Kerstin Zawatzky

Imaging the Absolute Configuration of a Chiral Epoxide in the Gas Phase

Foil-Forged Images X-ray diffraction is widely used to determine molecular geometries and can often distinguish mirror image isomers (enantiomers), which generally requires well-ordered crystals. Herwig et al. (p. 1084) report an imaging technique to characterize enantiomers in the gas phase. A succession of ionization events were induced by passage through a carbon foil that culminated in a Coulomb explosion of mutually repelling nuclei. The trajectories of these nuclei precisely reflected the original molecular structure. Ultrafast electron stripping by a carbon foil enables precise elucidation of molecular geometries as the nuclei fly apart. In chemistry and biology, chirality, or handedness, refers to molecules that exist in two spatial configurations that are incongruent mirror images of one another. Almost all biologically active molecules are chiral, and the correct determination of their absolute configuration is essential for the understanding and the development of processes involving chiral molecules. Anomalous x-ray diffraction and vibrational optical activity measurements are broadly used to determine absolute configurations of solid or liquid samples. Determining absolute configurations of chiral molecules in the gas phase is still a formidable challenge. Here we demonstrate the determination of the absolute configuration of isotopically labeled (R,R)-2,3-dideuterooxirane by foil-induced Coulomb explosion imaging of individual molecules. Our technique provides unambiguous and direct access to the absolute configuration of small gas-phase species, including ions and molecular fragments.

A Combined Experimental and Theoretical Study on the Stereodynamics of Monoaza[5]helicenes: Solvent‐Induced Increase of the Enantiomerization Barrier in 1‐Aza‐[5]helicene

Helicenes and heterohelicenes are attractive compounds with great potential in materials sciences to be used in optoelectronics as ligand backbones in enantioselective catalysis and as chiral sensors. The properties of these materials are related to the stereodynamics of these helical chiral compounds. However, little is known about features controlling stereodynamics in helicenes; in particular, for heterohelicenes the position of the heteroatom could be relevant in this respect. Herein the complete stereodynamic characterization of monoaza[5]helicenes is shown by enantioselective dynamic HPLC and DFT calculations. At variance with previous theoretical calculations, 1-aza[5]helicene shows a surprisingly high enantiomerization barrier, which is triggered by specific solvent interactions.

Coulomb Explosion Imaged Cryptochiral (R,R)-2,3-Dideuterooxirane: Unambiguous Access to the Absolute Configuration of (+)-Glyceraldehyde

The absolute configuration of (R,R)-2,3-dideuterooxirane, which has been independently determined using Coulomb explosion imaging, has been unambiguously chemically correlated with the stereochemical key reference (+)-glyceraldehyde. This puts the absolute configuration of D(+)-glyceraldehyde on firm experimental grounds.

Overcoming “speed limits” in high throughput chromatographic analysis

The combination of high speed autosampler technology and ultrafast chromatographic separations enables faster high throughput analysis. With an injection cycle time of 10.6 s, MISER (Multiple Injection in a Single Experimental Run) HPLC-MS analysis of a 96 well microplate can be completed in only 17min. As chromatographic separations in the sub 5s range become increasingly common, even faster autosamplers will be needed to realize further speed improvements in high throughput LC-MS analysis. Indeed with proper hardware sampling approaches, chromatographic analysis of microplates could approach speeds of spectrophotometric plate readers while maintaining the advantage of multicomponent detection and monitoring.

Toward structure-based predictive tools for the selection of chiral stationary phases for the chromatographic separation of enantiomers.

ChirBase, a database for the chromatographic separation of enantiomers containing more than 200,000 records compiled from the literature, was used to develop quantitative structure activity models for the prediction of which chiral stationary phase will work for the separation of a given molecule. Constructuion of QSAR models for the enantioseparation of nineteen chiral stationary phases was attempted using only analyte structural information, leading to the producton of self-consistent models in four cases. These models were tested by predicting which in-house racemic compounds would and would not be resolved on the different columns. Some degree of success was observed, but the sparseness of data within ChirBase, which contains enantioseparations for only a subset of molecules on a subset of columns under a variety of conditions may limit the creation of effective models. Augmented data sets gleaned from automated chromatographic method development systems deployed in academic and industrial research laboratories or the use of models that take other factors such as solvent composition, temperature, etc. into account could potentially be useful for the development of more robust models.

Using chromatogram averaging to improve quantitation of minor impurities.

Averaging of chromatograms can lead to enhancement of signal to noise ratio (S/N) in proportion to the square root of the number of measurements. Although the general principle has been known for decades, chromatogram averaging is almost never used in current pharmaceutical research. In this study we explore the utility of this approach, showing it to be a simple and easily accessible method for boosting sensitivity for quantification of minor components and trace impurities, where current techniques deliver insufficient S/N.

Chiral 1,2-Dialkenyl Diaziridines: Synthesis, Enantioselective Separation, and Nitrogen Inversion Barriers

trans-1,2-Disubstituted diaziridines form stable enantiomers at ambient conditions because of the two stereogenic pyramidal nitrogen atoms. Functionalized trans-1,2-disubstituted diaziridines can be utilized as a chiral switching moiety between two enantiomeric states in more complex molecular structures. However, the synthesis of functionalized diaziridines is quite challenging, because of the limited tolerance of reaction conditions that can be applied. Here we present a strategy to make trans-1,2-disubstituted diaziridines accessible as versatile building blocks in C-C-bond formations, i.e., the Heck reaction, and therefore introducing aryl substituents. The synthesis of trans-1,2-dialkenyl diaziridines with terminal alkenyl substituents and their stereodynamic properties are described.

An Asymmetric, Catalytic (4 + 3) Cycloaddition Reaction of Cyclopentenyl Oxyallylic Cations

Treatment of 2-tosyloxycyclopentanone with substituted furans in the presence of a chiral amino alcohol catalyst and K2HPO4 results in the formation of (4 + 3) cycloaddition products with enantioselectivities that exceed 90% in certain cases.

Mapping the dark space of chemical reactions with extended nanomole synthesis and MALDI-TOF MS

A rapid screen for complex reactants Chemists engaged in reaction discovery tend to report outcomes involving a few, relatively simple reactants. It remains a major challenge to fine-tune reported conditions when the reactants become more structurally complex, as often happens in pharmaceutical research. Lin et al. developed a protocol for rapidly screening different catalytic conditions for C–N coupling across a wide range of complex substrates. The product detection scheme relies on mass spectrometry of nanomole-scale reaction mixtures without any need for intervening chromatography. Science, this issue p. eaar6236 Mass spectrometry is used to screen catalytic conditions for C–N coupling of a wide variety of complex reactants. INTRODUCTION The invention of new chemical reactions provides new bond construction strategies for improved access to diverse regions of structural space. However, a pervasive, long-standing bias toward reporting successful results means that the shortcomings of even mature reaction methods remain poorly defined, making practical syntheses of structurally diverse targets far from certain. Distinct tools and experimental approaches are required to expose and record the problematic structural elements that limit different synthetic methods. The experimental space required to systematically survey reaction failure is vast, and existing ultrahigh-throughput (uHT) reaction screening approaches are inadequate for exploring the diversity of conditions pertaining in modern synthetic methods. Additionally, analytical approaches must continuously improve to meet the throughput demands of this expansive reaction screening. RATIONALE We report a nanomole-scale screening protocol that can be used to execute heterogeneous reactions with heating and agitation, use of volatile solvents, and capacity for photoredox chemistry. These advances in miniaturized chemistry screening were combined with the use of matrix-assisted laser desorption/ionization–time-of-flight mass spectrometry (MALDI-TOF MS), enabling analysis of 1536 reactions in ~10 min. Together, these advances create a platform that can enable systematic reaction evaluation and data capture to survey the dark space of chemical reactions. RESULTS Using the Buchwald-Hartwig C–N coupling reaction to exemplify this process, an uHT Glorius fragment additive poisons diagnostic approach was first applied to demonstrate that MALDI-MS could provide adequate data quality to monitor the formation of a single product under a wide variety of different synthetic conditions. Four catalytic methods—Ir/Ni and Ru/Ni dual-metal photoredox catalysis, as well as heterogeneous and high-temperature Cu and Pd catalysis—with extended nanomole chemistry requirements were evaluated for the synthesis of a single product in the presence of 383 structurally diverse simple and complex potential poisons. Using a normalizing internal standard that was closely related to the product and optimized operating parameters, MALDI-MS provided good correlation with existing ultra performance liquid chromatography (UPLC)–MS approaches (coefficient of determination R2 up to 0.85), allowing correct binning of “hits” and “misses” (defined as >50% product signal knockdown) up to 95% of the time. Next, the more challenging goal of exploring diverse whole-molecule C–N couplings was explored. In this case, it was not practical to have either product standards or closely related internal standards to enable analytical quantitation. A “simplest-partner test” was employed, in which 192 aryl bromides and 192 secondary amines were each coupled with a MS-active “simplest partner,” guaranteeing a somewhat normalized MS response for all products. The formation of 384 different products using the four aforementioned synthetic methods was monitored by MALDI-MS, with pass-fail binning of results correlating well with UPLC-MS in the identification of common structural elements (such as functional group counts, H-bond donors and acceptors, and polar surface area) that lead to reaction failure. CONCLUSION In the near future, each problematic structural element that is identified through systematic dark-space exploration can be promoted for in-depth examination to precisely define the specific parameters that determine reaction outcome at the atomic and quantum molecular level. Predictive machine learning models will use this focused data to enable synthetic practitioners to select the most appropriate reactions for use in a particular synthetic setting. In addition, functionality that persistently fails across synthetic methods can sharply define important challenges for the invention of improved chemical reactions. Extended nanomole chemistry and MALDI-TOF MS for systematic reaction profiling. Nanomole-scale chemistry tools that can execute a wide variety of synthetic protocols are combined with rapid MALDI-TOF MS analysis to enable broad reaction profiling to map the dark space of chemical reactivity. DMSO, dimethyl sulfoxide; DABCO, 1,4-diazabicyclo[2.2.2]octane. Understanding the practical limitations of chemical reactions is critically important for efficiently planning the synthesis of compounds in pharmaceutical, agrochemical, and specialty chemical research and development. However, literature reports of the scope of new reactions are often cursory and biased toward successful results, severely limiting the ability to predict reaction outcomes for untested substrates. We herein illustrate strategies for carrying out large-scale surveys of chemical reactivity by using a material-sparing nanomole-scale automated synthesis platform with greatly expanded synthetic scope combined with ultrahigh-throughput matrix-assisted laser desorption/ionization–time-of-flight mass spectrometry (MALDI-TOF MS).

Visualizing small differences using subtractive chromatographic analysis

Subtraction of chromatograms coming from two different samples collected under identical conditions can highlight small variations, serving as a useful tool for visualizing differences between experimental and control groups. While the basis for this general approach has been known for decades, the technique is seldom used in modern chromatographic analysis. We report an investigation into the application of subtractive chromatographic analysis in several areas of pharmaceutical research where detection of small differences between samples is important. Our investigation found that elimination of artifacts caused by peak misalignment was often necessary, especially for extremely sharp chromatographic peaks obtained in rapid injection MISER chromatography. Alignment of individual peaks prior to subtraction, combined with fast detector sampling rates, or data interpolation in cases where this is not possible, was found to afford convenient visualization of small differences (∼1%) among samples, suggesting potential utility in high throughput screening of process adsorbents or other applications in pharmaceutical research and development.