Kazuhiko Takatori

The cascade aza-Prins/Friedel-Crafts reaction of homocinnamyloxycarbamate with electron-rich aromatic aldehydes has been successfully established. Most of the aromatic aldehydes react with the carbamate stereoselectively to generate cis-hydroindeno-1,2-oxazinanes. However, the cascade reactions of benzaldehydes bearing two methoxy groups at the meta-positions exhibit a unique stereochemical profile. Furthermore, the cascade reaction of benzaldehyde bearing three methoxy groups at the meta- and para-positions proceeds along with a skeletal rearrangement. Additionally, the aza-Prins/Ritter reaction of cinnamyloxycarbamate with various aldehydes was found during the development of the cascade reaction. In contrast to the cascade aza-Prins/Friedel-Crafts reaction, the aza-Prins/Ritter reaction gave trans-disubstituted isoxazolidines. These stereochemical profiles for both reactions were considered on the basis of several transition-state models.

Hexahydro-2H-cyclopenta[b]furan fused to electron-rich aromatic rings reacts with various aromatic aldehydes in different modes to build diverse frameworks. The reaction of a dimethoxybenzene-fused cyclopentafuran generated diquinanes fused with a hydrofuran ring, indenopyrans, or diarylindanes depending upon the type of aromatic aldehydes, whereas an indole-annulated cyclopentafuran generated another type of diquinane fused with hydrofuran ring or benzylidenecyclopentafuran. The chemodivergence is due to the different properties between indole- and dimethoxybenzene-fused hydrocyclopentafurans. Namely, Lewis acid-promoted furan-ring opening of the substrates resulted in the formation of an electrophilic or a nucleophilic intermediate, respectively. Additionally, the observed chemodivergence can be attributed to the distinctive electronic properties of three classified aromatic aldehydes. Of particular interest is that 2,4-dimethoxybenzaldehyde reacted with the dimethoxybenzene-fused cyclopentafuran at the benzene ring, whereas it reacted with the indole-fused cyclopentafuran at the formyl group.

The possible structures of euvesperins A and B were synthesized, suggesting that euvesperin A may be a mixture of the (2 R ,3 R ,4 S ,7 S ) and (2 S ,3 S ,4 R ,7 S ) isomers and euvesperin B may be a mixture of the (2 R ,3 S ,4 S ,7 S ) and (2 S ,3 R ,4 R ,7 S ) isomers.

Cocrystallization is a crystallization technique for drugs that are difficult to crystallize as single components. In this study, we found a novel cocrystal hydrate consisting of captopril (CPL), which is an amino acid-derived drug and has a thiol group, and L-proline (LPR), although a CPL–LPR cocrystal anhydrate has been previously reported. Nano-spot screening elucidated a new LF Raman spectrum for the combination of CPL and LPR due to the formation of a crystalline complex. Single crystal X-ray diffraction analysis revealed that this crystalline complex was a cocrystal hydrate with a stoichiometric ratio of 1 : 1 : 1 CPL : LPR : H₂O in an asymmetric unit. Notably, the CPL–LPR cocrystal hydrate showed high hygroscopicity, and the degradation product of CPL upon a storage stability test could have resulted from the changes in the intermolecular interactions and the location of the water molecules involved in the thiolate formation in the crystal structure. The storage stability tests highlighted a higher amount of CPL degradation product in the CPL–LPR cocrystal hydrate than in the CPL crystal, potentially due to i) increased hygroscopicity, ii) decreased intermolecular interactions that contribute to CPL stabilization and iii) increased reactivity by water molecules for the crystal structure of the CPL–LPR cocrystal hydrate. Therefore, it is suggested to select a coformer with few OH groups involved in the interaction with water or low hygroscopicity to optimize the stable cocrystals of drugs.

A method is described for synthesizing succinonitrile derivatives bearing alkyl or aryl substituents from cyanohydrin derivatives using low-valent titanium. The active species in this reaction is proposed to be a resonance hybrid of the Ti^IV nitrile enolate and Ti^III alkyl radical.

A rapid and nondestructive analytical technique is critical for the analysis of cyclodextrin inclusion complexes in solid dosage forms. This study proposed a newly developed low-frequency Raman spectroscopy as a candidate technique for the analysis of cyclodextrin inclusion complexes. In this study, we selected a typical series of five crystalline cyclodextrin inclusion complexes and reported the usefulness of Raman spectroscopy for analyzing these inclusion complexes. Some inclusion complexes clearly differed from the raw materials in conventional Raman spectra. In another case, though specific differences were not observed between inclusion complexes and raw materials in conventional Raman spectra, clear differences were observed in low-frequency Raman spectra. Moreover, no characteristic differences between inclusion complexes consisting of different guest molecules were observed in conventional Raman spectra. The characteristic differences were observed only in low-frequency Raman spectra. Therefore, low-frequency Raman spectroscopy is a useful technique for solid-state analysis of crystalline inclusion complexes.

The first total synthesis of C3- and C9-oxidized ent-longipinane-type sesquiterpenoids containing acetoxymarsupellone, marsupellins A and B, has been accomplished. This unique core common to C3- and C9-oxidized ent-longipinane-type sesquiterpenoids was constructed via a new intramolecular reductive cyclization reaction of an epoxycyanohydrin derivative using Cp₂TiI.

Direct conversion of methylenebicyclo[4.2.0]octanone to methylenebicyclo[3.2.1]octanol by a Sm(II)-induced 1,2-rearrangement with ring expansion of the methylenecyclobutane is described. Three conditions were optimized to allow the adaptation of this approach to various substrates. A rearrangement mechanism is proposed involving the generation of a ketyl radical and cyclopentanation by ketyl–olefin cyclization, followed by radical fragmentation and subsequent protonation.