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Natural Products (NP) are essential for the discovery of novel drugs and products for numerous biotechnological applications. The NP discovery process is expensive and time-consuming, having as major hurdles dereplication (early identification of known compounds) and structure elucidation, particularly the determination of the absolute configuration of metabolites with stereogenic centers. This review comprehensively focuses on recent technological and instrumental advances, highlighting the development of methods that alleviate these obstacles, paving the way for accelerating NP discovery towards biotechnological applications. Herein, we emphasize the most innovative high-throughput tools and methods for advancing bioactivity screening, NP chemical analysis, dereplication, metabolite profiling, metabolomics, genome sequencing and/or genomics approaches, databases, bioinformatics, chemoinformatics, and three-dimensional NP structure elucidation.

Continuous-rotation 3D electron diffraction methods are increasingly popular for the structure analysis of very small organic molecular crystals and crystalline inorganic materials. Dynamical diffraction effects cause non-linear deviations from kinematical intensities that present issues in structure analysis. Here, a method for structure analysis of continuous-rotation 3D electron diffraction data is presented that takes multiple scattering effects into account. Dynamical and kinematical refinements of 12 compounds—ranging from small organic compounds to metal–organic frameworks to inorganic materials—are compared, for which the new approach yields significantly improved models in terms of accuracy and reliability with up to fourfold reduction of the noise level in difference Fourier maps. The intrinsic sensitivity of dynamical diffraction to the absolute structure is also used to assign the handedness of 58 crystals of 9 different chiral compounds, showing that 3D electron diffraction is a reliable tool for the routine determination of absolute structures.Continuous-rotation 3D electron diffraction is a powerful technique to determine structures from nanocrystals. A data treatment method that takes into account dynamical diffraction effects has now been shown to lead to more accurate structure models, better sensitivity to weak signals and a reliable determination of absolute configuration—even for materials containing only light atoms.

The asymmetric construction of all-carbon quaternary centres within acyclic settings represents a long-standing challenge for synthetic chemists. Alongside polar and radical methods, rearrangement reactions represent an attractive platform, but still broadly applicable methods are in high demand. Here we report an asymmetric, radical sulfinyl-Smiles rearrangement to access acyclic amides that bear an α-all-carbon quaternary centre. Our strategy uses enantioenriched N-arylsulfinyl acrylamides as acceptors for a variety of radicals produced in situ under mild photoredox conditions. The sulfinamido group not only directs the 1,4-migration of the aryl moiety onto the α-carbon of the amide, which thus governs its absolute configuration, but also functions as a traceless chiral auxiliary. The amides obtained in this multicomponent process are prevalent in pharmaceuticals, agrochemicals and bioactive natural products, and can be transformed into valuable chiral α,α-disubstituted acids, oxindoles as well as into β,β-disubstituted amines, highlighting the synthetic potential of this transformation.The assembly of a single configuration of an all-carbon quaternary centre within acyclic systems remains a challenge for synthetic chemists. Now, it has been shown that α-all-carbon quaternary centres can be installed in acyclic amides, with excellent levels of absolute stereocontrol, through a radical sulfinyl Truce–Smiles rearrangement.

Determination of the absolute configuration of organic molecules is essential in drug development and the subsequent approval process. We show that this determination is possible through electron diffraction using nanocrystalline material. Ab initio structure determination by electron diffraction has so far been limited to compounds that maintain their crystallinity after a dose of one electron per square angstrom or more. We present a complete structure analysis of a pharmaceutical cocrystal of sofosbuvir and L-proline, which is about one order of magnitude less stable. Data collection on multiple positions of a crystal and an advanced-intensity extraction procedure enabled us to solve the structure ab initio. We further show that dynamical diffraction effects are strong enough to permit unambiguous determination of the absolute structure of material composed of light scatterers.

The preparation of both enantiomers of chiral molecules is among the most fundamental tasks in organic synthesis, medicinal chemistry and materials science. Achieving this goal typically requires reversing the absolute configuration of the chiral component employed in the reaction system that is being used. The task becomes challenging when the natural source of the chiral component is not available in both configurations. Herein, we report a time-dependent enantiodivergent synthesis, in which an Ir-catalysed allylic substitution reaction uses one catalyst sequentially to promote two kinetic resolution reactions, enabling the synthesis of both enantiomers of the product using the same enantiomer of a chiral catalyst. The appropriate permutation of individual reaction rates is essential for the isolation of the chiral products in opposite configurations with high enantiopurity when quenched at different reaction times. This work provides an alternative solution for the preparation of both enantiomers of chiral molecules.Access to both enantiomers of a chiral target compound typically relies on reversing the absolute configuration of the chiral component in the reaction system that is used to make them. A time-dependent enantiodivergent synthesis is reported in which the same enantiomer of a chiral catalyst can give both enantiomers of the product, depending on the reaction time.

Single crystal X-ray diffraction is arguably the most definitive method for molecular structure determination, but the inability to grow suitable single crystals can frustrate conventional X-ray diffraction analysis. We report herein an approach to molecular structure determination that relies on a versatile toolkit of guanidinium organosulfonate hydrogen-bonded host frameworks that form crystalline inclusion compounds with target molecules in a single-step crystallization, complementing the crystalline sponge method that relies on diffusion of the target into the cages of a metal-organic framework. The peculiar properties of the host frameworks enable rapid stoichiometric inclusion of a wide range of target molecules with full occupancy, typically without disorder and accompanying solvent, affording well-refined structures. Moreover, anomalous scattering by the framework sulfur atoms enables reliable assignment of absolute configuration of stereogenic centers. An ever-expanding library of organosulfonates provides a toolkit of frameworks for capturing specific target molecules for their structure determination. Single crystal X-ray diffraction is an invaluable tool for molecular structure determination, but growing single crystals is often an arduous process. Here the authors find that the structures of a wide array of molecules can be determined by SCXRD when included in hydrogen-bonded guanidinium organosulfonate host frameworks in a single-step crystallization.

Chirality and molecular conformation are central components of life: biological systems rely on stereospecific interactions between discrete (macro)molecular conformers, and the impacts of stereochemistry and rigidity on the properties of small molecules and biomacromolecules have been intensively studied. Nevertheless, how these features affect the properties of synthetic macromolecules has received comparably little attention. Here we leverage iterative exponential growth and ring-opening metathesis polymerization to produce water-soluble, chiral bottlebrush polymers (CBPs) from two enantiomeric pairs of macromonomers of differing rigidity. Remarkably, CBPs with conformationally flexible, mirror image side chains show several-fold differences in cytotoxicity, cell uptake, blood pharmacokinetics and liver clearance; CBPs with comparably rigid, mirror image side chains show no differences. These observations are rationalized with a simple model that correlates greater conformational freedom with enhanced chiral recognition. Altogether, this work provides routes to the synthesis of chiral nanostructured polymers and suggests key roles for stereochemistry and conformational rigidity in the design of future biomaterials. The contributions of chirality and conformation as contributing factors to the biological properties of synthetic nanomaterials remain underexplored. A synthesis of bottlebrush polymers with mirror-image side chains has now been developed and it has been revealed that an interplay between side-chain absolute configuration and flexibility influences the biological properties of these polymers both in vitro and in vivo.

We report a method for determining the absolute configurations of chiral amino alcohols, amino acid esters, and secondary amines through the combined use of a m -quaterphenyl probe 1 and theoretical calculations. The probe 1 is covalently attached to chiral amines to form conjugates that exhibit exciton-coupled circular dichroism (ECCD) in the m -quaterphenyl chromophores. The calculated ratios of the P and M conformers, obtained via DFT calculations, show a correlation with both the sign and intensity of the experimentally observed CD spectra.

The advances of high-throughput experimentation technology and chemometrics have revolutionized the pace of scientific progress and enabled previously inconceivable discoveries, in particular when used in tandem. Here we show that the combination of chirality sensing based on small-molecule optical probes that bind to amines and amino alcohols via dynamic covalent or click chemistries and powerful chemometric tools that achieve orthogonal data fusion and spectral deconvolution yields a streamlined multi-modal sensing protocol that allows analysis of the absolute configuration, enantiomeric composition and concentration of structurally analogous—and therefore particularly challenging—chiral target compounds without laborious and time-consuming physical separation. The practicality, high accuracy, and speed of this approach are demonstrated with complicated quaternary and octonary mixtures of varying chemical and chiral compositions. The advantages over chiral chromatography and other classical methods include operational simplicity, increased speed, reduced waste production, low cost, and compatibility with multiwell plate technology if high-throughput analysis of hundreds of samples is desired. The stereoselective analysis of mixtures of chiral compounds typically requires time-consuming chromatography. Here, the authors combine reaction based chiroptical sensing and chemometric tools to directly determine the absolute configuration, enantiomeric composition and concentration of convoluted samples without physical separation.

The development of enantiodivergent catalysis for the preparation of both enantiomers of a chiral compound is of importance in pharmaceutical and bioorganic chemistry. With the design of a class of reactive and stereoselective organocatalysts, acyclic chiral secondary amines, a method for achieving the enantiodivergence is developed simply by changing the secondary N - i -Bu- to N -Me-group within the catalyst architecture while maintaining the same absolute configuration of the catalysts, which modulates the catalyst conformation. This catalyst-controlled enantiodivergent method not only enables challenging asymmetric transformations to occur in an enantiodivergent manner but also features a high level of stereocontrol and broad scope that is demonstrated in eight different reactions (90 examples), all delivering both enantiomers of a range of structurally diverse products including hitherto less accessible, yet important, compounds in good yields with high stereoselectivities. Enantiodivergent methods, which to access both enantiomers of the same compound, are of importance in drug synthesis. Here, the authors show that by simply changing a N i Bu- to a NMe-group in readily available amine organocatalysts, high stereocontrol and broad scope are achieved in eight asymmetric reactions.