Shū Kobayashi

Scandium Triflate in Organic Synthesis

Sc(OTf)3 is a new type of a Lewis acid that is different from typical Lewis acids such as AlCl3, BF3, SnCl4, etc. While most Lewis acids are decomposed or deactivated in the presence of water, Sc(OTf)3 is stable and works as a Lewis acid in water solutions. Many nitrogen-containing compounds such as imines and hydrazones are also successfully activated by using a small amount of Sc(OTf)3 in both organic and aqueous solvents. In addition, Sc(OTf)3 can be recovered after reactions are completed and can be reused. While lanthanide triflates [Ln(OTf)3] have similar properties, the catalytic activity of Sc(OTf)3 is higher than that of Ln(OTf)3 in several cases.

Catalytic asymmetric aza Diels-Alder reactions using a chiral lanthanide Lewis acid. Enantioselective synthesis of tetrahydroquinoline derivatives using a catalytic amount of a chiral source

Abstract In the presence of a catalytic amount of the chiral ytterbium Lewis acid, which was prepared from Yb(OTf) 3 , (R)-(+)-BINOL, diazabicyclo[5.4.0]undec-7-ene (DBU), and an additive, achiral imines reacted with achiral dienophiles to afford the corresponding tetrahydroquinoline derivatives in high yields with high diastereo- and enantioselectivities. This is the first example of aza Diels-Alder reactions using a catalytic amount of a chiral source.

Scandium trifluoromethanesulfonate (Sc(OTf)3). A novel reusable catalyst in the Diels-Alder reaction

Scandium trifluoromethanesulfonate (Sc(OTf)3) is found to be quite effective as a Lewis acid catalyst in the Diels-Alder reaction. The novel catalyst is available in both aqueous and organic media, is easily recovered from aqueous layer after the reaction is completed, and can be reused.

Three-component carbon–carbon bond-forming reactions catalyzed by a Brønsted acid–surfactant-combined catalyst in water

Abstract Reactions of aldehydes, amines, and various nucleophiles such as silyl enolates, ketones, Danishefskys diene, and allyltribuyltin in water were successfully carried out in the presence of p-dodecylbenzenesulfonic acid (DBSA) as a Bronsted acid–surfactant-combined catalyst.

Multistep continuous-flow synthesis of (R)- and (S)-rolipram using heterogeneous catalysts

Chemical manufacturing is conducted using either batch systems or continuous-flow systems. Flow systems have several advantages over batch systems, particularly in terms of productivity, heat and mixing efficiency, safety, and reproducibility. However, for over half a century, pharmaceutical manufacturing has used batch systems because the synthesis of complex molecules such as drugs has been difficult to achieve with continuous-flow systems. Here we describe the continuous-flow synthesis of drugs using only columns packed with heterogeneous catalysts. Commercially available starting materials were successively passed through four columns containing achiral and chiral heterogeneous catalysts to produce (R)-rolipram, an anti-inflammatory drug and one of the family of γ-aminobutyric acid (GABA) derivatives. In addition, simply by replacing a column packed with a chiral heterogeneous catalyst with another column packed with the opposing enantiomer, we obtained antipole (S)-rolipram. Similarly, we also synthesized (R)-phenibut, another drug belonging to the GABA family. These flow systems are simple and stable with no leaching of metal catalysts. Our results demonstrate that multistep (eight steps in this case) chemical transformations for drug synthesis can proceed smoothly under flow conditions using only heterogeneous catalysts, without the isolation of any intermediates and without the separation of any catalysts, co-products, by-products, and excess reagents. We anticipate that such syntheses will be useful in pharmaceutical manufacturing.

Asymmetric Carbon–Carbon Bond Formation under Continuous-Flow Conditions with Chiral Heterogeneous Catalysts

Catalytic asymmetric carbon-carbon bond-forming reactions provide one of the most efficient ways to synthesize optically active compounds, and, accordingly, many chiral catalysts for these reactions have been developed in the past two decades. However, the efficiency of the catalysts in terms of turnover number (TON) is often lower than that of some other reactions, such as asymmetric hydrogenation, and this has been one of the obstacles for industrial applications. Although there are some difficulties in increasing the efficiency, the issues might be solved by using continuous flow in the presence of chiral heterogeneous catalysts. Indeed, continuous-flow systems have several advantages over conventional batch systems. Here we summarize the recent progress in asymmetric C-C bond-forming reactions under continuous-flow conditions with chiral heterogeneous catalysts.

Scandium trisdodecylsulfate (STDS). A new type of lewis acid that forms stable dispersion systems with organic substrates in water and accelerates aldol reactions much faster in water than in organic solvents

Abstract A new type of Lewis acid, scandium trisdodecylsulfate (STDS), was prepared. In the presence of a catalytic amount of STDS, aldol reactions of silyl enol ethers with aldehydes proceeded smoothly in water without using any organic solvents. It was proven that stable dispersion systems including the catalyst and organic substrates were formed in water and that catalytic activity in water was much higher than that in organic solvents. As far as we know, this is the first example of Lewis acid catalysis in stable dispersion system in water.

Lewis acid catalysis in micellar systems. Sc(OTf)3-Catalyzed aqueous aldol reactions of silyl enol ethers with aldehydes in the presence of a surfactant

Abstract Scandium triflate (Sc(OTf) 3 )-catalyzed aldol reactions of silyl enol ethers with aldehydes were successfully carried out in micellar systems. While the reactions proceeded sluggishly in water, remarkable enhancement of the reactivity was observed in the presence of a small amount of a surfactant. In these systems, versatile carbon-carbon bond-forming reactions proceeded in water without using any organic solvents.

Specificity of inhibitors of serine palmitoyltransferase (SPT), a key enzyme in sphingolipid biosynthesis, in intact cells. A novel evaluation system using an SPT-defective mammalian cell mutant.

In the present study, we demonstrate a model cell system for evaluating the specificity of inhibitors of serine palmitoyltransferase (SPT), the enzyme that catalyzes the first step of sphingolipid biosynthesis. The LY-B strain is a Chinese hamster ovary (CHO) cell mutant defective in SPT, and the LY-B/cLCB1 strain is a genetically corrected revertant of the mutant. Although LY-B cells grew only slightly in sphingolipid-deficient medium, their growth was restored to the level of LY-B/cLCB1 cells under sphingosine-supplied conditions, indicating that, in CHO cells, the growth inhibition caused by SPT inactivation was rescued almost fully by the metabolic complementation of sphingolipids. Cultivation of LY-B/cLCB1 cells in sphingolipid-deficient medium in the presence of 10 microM sphingofungin B and ISP-1 (myriocin, thermozymocidin), potent inhibitors of SPT activity, caused severe growth inhibition with approximately 95% inhibition of de novo sphingolipid synthesis. The growth inhibition by sphingofungin B and ISP-1 was rescued substantially by exogenous sphingosine, whereas the cytotoxicity of two other types of SPT inhibitor, L-cycloserine and beta-chloro-L-alanine, was hardly rescued. Similar cytotoxic patterns of these inhibitors also were observed on the growth of SPT-defective LY-B cells cultured under sphingosine-supplied conditions. The SPT inhibitors did not affect metabolic conversion of exogenous [(3)H]sphingosine to complex sphingolipids. Thus, the cytotoxicity of sphingofungin B and ISP-1, but not L-cycloserine or beta-chloro-L-alanine, is due largely to inhibition of sphingolipid synthesis by inhibiting the SPT activity.

Aerobic oxidative esterification of alcohols catalyzed by polymer-incarcerated gold nanoclusters under ambient conditions

Environmentally benign aerobic oxidation of alcohols to methyl esters catalyzed by polymer-incarcerated gold nanoclusters (PI-Au) was developed and reactions proceeded under very mild conditions. The catalyst could be recovered by simple operations without significant loss of activity.