N-Acetylneuraminic acid (Neu5Ac) which is the predominant sialic acid in mammalian cells, is the important target for a pathologic bacteria. And neuraminidase (sialidase) is a kind of glycoside hydrolases, which catalyze the hydrolysis of a glycosidic bond of neuraminic acid, plays important roles in the cell functions such as differentiation, growth, apoptosis and migration, and in the virus replication cycle. A viral neuraminidase is also important for a drug target. So it is important to visualize the location of a neuraminidase activity. For this purpose, some neuraminidase substrates are commercially available and are also useful, but they are not able to stain the location of the neuraminidase activity on a tissue. Therefore we designed the novel neuraminidase substrate which is not fluorescent before enzymatic hydrolysis and is strong fluorescent after yielding water-insoluble BTP which is immobile from the neuraminidase activity position. BTP emits fluorescence through the process called excited state intramolecular proton transfer (ESIPT), so the phenolic proton of BTP is essential for the luminescence. A kind of protective moiety, such as glucose moiety, on phenolic oxygen inhibits the ESIPT fluoresce process. An enzymatic removal of “the protective group” results in the yielding of a strong fluorescent BTP particle and the yielded BTP stains the location of enzyme. We have developed a new artificial substrate for sialidase, which enabled to detect influenza infected cells or location of human colon cancer. This article describes the synthesis and demonstration of histochemical fluorescent staining of influenza infected living cells by detection of sialidase activity.
Development of novel C-C bond forming reactions providing useful synthetic blocks has been an important issue in the field of organic chemistry. Especially, multiple bond formation systems involving sequential activation of the molecules have been effective methodology known as a domino-type reaction. Herein, novel sequential molecular transformation systems involving intramolecular silyl migration(Brook rearrangement)recently developed in our laboratory are discussed. Depending on the structure of silyl-containing substrates(β-silylated alkynoates vs. β-silylated conjugate enones), different modes of reactions were observed. These reactions enable to prepare useful synthetic blocks such as highly functionalized enones, coumarin and chromene derivatives, and silyl enol ethers. Reaction mechanisms, rationale for the selectivity, and attempts on improvement to organo-catalytic systems are also considered and presented.
Selective oxyfunctionalization at the terminal carbon of alkenes, alkanes and other hydrocarbons using molecular oxygen can become industrially and/or synthetically useful, environmental load-reducing synthetic methods for oxygen-containing organic compounds such as primary alcohols, aldehydes, and their derivatives. In this paper, we report the palladium-catalyzed synthesis of aldehydes and terminal acetals by anti-Markovnikov oxidation of vinylarenes using molecular oxygen (and also p-benzoquinone), and oxygenation of a benzyl ligand in palladium complexes. The former catalytic aerobic anti-Markovnikov oxidation reactions were efficiently promoted in the presence of a catalytic amount of electron-deficient cyclic alkenes such as maleimides and p-quinones, which would coordinate to palladium to accelerate the reaction as well as to stabilize in-situ formed Pd(0) species and suppress the deactivation. The latter oxygenation was remarkably accelerated by the addition of anion sources or Brønsted acids, affording oxygenated compounds such as benzaldehyde, benzyl hydroperoxide, and benzyl alcohol. The oxygenation with anion sources proceeds in a radical chain mechanism, while the oxygenation with Brønsted acids proceeds in a non-radical chain mechanism. Especially, the oxygenation with acids would be promising because catalytic oxygenation of toluenes and other hydrocarbons can be developed by combining the oxygenation step with a deprotonative C-H bond activation step.
Design and synthesis of supporting ligands for transition-metal complexes are significant as an efficient method for development of new metal complex catalysts for organic synthesis. Metal complexes bearing chelate-type silyl supporting ligands are expected to show high catalytic performance toward activation of inert bonds such as C-H due to the strongly σ-donating and trans-labilizing properties of their silyl ligand moieties. This article describes recent progress of synthesis and catalysis of transition-metal complexes bearing a xanthene-based bis(silyl)supporting ligand “xantsil”, developed by our previous study, and a related silyl(phosphine)-xanthene chelate ligand “xantSiP”. These complexes were synthesized straightforwardly by reactions of (hydrosilyl)xanthene derivatives as ligand precursors with low-valent metal complexes via Si-H activation and ligand substitution. As a prominent result, the reaction of arylalkynes with hydrosilanes catalyzed by 16-electron ruthenium-xantsil complexes with bulky trialkylphosphine was found to give 2-silylstyrenes via ortho-C-H silylation and trans-selective hydrogenation (ortho-C-H silylation/hydrogenation). On the other hand, when catalysts with triaminophosphine instead of trialkylphosphine were used for the reaction, 2,α-bis(silyl)styrenes were formed in most cases via ortho-C-H silylation and trans-selective hydrosilylation (ortho-C-H silylation/hydrosilylation). These novel C-H silylation reactions proceeded under mild conditions(room temp.∼70 °C).
Iodine has unique properties that are hypervalency, soft Lewis acidity, and high leaving ability. During our efforts to develop new synthetic methods utilizing iodine reagents that show such unique properties, we discovered several reactions to introduce oxygen and nitrogen functionalities into organic molecules, especially into sp3 carbon centers, by judicious choice of substrates, iodine reagents, and reaction conditions. First, the decarboxylative functionalization of β,γ-unsaturated carboxylic acids, including C-O and C-N bond formation, was achieved by the use of appropriate mono- and trivalent iodine reagents. In addition, the oxidative cyclization of β,γ-unsaturated carboxylic acids with a highly electrophilic hypervalent iodine reagent, thus providing furan-2-one products, was also developed. Second, the new oxidation system that employs iodic acid (HIO3) and N-hydroxyphthalimide (NHPI) was found to be quite effective to transform a C-H bond at tertiary carbon centers and enabled the Ritter-type amination, hydroxylation, and lactonization. The effective introduction of oxygen and nitrogen functionalities into tertiary carbon centers was also achieved via decarboxylation of carboxylic acids by iodobenzene diacetate (PhI(OAc)2) in combination with molecular iodine (I2). Finally, a new class of hypervalent iodine reagents containing phthalimidate was synthesized, structurally characterized by X-ray analysis, and applied to the oxidative amination of C(sp3)-H bond.
Although transition metal catalyzed C-C bond transformation is among the most remarkable strategies for efficient organic synthesis, the C-C bond cleavage reaction is achieved with difficulty. We have developed unique and selective C-C bond cleavage reactions, involving metallacycles as the key intermediates. For instance, the C-C bond cleavage reaction proceeded via an oxanickelacyclopentane intermediate, which was prepared from 4-vinyl-1,3-dioxacyclohexan-2-one and a nickel (0) catalyst, to afford ω-dienyl aldehydes. The nickel (0) catalyst also promoted the multicomponent coupling reaction of diketene, alkyne, and Me2Zn, to provide 3-methylene-4-hexenoic acids. Use of a combination of the nickel catalyst and Et2Al(OEt), in the presence of PPh3, led to the regioselective synthesis of phenylacetic acid, through a formal [2+2+1+1] cycloaddition reaction, via the cleavage of the C-C double bond of the diketene. Furthermore, 4-methylene-1,3-dioxolan-2-one underwent oxidative addition with the nickel catalyst in the presence of Me2Al(OMe), followed by a coupling reaction with the alkynes, to form δ,ε-unsaturated β-ketocarboxylic acids, via the migration of the enolative metal carbonate, with high regio- and stereoselectively. This article describes a novel strategy, involving the transition metal catalyzed C-C bond cleavage reactions, for the efficient reconstruction of the carbon framework.
Edoxaban is a Factor Xa inhibitor which has been approved and marketed all over the world as a new direct oral anticoagulant (DOAC). Traditional anticoagulants such as warfarin require monthly blood test, dietary controls and attention to the possibility of uncontrolled bleeding. DOACs have a more rapid onset, predictable effect, and few drug-drug interactions. Hence, they can be given in fixed doses without monitoring.
We have developed a novel highly efficient manufacturing method to access a key intermediate of edoxaban to increase the productivity and to reduce the manufacturing cost. A salient feature of the new synthetic route is a unique rearrangement reaction to construct a differentially protected 1,2-cis-diamine from 1,2-trans-aminoalcohol utilizing neighboring group participation with excellent stereo- and regioselectivity via sulfonyl aziridine intermediate by using of a Burgess-type reagent. In addition, a flow reaction system has also been applied to the process in large scale in order to suppress the degradation of the unstable reaction intermediate in the preparation of the reagent. Furthermore, the efficiency of the optical resolution of a chiral lactone intermediate was improved by employing enzymatic resolution instead of the diastereomeric salt crystallization. These three key technologies improved the overall yield and reduced the manufacturing cost.
Condensed oxygen-heteropolycyclic compounds are one of attractive synthetic targets in organic synthetic chemistry. Among these useful compounds, chromenes and benzofurans are important structural motifs, which are found in a wide range of biologically active compounds and photochemical materials. Therefore, a number of research groups have developed methodologies to synthesize these compounds. ortho-Quinone methides are key reactive intermediates with a wide range of applications in organic synthesis. In this account, our recent research on acid-promoted inverse-electron-demand [4+2] cycloaddition reaction of electron-rich arylalkynes with ortho-quinone methides is described. This reaction can be applied to a variety of arylalkynes, affording high regioselective cycloadducts. The present reactions provide versatile access to functionalized multi-substituted chromenes and benzofurans, that would be a useful tool for the synthesis of biologically and photochemically active molecules.
Stereocontrol of alkenes is important concern in organic synthesis and particularly the practical method for the formation of thermodynamically less stable (Z)-alkenes is still demanded. This review highlights the recent development on catalytic photoisomerization of alkenes as a classic, meanwhile novel approach toward (Z)-alkenes.
The precise polymerization is essential method to make polymer materials with high performance and functionality. Recently, the precise polymerization such as radical, cationic, anionic, and coordination polymerization, which enables control of molecular weight and stereoselectivity, has been much attractive. This mini-review focuses on (co)polymerization with redox switchable ring-opening polymerization catalyst and its (co)polymerization mechanism.
Alkyne metathesis is powerful reaction for synthesis of rigid molecular-cages. This reaction selectively affords thermodynamically stable cages owing to the reversibility. Zhang et al. successfully synthesized several cages by using multidentate Mo(VI) carbyne as the metathesis catalyst. Moore et al. revealed that the geometry of cage precursors affect the yields of alkyne metathesis.
Biocatalytic reactions are recently attracting attention as they offer various advantage over chemocatalysts and classical organic synthesis. Aided by the development of engineering techniques, such as site-directed mutagenesis and directed evolution, biocatalysts are modified to realize sustainable organic synthesis of API and natural products. In this mini review, recent applications of biocatalytic reactions in total synthesis of natural products are presented.
Poly(ADP-ribose) is an important biomolecule that regulates various cellular events such as DNA-damage repair, apoptosis, and transcription. The length of the poly(ADP-ribose) chains ranges from 2 to 400 units and branching at the ribose moiety occurs once every 20 to 50 units. To elucidate the biological role of poly(ADP-ribose), well-defined fragments of poly(ADP-ribose) are essential. However, traditional enzymatic synthesis of poly(ADP-ribose) leads to nonhomogeneous products with a broad distribution of the chain length and branching points. Chemical synthesis will allow for the preparation of poly(ADP-ribose) with a well-defined structure.