Hidekazu Oyamada

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.

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.

Sodium Borohydride-t-butyl Alcohol-Methanol as an Efficient System for the Selective Reduction of Esters

Abstract Reduction of esters to the corresponding primary alcohols by metal hydrides is an important synthetic reaction.1 One may often encounter the problem of the selective reduction of esters in the presence of other functional groups such as amide, carboxylic acid or nitrile.2

Continuous flow hydrogenation using polysilane-supported palladium/alumina hybrid catalysts

Summary Continuous flow systems for hydrogenation using polysilane-supported palladium/alumina (Pd/(PSi–Al2O3)) hybrid catalysts were developed. Our original Pd/(PSi–Al2O3) catalysts were used successfully in these systems and the hydrogenation of unsaturated C–C bonds and a nitro group, deprotection of a carbobenzyloxy (Cbz) group, and a dehalogenation reaction proceeded smoothly. The catalyst retained high activity for at least 8 h under neat conditions.

Development of polysilane-supported palladium/alumina hybrid catalysts and their application to hydrogenation.

Novel immobilized Pd catalysts, polysilane-supported palladium/alumina hybrid catalysts, have been developed. The catalysts showed high catalytic activity for hydrogenation, and could be used in an organic solvent or under solvent-free conditions.

Polymer-supported acylhydrazones. Use in Sc(OTf)3-catalyzed Mannich-type reactions providing an efficient method for the preparation of diverse pyrazolone derivatives

Polymer-supported acylhydrazones, prepared from polystyrene resin (1%-divinylbenzene), reacted with ketene silyl acetals in the presence of a catalytic amount of scandium triflate (Sc(OTf)3), to afford the corresponding β-hydrazinoesters, which were cyclized and cleaved from the support simultaneously by treatment with a base to produce diverse pyrazolone derivatives.

Asymmetric reduction of prochiral 3-aryl-3-oxoesters with lithium borohydride using N,N′-dibenzoylcystine as a chiral auxiliary

Optically active 3-aryl-3-hydroxyesters of high enantiomeric excess (80–92% e.e.) are obtained by the reduction of 3-aryl-3-oxoesters with lithium borohydride which has been chirally modified with N,N′-dibenzoylcystine and t-butyl alcohol.

Polysilane-supported Pd and Pt nanoparticles as efficient catalysts for organic synthesis

Polysilane-supported Pd and Pt catalysts have been prepared for the first time, and used successfully in hydrogenation, Suzuki and Sonogashira reactions, and hydrosilylation respectively: the reactions proceeded in high yields, and the catalysts could be recovered almost quantitatively by simple filtration and reused.

Methylphosphinyl (Dmp): A new protecting group of tyrosine suitable for peptide synthesis by use of boc-amino acids

Abstract Use of dimethylphosphinyl (Dmp) group as a side-chain phenolic OH protecting group of tyrosine in peptide synthesis was studied. The Dmp group is resistant to trifluoroacetic acid and hydrogenolysis and removed by fluoride ion or liquid HF.

Powerful Continuous‐Flow Hydrogenation by using Poly(dimethyl)silane‐Supported Palladium Catalysts

We developed poly(dimethyl)silane‐supported Pd catalysts that are readily prepared from Pd(OAc)2, poly(dimethyl)silane, and Al2O3. The immobilization was achieved for the first time with a support that does not contain benzene rings. The Pd catalyst thus prepared was found to have higher hydrogenation activity than Pd/C. Furthermore, the catalyst was used in continuous‐flow hydrogenation with various substrates, including simple liquid substrates (neat) and dissolved solid substrates. Vegetable oils, squalenes, and phosphatidylcholine were successfully hydrogenated on gram to kilogram scales.