Asahi Laboratory — Physicochemical Science Group: Research Introduction

Thalidomide, a representative chiral drug, was marketed as an analgesic and sedative, but was withdrawn after severe teratogenic side effects were reported in pregnant women. In recent years, however, thalidomide has regained attention as its therapeutic efficacy against several intractable diseases — including Hansen's disease and multiple myeloma — has been reported, leading to renewed market approval.

The pharmacological effects of thalidomide differ markedly depending on its chirality. Furthermore, since the chirality of thalidomide can invert under certain conditions, it is essential from a safety standpoint to evaluate under what conditions chiral inversion occurs. Despite the fact that thalidomide is sold and consumed in the solid state, almost all research on its chirality has been conducted in solution; solid-state studies are extremely rare.

In this research, we use the G-HAUP — an optical measurement instrument developed uniquely by our group — to evaluate the chirality of solid-state thalidomide "in situ," thereby striving to more accurately elucidate the physicochemical properties of solid-state thalidomide, including its stability and reactivity (chiral inversion and hydrolysis).

We grew thalidomide crystals by solvent evaporation, and through single-crystal X-ray structure analysis and quantum chemical calculations, we were the first in the world to demonstrate that differences in physicochemical properties such as melting point and solubility originate from differences in crystal structure [1]. We also determined the absolute structure of the thalidomide metabolite CBG, which had not previously been established [2], and elucidated the hydrolysis and dehydration reaction mechanisms among metabolites including thalidomide and CBG [3–5]. Furthermore, we developed a crystal growth method by sublimation and experimentally demonstrated the possibility of chiral inversion of thalidomide in the gas phase [6, 7]. We were the first in the world to measure the temperature dependence of enantiomeric and racemic crystals, revealing that a distinct difference in thermal expansion behavior arises due to a subtle symmetry difference in the dimers [8]. We also systematically investigated the chiroptical properties of thalidomide (TD) through circular dichroism and optical rotation measurements in several solvents, including the polar aprotic solvent acetonitrile [9].

Superconductivity is expected to enable dramatic energy savings across a wide range of fields, including power, transportation, industry, and information technology. However, since superconductivity occurs only at extremely low temperatures, there is currently no clear path toward its practical application at room temperature. This is largely because the mechanism underlying high-temperature superconductivity has not yet been elucidated, which means there are no established guidelines for designing and synthesizing materials with even higher superconducting transition temperatures (T_c). To elucidate this mechanism, it is necessary to clarify the "special order" possessed by superconductors, but the debate surrounding this order has yet to be resolved.

In our laboratory, we aim to clarify the nature of the order formation in the pseudogap phase of copper-oxide high-temperature superconductors by using the G-HAUP — our unique optical measurement instrument — to determine whether symmetry breaking exists in the pseudogap phase. The G-HAUP is the only polarimetric spectroscopy method capable of simultaneously measuring optical activity, circular dichroism, linear birefringence, and linear dichroism.

Despite the extremely small lattice constant anisotropy along the a- and b-axes of the cleavable copper-oxide high-temperature superconductor Bi₂Sr₂CaCu₂O_8+δ (Bi2212) crystal, we discovered — surprisingly — that anomalous dispersion of linear birefringence and peaks in linear dichroism are observed at 345 and 330 nm, respectively [1]. We also grew Bi_2−xPb_xSr₂CaCu₂O_8+δ single crystals with various Pb contents by the floating-zone method, and clarified that the origin of the optical anisotropy is related to the "superstructure modulation" (incommensurate modulation) [2].

We are currently constructing a new G-HAUP capable of cooling measurement samples to low temperatures. Going forward, we aim to measure optical activity, circular dichroism, and optical anisotropy in the pseudogap phase using this low-temperature G-HAUP, thereby clarifying whether symmetry breaking exists in the pseudogap phase and ultimately revealing the special order of high-temperature superconductors.

Quantitative evaluation of the chirality of materials is extremely important. Techniques for evaluating chirality include measuring the difference in refractive index (optical activity) and the difference in absorbance (circular dichroism) for left and right circularly polarized light. Polarimeters and circular dichroism spectrometers have been commonly used as standard methods for measuring chiroptical properties. However, these techniques can only be applied to isotropic materials such as solutions and amorphous thin films. In anisotropic materials such as crystals and oriented thin films, optical anisotropy in the form of birefringence and linear dichroism coexists, making it impossible to quantitatively measure chirality using conventional polarimeters or circular dichroism spectrometers.

In 1983, Kobayashi et al. developed a groundbreaking optical measurement instrument — the High Accuracy Universal Polarimeter (HAUP) [1-2] — enabling simultaneous measurement of chiroptical properties and optical anisotropy in anisotropic materials. Our laboratory, which follows in the tradition of Kobayashi, developed the Generalized-HAUP (G-HAUP) [3,6,8,14] as a further evolution of HAUP, and has used it to measure optical activity in chiral crystals composed of achiral molecules [4,8,10,14], optical activity in amino acid crystals [4,8-9,14], chiroptical properties of organic dye molecules intercalated into layered inorganic crystals [3], optical activity in laminated collagen thin films as biomaterials [5-6,11], and chiroptical properties of chiral photomechanical crystals [7-8,14], thereby revealing various valuable insights unobtainable from any other physical measurement. We also extended our research from chiral optics into the magneto-optics field, and by modifying the G-HAUP optical system to allow application of a magnetic field to the sample, we achieved the world's first precise measurement of Faraday rotation perpendicular to the optical axis [12,14].

More recently, to overcome the limitations of the conventional HAUP method, we developed a new measurement principle based on an optical configuration in which the transmitted light intensity is maximized (diagonal position). The conventional HAUP method uses a configuration in which transmitted light intensity is minimized (extinction position), resulting in a decreased signal-to-noise (S/N) ratio for strongly absorbing samples or at wavelengths where light source intensity is low. In contrast, the new diagonal-position principle eliminates the need for the two-dimensional measurements required by the conventional method, and it was clarified that the influence of systematic errors arising from the imperfection of the linear polarizer can also be eliminated. This principle was applied to the non-absorbing uniaxial crystal MgF₂ and the strongly absorbing copper-oxide superconductor Bi₂Sr₂CaCu₂O_8+δ (Bi2212). The LB and LD values obtained from measurements near the diagonal position agreed with high accuracy with results from the conventional method [13,15], and it was also demonstrated that the measurement time can be shortened [16].

Liquid crystals or mesophases that combine fluidity with long-range orientational order underpin technologies ranging from displays and thermometers to pharmaceutical formulations. Among them, chiral liquid crystals are of particular interest because their broken inversion symmetry enables the conversion of thermal energy into directed mechanical motion. Such systems offer a promising route for harvesting low-grade waste heat, including that generated by high-performance computing, and could contribute to more sustainable energy technologies.

Most previous studies have focused on behaviours near phase-transition temperatures for experimental convenience. However, these states exist only within a narrow temperature window, limiting practical deployment under fluctuating conditions. To overcome this challenge, we are developing phase-separated liquid-crystal colloids capable of operating across a broad temperature range. By dispersing liquid-crystal domains in a special alcohol matrix, we have achieved stable operation from 0 to 100°C, greatly extending the accessible temperature range.

We are also exploring how geometry and topology influence energy-conversion efficiency. When confined within a liquid matrix, liquid crystals develop complex topological textures that strongly modify their collective behaviour. By harnessing these emergent soft-matter states, we aim to establish new mechanisms for thermal-energy transduction and ultimately create heat-harvesting devices that approach the Carnot limit.