Atomic-resolution structure analysis inside an adaptable porous framework.

We introduce a versatile metal-organic framework (MOF) for encapsulation and immobilization of various guests using highly ordered internal water network. The unique water-mediated entrapment mechanism is applied for structural elucidation of 14 bioactive compounds, including 3 natural product intermediates whose 3D structures are clarified. The single-crystal X-ray diffraction analysis reveals that incorporated guests are surrounded by hydrogen-bonded water networks inside the pores, which uniquely adapt to each molecule, providing clearly defined crystallographic sites. The calculations of host-solvent-guest structures show that the guests are primarily interacting with the MOF through weak dispersion forces. In contrast, the coordination and hydrogen bonds contribute less to the total stabilization energy, however, they provide highly directional point interactions, which help align the guests inside the pore.

Stability Orders of Acetaminophen and Theophylline Co-crystals Determined by Co-crystal Former Exchange Reactions and Their Correlation With In Silico and Thermal Parameters.

The aim of this study was to determine the thermodynamic stability order of co-crystals using co-crystal former exchange reactions and to validate 2 in silico parameters for predicting co-crystal formation. Co-crystal former exchange reactions were performed using acetaminophen (AC) co-crystals of oxalic acid (OX), maleic acid (MA), and theophylline (TH). The addition of TH to an AC-MA co-crystal (AC-MA) afforded AC-TH, suggesting that AC-TH was more stable than AC-MA. The stability order among the other co-crystals was determined in the same manner. The stability order of the AC co-crystals was determined to be AC-TH > AC-MA ≈ AC-OX. Interestingly, the addition of TH to AC-OX afforded TH-OX. The stability order of the TH co-crystals was also determined (OX-TH > AC-TH ≈ MA-TH). Although the stability order of the AC co-crystals was consistent with the differences in their hydrogen bond energy (ΔE), an in silico parameter for predicting co-crystal formation, it showed no relationship to the excess enthalpy (Hex). These results suggest that co-crystal formation can be predicted with greater accuracy using ΔE rather than Hex for AC co-crystals. The stability orders of the AC and TH co-crystals also correlated well with their melting points and disintegration temperatures.

Identification and physicochemical characterization of caffeine-citric acid co-crystal polymorphs.

The purpose of the present study was to identify a new caffeine-citric acid co-crystal (CA-CI) polymorph and characterize three CA-CI polymorphs. The stability order among the three CA-CI polymorphs was also determined. One new and two known CA-CI polymorphs were prepared by the liquid-assisted grinding method or the slurry methods. The three CA-CIs were then identified and characterized by powder X-ray diffraction (PXRD), thermal analysis, IR spectroscopy, Raman spectroscopy, and dynamic vapor sorption (DVS). The stability order of the CA-CIs was determined by the slurry conversion method. Each CA-CI showed distinct PXRD, IR, Raman, and DVS data. The melting points of CA-CIs were 131°C (a new form, Form III), 141°C (Form I), and 160°C (Form II). The order of thermodynamic stability was CA-CI Form II>CA-CI Form I>CA-CI Form III. CA-CI Forms I and II were relatively stable against humidity compared to CA, CI and CA-CI Form III.

Stability order of caffeine co-crystals determined by co-crystal former exchange reaction and its application for the validation of in silico models.

The purpose of the present study was to determine the thermodynamic stability orders of co-crystals by co-crystal former (CCF) exchange reactions. Caffeine (CA) was employed as a model drug. The CCF exchange reaction was performed by liquid-assisted grinding using ethanol. When oxalic acid (OX) was added to CA-citric acid co-crystal (CA-CI), CA-CI converted to CA-OX, suggesting that CA-OX is more stable than CA-CI. The stability orders of other co-crystals were determined in the same manner. The stability order of CA co-crystals was determined as CA-OX≈CA-p-hydroxybenzoic acid (HY)>CA-CI>CA-malonic acid>CA-maleic acid. The stability order correlated with the difference in hydrogen bond energy estimated in silico, except for CA-HY. The π-π stacking in CA-HY was suggested as a reason for this discrepancy. The CCF exchange reaction was demonstrated as a useful method to determine the stability order of co-crystals, which can be used for the validation of in silico parameters to predict co-crystal formation.

Total synthesis of epoxyquinols A, B, and C and epoxytwinol A and the reactivity of a 2H-pyran derivative as the diene component in the Diels-Alder reaction.

Full details of two versions of the total synthesis of epoxyquinols A, B, and C and epoxytwinol A (RKB-3564D) are described. In the first-generation synthesis, the HfCl(4)-mediated diastereoselective Diels-Alder reaction of furan with Corey's chiral auxiliary has been developed. In the second-generation synthesis, a chromatography-free preparation of an iodolactone, by using acryloyl chloride as the dienophile in the Diels-Alder reaction of furan, and the lipase-mediated kinetic resolution of a cyclohexenol derivative have been developed. This second-generation synthesis is suitable for large-scale preparation. A biomimetic cascade reaction involving oxidation, 6pi-electrocyclization, and then Diels-Alder dimerization is the key reaction in the formation of the complex heptacyclic structure of epoxyquinols A, B, and C. Epoxytwinol A is synthesized by the cascade reaction composed of oxidation, 6pi-electrocyclization, and formal [4 + 4] cycloaddition reactions. A 2H-pyran, generated by oxidation/6pi-electrocyclization, acts as a good diene, reacting with several dienophiles to afford polycyclic compounds in one step. An azapentacyclic compound is synthesized by a similar cascade reaction composed of the four successive steps: oxidation, imine formation, 6pi-azaelectrocyclization, and Diels-Alder dimerization.