The automation of multi-step chemical processes has been realized. A new concept for one-pot processes has been advanced which enables integration of various types of reactions involving carbon-carbon bond formations and functional group modifications. In the meantime, an automated synthesizer to accommodate such one-pot processes has been devised. This machine allows us to reproduce usual bench work : treatment of air-sensitive materials, control of temperature from -78°C to 100°C within ± 0.1°C accuracy, and successive addition of reagents. Several examples which were successfully conducted on the machine are described.
The efficient synthesis of the high mannose-type oligosaccharide-branched cyclodextrins was carried out. Evaluation of the dual molecular recognition consisting of saccharide-recognition with concanavalin A of the lectin protein, and the inclusion interactions with immobilized cholic acid and doxorubicin as a model drug analyzed by SPR assay. The high mannosyl type oligosaccharide-branched CD (M6CD and M7CD) showed a tight interaction both with lectin and a drug, showing a Ka of 107M-1 or more. The number of sugar antennas and the length of the spacer arm are quite important for the dual recognition with protein and drug. We can foresee applications of the sugar cluster-branched CD to a targeting drug delivery system.
Trifluoromethyl ketones (TFMKs) are of considerable current interest due to their importance as synthetic intermediates and their ability to act as potent enzyme inhibitors. This article briefly reviews recent ten-years progress in the chemistry of TFMKs and describes our studies on the new method for the preparation of TFMKs. Furthermore, screenings of a variety of structurally diverse TFMKs, with the view to identify a lead TFMK with anti-Helicobacter pylori, antimicrobial or apoptosis-inducing and -inhibitory activities are shown. These studies led to the identification of several TFMKs as a lead molecule.
The design, synthesis, and application of a new bifunctional enantioselective catalyst, containing both Lewis acidity and Lewis basicity, are described. The catalysts are composed of a Lewis acid metal (aluminum or titanium) and a Lewis base (the oxygen atom of a phosphine oxide), of which positions are defined by BINOL or carbohydrate scaffold. Utilizing these catalysts, we have developed a variety of enantioselective cyanation reactions, such as cyanosilylation of aldehydes and ketones, Strecker-type reaction, and Reissert-type reaction. These reactions showed a broad sub-strate generality. Investigations toward elucidation of the reaction mechanism, involving kinetic studies, comparison with results by control catalysts, and absolute configurations of the products, revealed that these reactions are catalyzed by a dual activation of a substrate and TMSCN by the Lewis acid and the Lewis base of these catalysts. Catalytic enantioselective total synthesis of anticancer epothilones and a potent NMDA receptor antagonist was achieved, using these reactions as key steps.
Summarized in this article are the syntheses of nitrogen-containing compounds by means of nitrobenzenesulfonamides (Ns-amides), which serve both as protecting and activating groups. Ns-Amides, readily prepared from primary amines, were converted to the N, N-disubstituted sulfonamides by conventional alkylation or Mitsunobu conditions. The Ns group was readily removed with soft nucleophiles via Meisenheimer complexes to give the corresponding secondary amines. The major advantage of this method is that both alkylation and deprotection proceed under mild conditions. Furthermore, Ns-amides allow efficient synthesis of a variety of diamines and protected primary amines. When treated with NsCl, symmetrical diamines gave mono-nosylated diamines selectively. Using these diamines as starting material, natural polyamine toxins were synthesized in short steps and in high yields. In the case of HO-416b and Agel-489, Ns group was removed while the substrates were on a solid support, thus allowing an efficient isolation of these highly polar compounds. Lipogrammistin-A was synthesized using Ns-assisted macrocyclization as a key step.
New catalyst systems for the direct synthesis of diphenyl carbonate (DPC) from carbon monoxide (CO) and phenol were investigated. Palladium-tin complexes [Pd2(dPPm)2(SnCl3) Cl and Pd2(dppm)2(SnCl3)2, dppm : bis (diphenylphospino) methane] with manganese redox catalyst [Mn(TMHD)3, TMHD : 2, 2, 6, 6-tetramethyl-3, 5-heptanedionate] were found to produce DPC effectively without any addition of ammonium halide. Furthermore, palladium catalyst systems such as, palladium dinuclear complexes, palladium-diimine complexes, and palladium-6, 6'-disubstituted-2, 2'-bipyridyl complexes promoted the oxidative carbonylation of phenol more effectively in the presence of ammonium halide. Especially, the efficiencies of Pd2(Ph2PPY)2(NO2)2(Ph2PPy : 2-pyridyldiphenylphosphine) and Pd(6, 6'-Me2bpy)Cl2(6, 6'-Me2bpy : 6, 6'-dimethyl-2, 2'-bipyridyl) were highest among these palladium complexes. These palladium catalyst systems were applied for the direct synthesis of polycarbonate (PC) from bisphenol A and CO. PC with the number-and weight-average molecular weights of 5600 and 12900 respectively, was successfully obtained using Pd (6, 6'-Me2bpy) Cl2 catalyst system. These molecular weights were highest among the direct syntheses of PC by oxidative carbonylation.
A new direct thermal full color recording paper named TA paper has been on the market. TA paper has three recording layers : an outermost yellow color forming layer, a magenta layer and an innermost cyan color forming layer. The yellow color forming layer comprises a diazonium salt decomposable by 420 nm light and a coupler which reacts to form a yellow dye. The magenta comprises a diazonium salt decomposable by 365 nm light and a coupler which reacts to form a magenta dye. The cyan color forming layer comprises a basic leuco dye and a phenolic color developer. In this article we will describe how to design functional materials for TA paper such as diazonium salts, couplers, basic leuco dyes, phenolic color developers and ultraviolet absorber precursors.