Inspired by DFT calculations on the mechanism of the Corey-Winter olefination (CWO), it seemed possible that the desulfuration of isothiocyanates using P(iii)-reagents should proceed smoothly to furnish the corresponding isocyanides. A detailed theoretical study on the mechanism of the desulfuration reaction revealed similar intermediates and transition states as compared to the CWO. Here, the only intermediate results from attack of the P reagent on the thiocarbonyl group. This ylide-type structure then undergoes smooth cycloreversion to directly liberate the corresponding isocyanide. The isothiocyanate substrate scope, limitations of the P(iii)-reagent, and solvent effects are evaluated computationally and compared to experimental synthetic studies. Experimentally, the functional group tolerance of the isothiocyanate desulfuration proves to be excellent, and a large variety of solvents is tolerated including solvent-free variants. The reaction is pleasing invariant to steric hinderance and proceeds under very mild conditions, rendering this method valuable especially to otherwise difficult to synthesize isocyanides. The kinetics of various desulfuration reactions was followed by NMR spectroscopy, and the scope of this reaction and its applicability to ensuing reactions with and without isolation of the isocyanides is explored.

The regiospecific ring expansion of 2H-azetines into halogenated pyrroles is disclosed. Simple reaction sequences have been developed to conceptualize this 4 → 5 skeletal editing strategy, taking advantage of the inherent reactivity of double bonds present in the initial four-membered ring systems. Detailed density functional theory (DFT) calculations are presented to explain this unusual rearrangement. Such a reaction design allows for the preparation of highly substituted halogenated pyrrole derivatives.

In this paper, we describe, for the first time, the combined and original use of spatially resolved anisotropic natural abundance deuterium (ANAD) 2D-NMR experiments and bimesophasic lyotropic chiral systems to extract two independent sets of anisotropic parameters such as 2H-RQCs from a single NMR sample. As a pioneering example, we focus on a mixture of immiscible polypeptides (PBLG) and polyacetylene helical polymers (L-MSP) dissolved in weakly polar organic solvents (chloroform). Nondeuterated (D)-(+)-camphor is used as a model chiral solute. By providing two series of 2H-RQCs, this new analytical approach paves the way for applications in 3D structure elucidation with increased reliability and also opens up original investigations in terms of spectral enantiomeric discriminations and mixing of helical polymers.

Polymers that degrade on demand have the potential to facilitate chemical recycling, reduce environmental pollution and are useful in implant immolation, drug delivery or as adhesives that debond on demand. However, polymers made by radical polymerization, which feature all carbon-bond backbones and constitute the most important class of polymers, have proven difficult to render degradable. Here we report cyclobutene-based monomers that can be co-polymerized with conventional monomers and impart the resulting polymers with mechanically triggered degradability. The cyclobutene residues act as mechanophores and can undergo a mechanically triggered ring-opening reaction, which causes a rearrangement that renders the polymer chains cleavable by hydrolysis under basic conditions. These cyclobutene-based monomers are broadly applicable in free radical and controlled radical polymerizations, introduce functional groups into the backbone of polymers and allow the mechanically gated degradation of high-molecular-weight materials or cross-linked polymer networks into low-molecular-weight species. Radical polymerizations yield polymers that cannot easily be degraded. The co-polymerization of cyclobutene-based monomers with conventional vinyl monomers has now been shown to result in co-polymers with cyclobutane mechanophores in their backbone, which facilitate on-demand degradation through a combination of mechanical activation and hydrolysis. This approach offers a promising avenue for the degradation of all-carbon-bond-backbone polymers.

Bis(sulfoximine) yttrium complexes as catalysts for enantioselective intramolecular hydroaminations were prepared for the first time and characterized by a multinuclear NMR study including the nuclei 1H, 13C, 15N and 89Y. The stoichiometries of the complexes were confirmed by a Job plot. In addition to the experimental results, the 89Y NMR shifts and the complex structures were elucidated by DFT calculations.

Anisotropic NMR spectroscopy, revealing residual dipolar couplings (RDCs) and residual chemical shift anisotropies (RCSAs) has emerged as a powerful tool to determine the configurations of synthetic and complex natural compounds. The deduction of the absolute in addition to the relative configuration is one of the primary goals in the field. Therefore, the investigation of the enantiodiscriminating capabilities of chiral alignment media becomes essential. While RDCs and RCSAs are now used for the determination of the relative configuration routinely, RCSAs have not been measured in chiral alignment media such as chiral liquid crystals. Herein, we present this application by measuring RCSAs for chiral analytes such as indanol and isopinocampheol in the lyotropic liquid crystalline phase of an L-valine derived helically chiral polyacetylenes. We have also demonstrated that a single 1D 13 C-{1 H} NMR spectrum suffices to get the RCSAs circumventing the necessity to acquire two spectra at two alignment conditions.

Identifying and understanding the role of key molecular factors involved in the orientation/discrimination phenomena of analytes in polymer-based chiral liquid crystals (CLCs) are essential tasks for optimizing computational predictions (molecular dynamics simulation) of the existing orienting systems, as well as designing novel helically chiral polymers as new enantiodiscriminating aligning media. From this perspective, we propose to quantify and compare the enantiodiscrimination power of four homochiral polymer-based lyotropic liquid crystals (LLCs) toward a given chiral solute using their 2H residual quadrupolar couplings (2H-RQCs) measured by anisotropic natural abundance deuterium 2D-NMR (ANAD 2D-NMR). Two families of chiral polymers are investigated in this study: (i) poly-peptide polymers (PBLG and PCBLL), and (ii) polyacetylene polymers (PDA and L-MSP, a new system never published so far). As model solute, we investigate the case of camphor, an interesting rigid bicyclic chiral molecule possessing ten 2H-RQCs (10 inequivalent monodeurated isotopomers per enantiomer). In order to analyse the orientational behaviour of each enantiomer in a single oriented sample, while simplifying the identification of the (D/L)-isomer signals on spectra, a D-isomer enriched scalemic mixture (ee(D) = 30%) was used. Orientational data of camphor in each mesophase were calculated for the first time using the computer program ConArch+, modified to accept 2H-RQCs as anisotropic data input. Differences in enantiodiscriminations provided by the four aligning systems are examined and discussed in terms of structural and chemical features between polymers. The new L-MSP mesophase described in this work exhibits very promising enantiodiscrimination capacities.

Floating chirality restrained distance geometry (fc-rDG) calculations are used to directly evolve structures from NMR data such as NOE-derived intramolecular distances or anisotropic residual dipolar couplings (RDCs). In contrast to evaluating pre-calculated structures against NMR restraints, multiple configurations (diastereomers) and conformations are generated automatically within the experimental limits. In this report, we show that the “unphysical” rDG pseudo energies defined from NMR violations bear statistical significance, which allows assigning probabilities to configurational assignments made that are fully compatible with the method of Bayesian inference. These “diastereomeric differentiabilities” then even become almost independent of the actual values of the force constants used to model the restraints originating from NOE or RDC data.

Using NMR data, the assignment of the correct 3D configuration and conformation to unknown natural products is of pivotal importance in pharmaceutical and medicinal chemistry. In this report, we quantify the quality and probability of structural elucidations using Bayesian inference in combination with floating chirality distance geometry simulations. Here, we will discuss the configurational analysis of three complex natural products including isopinocampheol (1), plakilactone H (2), and iodocallophycoic acid A (3) using NMR restraints of various types and in different combinations (residual dipolar couplings (RDCs) and NOE-derived distances). Our results quantitatively demonstrate how reliably molecular geometries can be inferred from experimental NMR data, unequivocally unveiling remaining assignment ambiguities. The methodology presented here can dramatically reduce the risk of incorrect structural assignments based on the overinterpretation of incomplete data in chemistry.

Using NMR data, the assignment of the correct 3D configuration and conformation to unknown natural products is of pivotal importance in pharmaceutical and medicinal chemistry. In this report, we quantify the probability of configurational assignments to judge the quality of structural elucidations using Bayesian inference in combination with floating-chirality distance geometry simulations. Based on reference-free NOE/ROE data, residual dipolar couplings (RDCs), and residual quadrupolar couplings (RQCs) in various combinations, we demonstrate how the relative configurations of three natural compounds, namely, jatrohemiketal (1), artemisinin (2), and Taxol (3), can be unambiguously established without the necessity to carry out time-consuming DFT-based configurational and conformational analyses. Our results quantitatively describe how reliably molecular geometries can be inferred from experimental NMR data, thereby unequivocally unveiling remaining assignment ambiguities. The methodology presented here will dramatically reduce the risk of incorrect structural assignments based on the overinterpretation of incomplete data and DFT-based structure models in chemistry.

Lyotropic liquid crystalline (LLC) phases of amino acid derived polyarylisocyanides were employed as chiral alignment media for the measurement of residual dipolar couplings (RDCs) of small chiral organic molecules. Anisotropic samples in CDCl3 displayed quadrupolar splittings of the deuterium signal in the range of several hundreds of Hertz. The LLC phases showed excellent orienting properties for a broad range of analytes bearing various functional groups. The precise extraction of RDCs in the range of up to ±40 Hertz from F2-coupled HSQC spectra was possible. Additionally, the chiral environment offers the opportunity for diastereomorphous interactions with the enantiomers of chiral analytes leading to two different sets of RDCs. This differential order effect was particularly pronounced with ketones and alcohols.

The NMR-based configurational analysis of complex marine natural products is still not a routine task. Different NMR parameters are used for the assignment of the relative configuration: NOE/ROE, homo- and heteronuclear J couplings as well as anisotropic parameters. The combined distance geometry (DG) and distance bounds driven dynamics (DDD) method allows a model-free approach for the determination of the relative configuration that is invariant to the choice of an initial starting structure and does not rely on comparisons with (DFT) calculated structures. Here, we will discuss the configurational analysis of five complex marine natural products or synthetic derivatives thereof: the cis-palau'amine derivatives 1a and 1b, tetrabromostyloguanidine (1c), plakilactone H (2), and manzamine A (3). The certainty of configurational assignments is evaluated in view of the accuracy of the NOE/ROE data available. These case studies will show the prospective breadth of application of the DG/DDD method.

The configurational analysis of complex natural products by NMR spectroscopy is still a challenging task. The assignment of the relative configuration is usually carried out by analysis of interproton distances from NOESY or ROESY spectra (qualitative or quantitative) and scalar (J) couplings. About 15 years ago, residual dipolar couplings (RDCs) were introduced as a tool for the configurational determination of small organic molecules. In contrast to NOEs/ROEs which are local parameters (distances up to 400 pm can be detected for small organic molecules), RDCs are global parameters which allow to obtain structural information also from long-range relationships. RDCs have the disadvantage that the sample needs a setup in an alignment medium in order to obtain the required anisotropic environment. Here, we will discuss the configurational analysis of five complex natural products: axinellamine A (1), tetrabromostyloguanidine (2), 3,7-epi-massadine chloride (3), tubocurarine (4), and vincristine (5). Compounds 1–3 are marine natural products whereas 4 and 5 are from terrestrial sources. The chosen examples will carefully work out the limitations of NOEs/ROEs in the configurational analysis of natural products and will also provide an outlook on the information obtained from RDCs.

The certainty of configurational assignments of natural products based on anisotropic NMR parameters, such as residual dipolar couplings (RDCs), must be amended by estimates on structural noise emerging from thermal vibrations. We show that vibrational analysis significantly affects the error margins with which RDCs can be back-calculated from molecular models, and the implications of thermal motions on the differentiability of diastereomers are derived.

Two independent statistical models for evaluating the certainties of configurational assignments of compounds based on nuclear magnetic resonance (NMR) data are evaluated and compared. Both methods yield weights or probabilities with which two or more structure models (constitutional or configurational isomers or even conformers) could be differentiated based on experimental parameters. Although this paper focusses on the use of residual dipolar couplings (RDCs) for the differentiation of diastereomers, the concept can be expanded to any set of experimental NMR-derived parameters. It is demonstrated that highly reliable configurational assignments crucially must depend on thorough statistical analysis, which is frequently neglected in the literature.

The cover image is based on the Article Configurational analysis by residual dipolar couplings: A critical assessment of diastereomeric differentiabilities by Stefan Immel et al., https://doi.org/10.1002/chir.23065. Design Credit: Stefan Immel.

A new method implemented into a computer program (ConArch+ ) has been developed and applied to demonstrate the successful implementation of residual dipolar couplings (RDCs) in distance geometry (DG) calculations for the configurational assignment of chiral compounds. Unlike established protocols, the new approach combines floating chirality (fc) in 4D- and 3D-distance bounds driven dynamics (DDD) calculations with structural information from RDCs. Thus, relative configurations of chiral compounds were generated only by observables (e.g., NOEs, RDCs) rendering tedious evaluations of calculated structures against RDCs obsolete. We demonstrate the potential of this novel procedure by the simultaneous determination of the configuration and the conformation of three natural products, (-)-isopinocampheol (1), tubocurarine (2), and vincristine (3), as well as for diisopropylidene-β-d-fructopyranose (4).

SummarySimilar to Bacillus subtilis, Enterococcus faecalis transports and phosphorylates maltose via a phosphoenolpyruvate (PEP):maltose phosphotransferase system (PTS). The maltose‐specific PTS permease is encoded by the malT gene. However, E. faecalis lacks a malA gene encoding a 6‐phospho‐α‐glucosidase, which in B. subtilis hydrolyses maltose 6′‐P into glucose and glucose 6‐P. Instead, an operon encoding a maltose phosphorylase (MalP), a phosphoglucomutase and a mutarotase starts upstream from malT. MalP was suggested to split maltose 6‐P into glucose 1‐P and glucose 6‐P. However, purified MalP phosphorolyses maltose but not maltose 6′‐P. We discovered that the gene downstream from malT encodes a novel enzyme (MapP) that dephosphorylates maltose 6′‐P formed by the PTS. The resulting intracellular maltose is cleaved by MalP into glucose and glucose 1‐P. Slow uptake of maltose probably via a maltodextrin ABC transporter allows poor growth for the mapP but not the malP mutant. Synthesis of MapP in a B. subtilis mutant accumulating maltose 6′‐P restored growth on maltose. MapP catalyses the dephosphorylation of intracellular maltose 6′‐P, and the resulting maltose is converted by the B. subtilis maltose phosphorylase into glucose and glucose 1‐P. MapP therefore connects PTS‐mediated maltose uptake to maltose phosphorylase‐catalysed metabolism. Dephosphorylation assays with a wide variety of phospho‐substrates revealed that MapP preferably dephosphorylates disaccharides containing an O‐α‐glycosyl linkage.