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Small-ring cage hydrocarbons are popular bioisosteres (molecular replacements) for commonly found para-substituted benzene rings in drug design1. The utility of these cage structures derives from their superior pharmacokinetic properties compared with their parent aromatics, including improved solubility and reduced susceptibility to metabolism2,3. A prime example is the bicyclo[1.1.1]pentane motif, which is mainly synthesized by ring-opening of the interbridgehead bond of the strained hydrocarbon [1.1.1]propellane with radicals or anions4. By contrast, scaffolds mimicking meta-substituted arenes are lacking because of the challenge of synthesizing saturated isosteres that accurately reproduce substituent vectors5. Here we show that bicyclo[3.1.1]heptanes (BCHeps), which are hydrocarbons for which the bridgehead substituents map precisely onto the geometry of meta-substituted benzenes, can be conveniently accessed from [3.1.1]propellane. We found that [3.1.1]propellane can be synthesized on a multigram scale, and readily undergoes a range of radical-based transformations to generate medicinally relevant carbon- and heteroatom-substituted BCHeps, including pharmaceutical analogues. Comparison of the absorption, distribution, metabolism and excretion (ADME) properties of these analogues reveals enhanced metabolic stability relative to their parent arene-containing drugs, validating the potential of this meta-arene analogue as an sp3-rich motif in drug design. Collectively, our results show that BCHeps can be prepared on useful scales using a variety of methods, offering a new surrogate for meta-substituted benzene rings for implementation in drug discovery programmes.

Hydrogen bonding interactions are ubiquitous across the biochemical and chemical sciences, and are of particular interest to supramolecular chemists. They have been used to assemble hydrogen bonded polymers, cages and frameworks, and are the functional motif in many host–guest systems. Single crystal X-ray diffraction studies are often used as a key support for proposed structures, although this presents challenges as hydrogen atoms interact only weakly with X-rays. In this Tutorial Review, we discuss the information that can be gleaned about hydrogen bonding interactions through crystallographic experiments, key limitations of the data, and emerging techniques to overcome these limitations. [ABSTRACT FROM AUTHOR]

The first examples of halogen bonding (XB) heteroditopic homo[2]catenanes were prepared by discrete Na+ template‐directed assembly of oligo(ethylene glycol) units derived from XB donor‐containing macrocycles and acyclic bis‐azide precursors, followed by a CuI‐mediated azide‐alkyne cycloaddition macrocyclisation reaction. Extensive 1H NMR spectroscopic studies show the [2]catenane hosts exhibit positive cooperative ion‐pair recognition behaviour, wherein XB‐mediated halide recognition is enhanced by alkali metal cation pre‐complexation. Notably, subtle changes in the catenanes' oligo(ethylene glycol) chain length dramatically alters their ion‐binding affinity, stoichiometry, complexation mode, and conformational dynamics. Solution‐phase and single‐crystal X‐ray diffraction studies provide evidence for competing host‐separated and direct‐contact ion‐pair binding modes. We further demonstrate the [2]catenanes are capable of extracting solid alkali‐metal halide salts into organic media. [ABSTRACT FROM AUTHOR]

Sulfonylated aromatics are commonplace motifs in drugs and agrochemicals. However, methods for the direct synthesis of sulfonylated non‐classical arene bioisosteres, which could improve the physicochemical properties of drug and agrochemical candidates, are limited. Here we report a solution to this challenge: a one‐pot halosulfonylation of [1.1.1]propellane, [3.1.1]propellane and bicyclo[1.1.0]butanes that proceeds under practical, scalable and mild conditions. The sulfonyl halides used in this chemistry feature aryl, heteroaryl and alkyl substituents, and are conveniently generated in situ from readily available sulfinate salts and halogen atom sources. This methodology enables the synthesis of an array of pharmaceutically and agrochemically relevant halogen/sulfonyl‐substituted bioisosteres and cyclobutanes, on up to multidecagram scale. [ABSTRACT FROM AUTHOR]

X-ray characterisation methods have undoubtedly enabled cutting-edge advances in all aspects of materials research. Despite the enormous breadth of information that can be extracted from these techniques, the challenge of radiation-induced sample change and damage remains prevalent. This is largely due to the emergence of modern, high-intensity X-ray source technologies and the growing potential to carry out more complex, longer duration in situ or in operando studies. The tunability of synchrotron beamlines enables the routine application of photon energy-dependent experiments. This work explores the structural stability of [Rh(COD)Cl]2, a widely used catalyst and precursor in the chemical industry, across a range of beamline parameters that target X-ray energies of 8 keV, 15 keV, 18 keV and 25 keV, on a powder X-ray diffraction synchrotron beamline at room temperature. Structural changes are discussed with respect to absorbed X-ray dose at each experimental setting associated with the respective photon energy. In addition, the X-ray radiation hardness of the catalyst is discussed, by utilising the diffraction data collected at the different energies to determine a dose limit, which is often considered in protein crystallography and typically overlooked in small molecule crystallography. This work not only gives fundamental insight into how damage manifests in this organometallic catalyst, but will encourage careful consideration of experimental X-ray parameters before conducting diffraction on similar radiation-sensitive organometallic materials. [ABSTRACT FROM AUTHOR]