing selectivity, we quantified the Gibbs energies of interactions of the peptide with both enantiomers of trans-cyclohexane-1,2-diol using nuclear magnetic resonance (NMR) spectroscopy. For this we use advanced methods such as transverse relaxation (R2), diffusion measurements, saturation transfer difference (STD), and chemical shift (δ) analysis of peptide-diol mixtures upon varying their composition (NMR titrations). The methods employed give comparable and consistent results: The molecular recognition by the catalyst is approx. 3 kJmol−1 in favor of the preferentially acetylated (R,R)-enantiomer in the temperature range studied. Interestingly, the difference of 3 kJ mol−1 is also confirmed by results from reaction monitoring of the acylation step under catalytic conditions, indicating that this finding is true regardless of whether the investigation is performed on the acetylated species or on the free catalyst. To arrive at these conclusions the self-association of both catalyst and substrate in toluene were found to play an important role and thus need to be taken into account in reaction screening.

Until now, the intermediate responsible for the acyl transfer of a highly enantioselective tetrapeptide organocatalyst for the kinetic resolution of trans-cycloalkane-1,2-diols has never been directly observed. It was proposed computationally that a π-methylhistidine moiety is acylated as an intermediate step in the catalytic cycle. In this study we set out to investigate whether we can detect and characterize this key intermediate using NMR-spectroscopy and mass spectrometry. Different mass spectrometric experiments using a nano-ElectroSpray Ionization (ESI) source and tandem MS-techniques allowed the identification of tetrapeptide acylium ions using different acylation reagents. The complexes of trans-cyclohexane-1,2-diols with the tetrapeptide were also detected. Additionally, we were able to detect acylated tetrapeptides in solution using NMR-spectroscopy and monitor the acetylation reaction of a trans-cyclohexane-1,2-diol. These findings are important steps towards the understanding of this highly enantioselective organocatalyst.

For more than twenty years chemists use peptidic organocatalysts to transfer acyl groups onto alcohols. The goal was and still is the increase of selectivity towards the substrate of choice. One carefully designed example is a highly enantioselective tetrapeptide organocatalyst for the kinetic resolution of trans-cycloalkane-1,2-diols. Until now, the intermediate responsible for the acyl transfer of this tetrapeptide has never been directly observed. It was proposed computationally that a π-methylhistidine moiety is acylated as an intermediate step in the catalytic cycle. In this study we set out to investigate whether we can detect and characterize this key intermediate using NMR-spectroscopy and mass spectrometry. Different mass spectrometric experiments using a nano-ElectroSpray Ionization (ESI) source and tandem MS-techniques allowed the identification of tetrapeptide acylium ions using different acylation reagents. The complexes of trans-cyclohexane-1,2-diols with the tetrapeptide were also detected. Additionally, we were able to detect acylated tetrapeptides in solution using NMR-spectroscopy and monitor the acetylation reaction of a trans-cyclohexane-1,2-diol. These findings are important steps towards the understanding of this organocatalyst and its high enantioselectivity.