Hiroki Takezawa

The second‐generation crystalline sponge (2G‐CS) is a novel type of crystalline sponge that incorporates hollow cages as molecular recognition modules within its crystalline framework. This advanced CS technology provides a versatile structural analysis technique applicable to a broad range of guest molecules, regardless of polarity, with molecular weights ranging from 300 to 1500. However, the method often fails when analyzing rather low‐polarity small molecules (MW 200–300) due to an “unfavorable chemical space,” where the host cavities are too large to facilitate sufficient host–guest interactions. Here we overcome this limitation by establishing a size‐compensation strategy based on cage‐mediated pair‐selective bimolecular recognition. By co‐encapsulating a target analyte with a shape‐complementary “modulator” (e.g., phenanthrene), we precisely tailor the cavity environment without the need for chemical modification of the host. This adaptive approach enabled the x‐ray structural determination of 24 of 30 low‐polarity C15 analytes, predominantly sesquiterpenoids, including absolute configuration determination for selected chiral analytes. This work translates a decades‐old molecular recognition phenomenon into a practical approach to crystallographic structure determination of low‐polarity sesquiterpenoids.

The second‐generation crystalline sponge (2G‐CS) is a novel type of crystalline sponge that incorporates hollow cages as molecular recognition modules within its crystalline framework. This advanced CS technology provides a versatile structural analysis technique applicable to a broad range of guest molecules, regardless of polarity, with molecular weights ranging from 300 to 1500. However, the method often fails when analyzing rather low‐polarity small molecules (MW 200–300) due to an “unfavorable chemical space,” where the host cavities are too large to facilitate sufficient host–guest interactions. Here we overcome this limitation by establishing a size‐compensation strategy based on cage‐mediated pair‐selective bimolecular recognition. By co‐encapsulating a target analyte with a shape‐complementary “modulator” (e.g., phenanthrene), we precisely tailor the cavity environment without the need for chemical modification of the host. This adaptive approach enabled the x‐ray structural determination of 24 of 30 low‐polarity C15 analytes, predominantly sesquiterpenoids, including absolute configuration determination for selected chiral analytes. This work translates a decades‐old molecular recognition phenomenon into a practical approach to crystallographic structure determination of low‐polarity sesquiterpenoids.

To achieve on-demand mechanical control over encapsulated guests, a molecular host must be both structurally robust and dynamically responsive, which are notoriously difficult to reconcile in self-assembled systems. Here, we introduce a single-site labilization strategy, where a single labile site is installed into an otherwise kinetically inert coordination cage. We synthesized a heterometallic PdPt8L6 cage with a chemically detachable site by incorporating one labile Pd(II) unit onto a stable Pt8L6 scaffold. This design enables the cage to switch between expanded and contracted states without releasing its guest, thereby mechanically controlling the guest’s shape. This mechanical control translates into a hierarchical function: regulating secondary guest binding to the encapsulated host molecule. This approach provides a blueprint for designing advanced molecular machinery with multistate, on-demand functions.

We present a cage-based crystalline sponge method as a practical strategy for the relative stereochemical determination of flexible saturated heterocycles that are not amenable to nuclear magnetic resonance analysis. Validated using a bis-tetrahydrofuran series and complex bioactives, this method offers a robust solution for resolving stereochemical ambiguities in conformationally flexible molecular systems.

Crystallization is typically highly sensitive to even minor structural differences in target molecules. As a result, obtaining crystals of complex compounds often requires extensive trial‐and‐error experiments for each target molecule. We recently reported a second‐generation crystalline sponge (2G‐CS), in which a coordination cage is fixed within a crystal lattice. In the 2G‐CS, target molecules are first encapsulated within the cage in solution, followed by salt formation with a symmetry‐mismatched polyanion, leading to the formation of single crystals suitable for structure analysis. However, practical implementation still requires case‐by‐case optimization of crystallization conditions. In this study, we demonstrate that combining the cage with a specific polyanion enables crystallization of a wide range of structurally distinct guest molecules under a single set of standardized conditions. In a test set comprising 39 guest molecules, 31 cases (80%) were successfully crystallized using the same conditions. These examples include polar, medium‐sized, and structurally complex molecules, most of which are of pharmaceutical interest. Crystal structures showed that the polyanion induced a predominant packing type for cages and anions in crystals. We suggest that this recurrent packing type may contribute to the ability to obtain crystals under standardized conditions despite variations in guest structures.

Crystallization is typically highly sensitive to even minor structural differences in target molecules. As a result, obtaining crystals of complex compounds often requires extensive trial‐and‐error experiments for each target molecule. We recently reported a second‐generation crystalline sponge (2G‐CS), in which a coordination cage is fixed within a crystal lattice. In the 2G‐CS, target molecules are first encapsulated within the cage in solution, followed by salt formation with a symmetry‐mismatched polyanion, leading to the formation of single crystals suitable for structure analysis. However, practical implementation still requires case‐by‐case optimization of crystallization conditions. In this study, we demonstrate that combining the cage with a specific polyanion enables crystallization of a wide range of structurally distinct guest molecules under a single set of standardized conditions. In a test set comprising 39 guest molecules, 31 cases (80%) were successfully crystallized using the same conditions. These examples include polar, medium‐sized, and structurally complex molecules, most of which are of pharmaceutical interest. Crystal structures showed that the polyanion induced a predominant packing type for cages and anions in crystals. We suggest that this recurrent packing type may contribute to the ability to obtain crystals under standardized conditions despite variations in guest structures.

The encapsulation of medium-sized molecules in synthetic hosts remains a major challenge, hindered by both the lack of suitable hosts that combine a large size with high molecular recognition capability and kinetic and thermodynamic barriers to encapsulating bulky molecules in solution. Here, we demonstrate that solid-state mechanochemical grinding of a large M₉L₆ coordination cage with various medium-sized guests efficiently overcomes these barriers. This simple, solvent-free approach enables the high-yielding formation of inclusion complexes that are inaccessible or form exceedingly slowly under conventional solution conditions. The resulting complexes, featuring synthetic macrocycles and pharmaceuticals, are kinetically persistent in solution for hours to days, allowing for not only their full characterization, including by X-ray crystallography, but also for their subsequent chemical manipulation. The versatility of this method was confirmed with a smaller cage system. This study establishes solid-state grinding as a powerful strategy for accessing metastable host-guest systems, opening new avenues for the structural analysis of challenging molecules and the design of complex, functional supramolecular architectures.

Host-guest complexation enhances or even alters photoreaction selectivity by preorganizing substrates within the host's confined cavities. Since most previous hosts exhibited no visible-light absorption, at least one of the reactants needed to be an aromatic compound with UV-light absorption. Here, we developed a visible-light-responsive M₆L₄ octahedral cage that retains the encapsulation ability of standard M₆L₄ cages by simply replacing the photoinert metal unit at every vertex with a photoactive cyclometalated Pt(II) unit. This design enabled efficient visible-light-induced cross-[2 + 2] cycloadditions of inert substrates, demonstrating perfect stereo- and site-selectivity via confinement. The selective cross-[2 + 2] cycloaddition was achieved even catalytically, which was impossible with previous M₆L₄ cages.

The self‐assembly process of a double‐walled cage formed from a semiflexible tripodal ligand and a Pd(II) 90‐degree block was tracked by NMR and x‐ray analysis. At least two intermediate structures with distinct topologies were observed prior to the formation of the final double‐walled cage. By optimizing the self‐assembly conditions (e.g., time, solvent, and concentration), these topological intermediates were successfully isolated and analyzed by x‐ray crystallography. They are considered crucial metastable structures that navigate the shortest pathway to the final structure, demonstrating the critical role of molecular topology in guiding and controlling the kinetics of metal‐directed self‐assembly.

Capillary is a handy tool for transferring, mixing, and storing small volumes of liquid. Here, we show that the stepwise dipping of host and guest solutions into a capillary allows efficient preparation, crystallization, and X‐ray analysis of various host–guest complexes. The crystals formed in capillaries are comparable in quality to those grown in regular flasks and subjected to X‐ray analysis without being removed from the capillary. We further apply the capillary technique to the crystalline sponge method, a practical domain of host–guest chemistry, successfully overcoming several technical issues.