Glaucoma is one of the most common, but serious eye disease that can damage the optic nerve and result in vision loss and blindness. It is thought that high pressure within the eye, known as intraocular pressure （IOP）, is the main cause of this optic nerve damage. Our research group has studied fluorinated prostaglandins （PGs） over the years, and recently discovered a 15-deoxy-15,15-difluoro-PGF2α derivative, tafluprost as a novel anti-glaucoma agent. Drug design by introducing two fluorine atoms into the PG skeleton brings various beneficial effects on chemical and metabolic stabilities and also receptor binding of the drug. A key to synthesizing the molecule is to develop an efficient geminal difluorination reaction of the enone and stereoselective Wittig reaction. Tafluprost showed an excellent pharmacological profile as an anti-glaucoma agent. It increased uveoscleral outflow of the aqueous humor, and showed a potent and stable IOP-lowering effect. In clinical studies, it also has been confirmed to have a potent IOP-lowering effect in normal tension glaucoma, a disease seen in a high ratio of the Japanese glaucoma patients. Tafluprost has been recently approved and marketed as a new anti-glaucoma agent in Japan, Europe, USA, and Asia. We herein describe our studies on the synthesis, drug design, structure-activity relationship, and molecular modeling in the development of tafluprost.
A catalyst is a substance that changes the course of reactions without affecting the relative stability of substrates and products. The development of an efficient catalyst, which decreases the activation energy of a reaction, results in equilibrium when the relative thermodynamic stabilities of the substrates and products are close. I found that a transition-metal complex could be used as a catalyst in the synthesis and transformation of organosulfur and organophosphorus compounds, and a variety of rhodium-catalyzed reactions involving cleavage of heteroatom bonds such as C-H, C-S, C-F, S-S, P-P bonds were developed. Such single bond metathesis reactions are often under equilibrium. The control of such equilibrium to provide the desired products with high efficiency has recently become a subject of interest. I developed an equilibrium control method using co-substrates. I also developed another method, that uses thermodynamically intermediate compounds to shift equilibrium. This method using a combination of transition-metal catalysis and equilibrium control can be generally used for the synthesis of organoheteroatom compounds.
Replacement of internucleoside phosphodiester linkages of DNA or RNA with non-natural structures would generate intriguing oligonucleotides with functions that could explore the field of medicinal chemistry, chemical biology and materials science. The Nature’s choice of phosphate for the internucleoside linkage is so divine that allows the connection and cleavage of the oligonucleotides at will. When chemists wish to explore the tailor-made variants, an elaborate design of molecular structures is required: an easy synthetic access to the monomeric units, efficient elongation processes, and duplex- or multiplex-forming strands. In this account, we overview the progress of our efforts over the past half a decade on the development of non-natural oligonucleotides with an internucleosidic modification. Adopting an effective reaction from the click chemistry, copper-catalyzed Huisgen cycloaddition, we designed and synthesized the new analogues, triazole-linked DNA and RNA(TLDNA/TLRNA). The robust synthesis supported the concise synthesis of oligonucleotides with triazole-linkages and the development of their functions in bioorganic and materials chemistry.
In this article the author summarizes analysis of intermolecular interactions (π/π interactions of benzene, naphthalene, thiophene dimers and benzene-perfluorobenzene cluster, CH/π interactions of benzene clusters with methane, ethylene, acetylene and chloroform, cation/π inteactions of benzene clusters with alkali and alkaline metal cations and N-alkylpyridinium cation, halogen bonds of halobenzene and pentafluorohalobenzene with pyridine and hydrogen bond coorperativity in water-crownophane complex) by high-level ab initio calculations. The ab initio calculations provide detailed information on the interactions (magnitude of attraction, directionality, origin of attraction). The dispersion interaction is the major source of the attraction in the π/π and CH/π interactions. The electrostatic and induction interactions are responsible for the strong attraction in cation/π interactions. The electrostatic interaction is the origin of the attraction and strong directionality of halogen bonds. The basis set and electron correlation effects on the calculated interaction energies are discussed. Although the structure of CH/π interactions is similar to π hydrogen bonds, the nature of CH/π interactions is completely different from hydrogen bonds, which shows that it is sometimes misleading to discuss the nature of the interactions based solely on the structural information.
In 2008, we reported a new class of macrocyclic hosts and named “Pillararenes”. They combine the advantages and aspects of traditional hosts and have a composition similar to those of typical calix[n]arenes. Pillararenes have repeating units connected by methylene bridges at the para-position, and thus they have a unique symmetrical pillar architecture differing from the basket-shaped structure of meta-bridged calix[n]arenes. Pillararenes show high functionality similar to cyclodextrins, and can capture electron accepting guest molecules within their cavity similarly to cucurbit[n]urils. In this review, the synthesis, structure, rotation, host-guest properties, planar chirality and functionality of pillararenes are discussed, along with pillararene-based supramolecular architectures.
Lautens and Tong have independently developed the unique palladium-catalyzed carbohalogenation of alkenes in both intra- and intermolecular fashions. It is quite interesting that the reaction mechanism involves the reductive elimination giving carbon-iodine bonds. This type of reactions will provide new synthetic methods of complex molecules including carbon-halogen bonds.
Recent progress in asymmetric synthesis based on the formation of chiral boron “ate” complex is overviewed. Hoppe and Aggarwal have reported stereo-controlled homologation of chiral boron “ate” complex via stereoselective 1,2-rearrangement. Aggarwal has also observed the inversion of stereochemistry during the formation of boron “ate” complex, in the reaction of sterically-hindered chiral carbanion with boronic acid ester. These results will provide a new direction to the field of asymmetric synthesis.
In this article, the author recalls the years he spent from 1967 to 1973 studying in the United States at the University of Hawaii in Honolulu. In particular, he focuses on his motivations, scholarship, experiences with undergraduate and graduate school classes and examinations, job opportunities, English language problems, professor, roommates and friends. He strongly urges Japanese youths to find their path in life by living abroad and viewing Japan and the world more objectively. He also comments that society will need to be more accepting of individualism and different lifestyles in order for overseas study to bring about positive changes in Japan.