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Article / Book Information
題目(和文)

生物活性化合物の構造解析に向けたアザフェナレニル配位子からなる機能性細孔の構築

Title(English)

Design of functional pores using azaphenalenyl ligands and theirapplication for the structure determination of bioactive molecules

著者(和文)

和田雄貴

Author(English)

Yuki Wada

出典(和文)

学位:博士(理学),学位授与機関:東京工業大学,
報告番号:甲第12321号,授与年月日:2023年3月26日,
学位の種別:課程博士,
審査員:河野 正規,石谷 治,大森 建,吉沢 道人,小野 公輔

Citation(English)

Degree:Doctor (Science),
Conferring organization: Tokyo Institute of Technology,
Report number:甲第12321号,
Conferred date:2023/3/26,
Degree Type:Course doctor,
Examiner:,,,,

学位種別(和文)

博士論文

Category(English)

Doctoral Thesis

種別(和文)

要約

Type(English)

OutlinePowered by T2R2 (Tokyo Institute Research Repository)Design of functional pores using azaphenalenyl ligands and theirapplication for the structure determination of bioactive molecules
Yuki Wada (Supervisor: Masaki Kawano)[Introduction]
Single crystal X-ray diffraction is one of the mostpowerful structure elucidation tools, since it can
providecriticalinformation

regarding

three-dimensional atom arrangement and the type ofbonding involved, as well as revealing intermolecularinteractions and absolute chirality. However, growing
crystals of sufficiently large size for structure

Figure 1 Schematic illustration of the difficulty ofdesigning a universally accommodating PCN

elucidation can be a daunting task, with a considerable interest in developing alternative techniques. One
solution is incorporation into crystalline porous solids. X-ray analysis of compounds encapsulated in the porous
materials could reveal a plethora important information about the guest structure and host-guest interactions, aswell as monitoring reaction intermediates and detecting metastable species. In particular, structuredetermination of complex organic molecules has garnered a strong attention since this technique can be applied
to non-crystalline solids, oils, and compounds that can only be obtained in trace amounts in what is known as
the “crystalline sponge” method. However, to date, only a handful of PCNs have been identified to becompatible for a wide range of substrates since guest capture and stabilization is typically facilitated by a seriesof finely balanced host-guest interactions, which are difficult to rationally design (Figure 1).

[General Method]
The analysis was performed on a diffractometer equipped in a beamline BL-5A at KEK with a Pilatus3 S6Mdetector (synchrotron, l = 0.7500 Å, T = 95 K). Powder X-ray diffraction patterns were measured on a Rigaku
Miniflex powder diffractometer with D/teX Ultra (1D) detector using Cu Kα radiation at room temperature.

[Result and discussion]
1. Visualization of interactivity of hexaazaphenalenyl (HAP) by single crystal X-ray diffraction
A new 3-pyridyl-substituted derivative of HAP, 3-TPHAP−, was synthesized and characterized. This
compound was used as a versatile multi-interactive ligand in the construction of a Co-based coordination
network, Co-3TPHAP. The restricted rotation of coordinated pyridyl groups led to a structure with minimized
crystallographic disorder. Because of this unique multi-interactive structure, it was possible to assign the porecontents despite its relatively large size. Several guest molecules were encapsulated into Co-3TPHAP. First
were the aromatic guests, anthracene and triphenylene. Although they contain large π planes suitable for π−πinteractions, no such interaction with the HAP core was observed in either encapsulated structure. In fact,weaker interactions, including CH−π and weak hydrogen bonds with the network backbone and surrounding
solvent molecules, were more prevalent. This behavior was attributed to the unique electronic environment of
the pore interior. Second, iodine encapsulation was carried out in different solvents. When ethyl acetate wasused, iodine formed two charge transfer complexes with the HAP core. DFT calculations estimated the degreeof charge transfer to be ∼0.2 electron. The encapsulation from the DMF solution, on the contrary, led to a chargetransfer complex with the solvent molecules rather than the network. The presence of these iodine species inboth structures was confirmed by UV−vis spectroscopy.

2. Adaptable water networks inside the pore for structure elucidation of bioactive molecules
From the above results,
thehost-guest

crystalstructures were shown tocontainseveralsolvent

molecules in the pore (water,DMF, ethyl acetate), whichwere highly ordered andcould be fully resolved by
crystallography. They wereinteracting with both, thehost network, and aromatic
guests, forming a kind ofsolvation shell. From theseresults, we theorized that theencapsulation process could

Figure 2 Electron density maps (2Fo - Fc) for elucidated structures ofbe additionally mediated bybioactive guest compounds inside the PCN. a) commercially available

thecompounds and b) newly reported compounds. Compounds marked with x

solvent

molecules

forming a complex series ofwere racemic mixtures.

host-solvent-guest interactions. The solvent component can be highly malleable and adjust its structure andinteractions uniquely for each guest to provide maximum stabilization inside the pore. Such mechanism could
considerably enhance capabilities of the crystalline sponge method. To explore this concept further, structure
elucidation of several pharmaceutically active compounds was undertaken. These were divided based on theircommon structural features into artemisinin series, steroid series, and aromatic polycyclic molecules (Figure 2).
Moreover, three previously unreported compounds for which crystal structures were not available were also
analyzed using this method.
The single crystal analysis revealed that the incorporated guests were surrounded by hydrogen-bonded water
networks and clusters inside the pores, which uniquely adapted depending on each molecule, providing clearlydefined crystallographic sites. As a result, the guest structures could be determined with high resolution, andlimited number of constraints and restraints. The calculations of host-solvent-guest structures showed that theguests were primarily interacting with the PCN through weak dispersion interaction. Comparatively, thecoordination and hydrogen bonds contributed less to the overall stabilization energy, however they provided
highly directional point interactions, thus helping to align the guests inside the pore leading to crystal structureswith atomic-level resolution.

3. Synthesis of novel C3 symmetric triazaphenalenyl based ligands
Increased interactivity allowed the structural analysis to be performed on a wider range of molecules. To
further explore the arrangements of interactive sites, a new C3 symmetric triazaphenalenyl (TAP) moiety wasdeveloped as a core for the ligand design. TAP has moderate electron-donating ability and is expected toparticipate in donor-acceptor interactions with guest compounds helping them align along the pore surface. The
TAP core can be obtained by a cyclotrimerization reaction followed by an ester hydrolysis to give the HCTAP
derivative. After that, the unsubstituted TAP and TCTAP analogues were synthesized from HCTAP by a twostep decarboxylation reaction. Finally, CITAP was prepared through the anhydride of HCTAP followed bycondensation with amines.

[Conclusion]
In summary, a wide range of guests was analyzed by the crystalline sponge method using Co-3TPHAP as ahost. This network was suitable for guest encapsulation screening in a wide range of solvents. The novel
encapsulation mechanism utilizing adaptable water networks presents a significant advancement in precise andrapid elucidation of molecular structures. Additionally, a new family of ligands with promising interacting
capabilities was synthesized and is currently being employed for the synthesis of new PCNs.