One-pot Tandem Coupling Method for the Short Step Formal Synthesis of Riccardin C

One-pot reactions reduce reagent amounts and circumvent process treatments, such as work-up and purifications in multi-step reactions. In this study, we achieved the formal total synthesis of riccardin C through a one-pot reaction by simultaneously linking four units through two Sonogashira coupling reactions and one Suzuki coupling reaction, followed by reduction and deprotection. Thus, this one-pot method comprised five steps and did not require the purification of intermediate reaction mixtures, which saves resources, such as reagents and solvents, and expedites the work process.


Chlamydial Infection-Dependent Synthesis of Sphingomyelin as a Novel Anti-Chlamydial Target of Ceramide Mimetic Compounds

International Journal of Molecular Sciences


Practical Method for Hydroxyl-Group Protection Using Strontium Metal and Readily Available Silyl Chlorides

We have found that the etherification of silyl-protected secondary alcohols proceeds smoothly in the presence of strontium metal using silyl chloride instead of the expensive, yet more reactive, and commonly used silyl triflate. The reaction occurred almost completely with various alcohols.


Chemoselective Ketone Synthesis by the Strontium-mediated Alkylation or Arylation of N,N-Dimethylamides or Urea


Three-component, one-pot tandem Sonogashira/Suzuki-Miyaura coupling reactions for the synthesis of a library of ceramide-transport protein inhibitors that were designed in silico

We have developed a onepot, tandem Sonogashira/SuzukiMiyaura coupling reaction, which is unknown synthetically, and applied it for the synthesis of a library of potential natural ligand nonmimetic inhibitors of the lipidtransfer protein, ceramidetransport protein (CERT). The characteristic feature of this reaction is that the twostep coupling reaction proceeds smoothly with only 5 mol% of palladium catalyst. Furthermore, the location of the formed carboncarbon bond would be strictly defined because of the difference in reactivity. Therefore, many derivatives could be synthesized in high yields without the formation of regioisomeric byproducts by the same procedure. We also performed a semigram scale synthesis of several derivatives to provide the bioactive assey. After synthesizing as many as 113 derivatives, we identified a nonnatural mimetic inhibitor with activity comparable to that of the known inhibitor (1R,3S)-HPA-12.


Methoxycarbonyl Group as a Conformational Regulator for the Benzene Ring of Triphenylamines


Natural ligand-nonmimetic inhibitors of the lipid-transfer protein CERT. (N.N., M.U., and S.S. equally contributed to this study and are the co-first authors)

Lipid transfer proteins mediate inter-organelle transport of membrane lipids at organelle contact sites in cells, playing fundamental roles in the lipidome and membrane biogenesis in eukaryotes. We previously developed a ceramide-mimetic compound as a potent inhibitor of the ceramide transport protein CERT. Here we develop CERT inhibitors with structures unrelated to ceramide. To this aim, we identify a seed compound with no ceramide-like structure but with the capability of forming a hydrogen-bonding network in the ceramide-binding START domain, by virtual screening of ~3×106 compounds. We also establish a surface plasmon resonance-based system to directly determine the affinity of compounds for the START domain. Then, we subject the seed compound to a series of in silico docking simulations, efficient chemical synthesis, affinity analysis, protein-ligand co-crystallography, and various in vivo assays. This strategy allows us to obtain ceramide-unrelated compounds that potently inhibited the function of CERT in human cultured cells.


Aerobic oxidation of alcohols using bismuth bromide as a catalyst

We developed an environmentally friendly method for aerobic oxidation of alcohols using a commercially available, relatively benign bismuth salt as a catalyst. We found that the catalytic combination of BiBr3 with nitric acid is key for enhancing the reactivity. The reaction proceeds well under air, making the use of pure oxygen unnecessary. Each of the primary or secondary alcohols tested was oxidized to the corresponding aldehydes or ketones using this protocol.


Environmentally Benign Ritter Reaction Using Bismuth Salt as a Catalyst

We developed the environmentally benign Ritter reaction using commercially available, less harmful bismuth salt as a catalyst. The reaction proceeded smoothly even using stoichiometric amount of nitrile to alcohol without any solvents. We also succeeded in establishing a purification process without using any organic solvents.


Strontium-mediated selective protonation of unsaturated linkage of aromatic hydrocarbons and these derivatives


Superior Alkylating Agents for Bulky Esters/Ketones via Strontium-Mediated Barbier-Type Reaction


Selective Hydrogenation of Nitriles to Primary Amines Catalyzed by a Polysilane/SiO2-Supported Palladium atalyst unde Continuous-Flow Conditions


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


Catalytic Flow Hydrogenation of Aromatic Nitro Compounds Using Polysilane-Supported Palladium


Catalytic Organic Reactions on the Surface of Silver(I) Oxide in Water


Allylation reactions of aldehydes with allylboronates in aqueous media: unique reactivity and selectivity that are only observed in the presence of water.

Zn(OH)2-catalyzed allylation reactions of aldehydes with allylboronates in aqueous media have been developed. In contrast to conventional allylboration reactions of aldehydes in organic solvents, the -addition products were obtained exclusively. A catalytic cycle in which the allylzinc species was generated through a B-to-Zn exchange process is proposed and kinetic studies were performed. The key intermediate, an allylzinc species, was detected by HRMS (ESI) analysis and by online continuous MS (ESI) analysis. This analysis revealed that, in aqueous media, the allylzinc species competitively reacted with the aldehydes and water. An investigation of the reactivity and selectivity of the allylzinc species by using several typical allylboronates (6a-6d) clarified several important roles of water in this allylation reaction. The allylation reactions of aldehydes with allylboronic acid 2,2-dimethyl-1,3-propanediol esters proceeded smoothly in the presence of catalytic amounts of Zn(OH)2 and achiral ligand 4d in aqueous media to afford the corresponding syn-adducts in high yields with high diastereoselectivities. In all cases, the -addition products were obtained and a wide substrate scope was tolerated. Furthermore, this reaction was applied to asymmetric catalysis by using chiral ligand 9. Based on the X-ray structure of the Zn-9 complex, several nonsymmetrical chiral ligands were also found to be effective. This reaction was further applied to catalytic asymmetric alkylallylation, chloroallylation, and alkoxyallylation processes and the synthetic utility of these reactions has been demonstrated.


Revised stereochemistry of ceramide-trafficking inhibitor HPA-12 by X-ray crystallography analysis.

In response to Berkeš's report revising the stereochemistry of HPA-12, an important ceramide-trafficking inhibitor that was discovered and synthesized and its stereochemistry determined in 2001, the synthesis and the stereochemistry were reinvestigated. A large-scale synthetic method for HPA-12 based on a Zn-catalyzed asymmetric Mannich-type reaction in water was developed. Single crystals of HPA-12 for X-ray crystallographic analysis were obtained from ethyl propionate/n-hexane, and the stereochemistry was definitely determined to be 1R,3S, consistent with Berkeš's revised structure.


Chiral copper(II)-catalyzed enantioselective boron conjugate additions to ,-unsaturated carbonyl compounds in water.


Chiral-Sc catalyzed asymmetric Michael addition/protonation of thiols with enones in water.

Asymmetric Michael reactions and enantioselective protonations between enones and thiols were catalyzed by a Sc(OTf)(3)-chiral 2,2'-bipyridine complex in water. The remarkable governing of the enantioselectivity for simple introduction of protons despite their abnormally high mobility in water may provide us with new synthetic opportunities as well as significant chemical advances.


Several bismuth-catalyzed synthetic reactions, which proceed well in aqueous media, are discussed. Due to increasing demand of water as a solvent in organic synthesis, catalysts that can be used in aqueous media are becoming more and more important. Although bismuth Lewis acids are not very stable in water, it has been revealed that they can be stabilized by basic ligands. Chiral amine and related basic ligands combined with bismuth Lewis acids are particularly useful in asymmetric catalysis in aqueous media. On the other hand, bismuth hydroxide is stable and works as an efficient catalyst for carbon-carbon bond-forming reactions in water.


Chiral zinc-catalyzed asymmetric -alkylallylation and -chloroallylation of aldehydes.


Chiral Sc-catalyzed asymmetric Michael reactions of thiols with enones in water.

Asymmetric Michael reactions of thiols with enones were catalyzed by a Sc(OTf)(3)-chiral bipyridine complex at room temperature in water without using any organic solvents, to afford the desired sulfides in high yields with high enantioselectivities.


Copper(II) and Bismuth(III) Hydroxide Catalyzed Addition Reactions of Hydrazonoester with Allenylboronate in Aqueous Media


Silver Oxide as a Novel Catalyst for CarbonCarbon Bond-forming Reactions in Aqueous Media


Aldehyde allylation with allylboronates providing alpha-addition products.

Zn(OH)(2)-catalyzed allylation reactions of allylboronates with aldehydes proceeded smoothly in aqueous media; when alpha-substituted allylboronates were employed, the alpha-addition products were obtained exclusively, and syn-adducts were formed selectively in most cases; the use of Zn(OH)(2) with dmp (ligand) in aqueous media is the key to these reactions.


A gold-immobilized microchannel flow reactor for oxidation of alcohols with molecular oxygen.

Golden capillaries: A gold-immobilized capillary column reactor allows oxidation of alcohols to carbonyl compounds using molecular oxygen. These capillary columns (see picture) can be used for at least four days without loss of activity.


Catalytic use of indium(0) for carbon-carbon bond transformations in water: general catalytic allylations of ketones with allylboronates.

We have discovered the unprecedented catalytic use of In(0) for catalytic C-C bond transformations. Remarkably, these general catalytic allylations of ketones proceeded smoothly in water as a sole solvent under mild conditions, and water proved to be essential for these reactions. Both the displayed substrate scope and the functional group tolerance were excellent. Importantly, the In metal catalyst could be easily recovered and reused without loss of catalytic activity. Moreover, when an alpha-substituted allylboronate was used, an unusual constitutional selectivity was observed providing exclusively the formal alpha-adduct. Additionally, the resulting tertiary homoallylic alcohols were obtained with exceptionally high diastereoselectivities. The applicability of this concept to asymmetric catalysis in water by using In(0) combined with a chiral bis(oxazoline) ligand was demonstrated as well.

Journal of the American Chemical Society


Immobilization of ruthenium in organic-inorganic hybrid copolymers: a reusable heterogeneous catalyst for oxidation of alcohols with molecular oxygen.

A novel organic-inorganic hybrid ruthenium (HB Ru) catalyst for the oxidation of alcohols with molecular oxygen has been developed. The catalyst was prepared from a polystyrene-based copolymer, which includes a trimethoxysilyl functionality, and dichlorotris(triphenylphosphine)ruthenium, [RuCl2(PPh3)3], as the metal source. A sol-gel process was employed for heterogenization of the catalyst. The choice of both ruthenium species and trialkoxysilyl-bearing monomers was found to be important for high catalytic activity. In the presence of HB Ru corresponding to 5 mol % loading of ruthenium, the alcohols were oxidized with molecular oxygen or air at atmospheric pressure without any additives to afford the corresponding aldehydes or ketones in good to excellent yields. The catalyst could be recovered and reused at least five times without loss of activity.


Development of microchannel reactors using polysilane-supported palladium catalytic systems in capillaries.

A new method of immobilizing Pd catalysts on the channel wall of a capillary by using polysilane with metal oxide has been developed, and applied to hydrogenation reactions.


An air-stable chiral Hf-based catalyst for asymmetric Mannich-type reactions


Polymer Incarcerated Ruthenium Catalyst for Oxidation of Alcohols with Molecular Oxygen


Storable, powdered chiral zirconium complex for asymmetric aldol and hetero Diels-Alder reactions.

A storable, powdered chiral zirconium catalyst for asymmetric aldol and hetero Diels-Alder reactions has been developed. The catalyst has the same activity as that prepared in situ even after being stored for 3 months. Moreover, this chiral Zr catalyst worked efficiently not only for asymmetric aldol reactions but also for asymmetric hetero Diels-Alder reactions affording the corresponding addition products with high enantioselectivities.


Toward the total synthesis of onchidin, a cytotoxic cyclic depsipeptide from a mollusc.

The total synthesis of onchidin (1), a cytotoxic, C2-symmetric cyclic decadepsipeptide from a marine mollusc, according to the published structure, is described. A novel beta-amino acid, (2S,3S)-3-amino-2-methyl-7-octynoic acid (AMO), was efficiently prepared in high yield with high diastereo- and enantioselectivity based on a catalytic asymmetric three-component Mannich-type reaction with a chiral zirconium catalyst. The formation of sterically unfavorable N-methyl amide and hindered ester bonds were successfully demonstrated, and final macrocyclization was achieved at a secondary-amide site. Completion of the synthesis of 1 suggested that a revision of the structure of the natural product is required. Two diastereomers were also synthesized as candidates for the actual structure of onchidin. Furthermore, efficient solid-phase methods were employed for the combinatorial synthesis of other derivatives to clarify the real structure of onchidin. The solid-phase assembly of a pentadepsipeptide containing all the building blocks was established followed by dimeric cyclization in solution.


Polymer-Incarcerated Palladium with Active Phosphine as Recoverable and Reusable Pd Catalyst for the Amination of Aryl Chlorides


Instantaneous carbon-carbon bond formation using a microchannel reactor with a catalytic membrane.

Instantaneous catalytic carbon-carbon bond forming reactions were achieved in a microchannel reactor having a polymeric palladium complex membrane. The catalytic membrane was constructed inside the microchannel via self-assembling complexation at the interface between the organic and aqueous phases flowing laminarly, where non-cross-linked polymer-bound phosphine and ammonium tetrachloropalladate dissolved, respectively. A palladium-catalyzed coupling reaction of aryl halides and arylboronic acids was performed using the microchannel reactor to give quantitative yields of biaryls within 4 s of retention time in the defined channel region.


Supercooled micro flows and application for asymmetric synthesis.

Supercooled micro flow in microchannels was demonstrated. In order to clarify fundamental properties of the supercooling state in microchannels, freezing temperature was measured in the microchannels having widths ranging from 70 microm to 300 microm. The freezing temperature decreased with decreasing width of the microchannel when the microchannel wall was chemically modified with octadecylsilane group. The lowest freezing temperature was observed as -28 degrees C for water in the 70 microm wide microchannel. By contrast, the freezing temperature was -15 degrees C and did not depend on width when a microchannel with a bare glass surface was used. Next, the freezing point was measured with flow rates ranging from 0.1 to 2.0 microl min(-1) and no dependence on flow rate was observed. Then, the supercooled micro flow was applied to an asymmetric reaction in micro two-phase flow of aqueous and CH2Cl2 phases. As expected from thermodynamic prediction, enantiomeric selectivity increased in the supercooled state of water.


Continuous-flow chemical processing in three-dimensional microchannel network for on-chip integration of multiple reactions in a combinatorial mode


Surface modification method of microchannels for gas-liquid two-phase flow in microchips.

A capillarity restricted modification method for microchannel surfaces was developed for gas--liquid microchemical operations in microchips. In this method, a microstructure combining shallow and deep microchannels and the principle of capillarity were utilized for chemical modification of a restricted area of a microchannel. A hydrophobic--hydrophilic patterning in microchannels was prepared as an example for guiding gas and liquid flows along the respective microchannels. Validity of the patterning was confirmed by measuring aqueous flow leak pressure from the hydrophilic microchannel to the hydrophobic one. The leak pressure of 7.7-1.1 kPa agreed well with that predicted theoretically from the Young-Laplace equation for the microchannel depth of 8.6-39 microm. In an experiment to demonstrate usefulness and effectiveness of the method, an air bubble was first introduced into the hydrophilic microchannel and purged from the hydrophobic-hydrophilic patterned microchannels. Next, the patterning structure was applied to remove dissolved oxygen by contacting the aqueous flow with a nitrogen flow. The concentration of dissolved oxygen decreased with contact time, and its time course agreed well with numerical simulation. These demonstrations showed that the proposed patterning method can be used in general microfluidic gas-liquid operations.


A microfluidic device for conducting gas-liquid-solid hydrogenation reactions.

We have developed an efficient system for triphase reactions using a microchannel reactor. Using this system, we conducted hydrogenation reactions that proceeded smoothly to afford the desired products quantitatively within 2 minutes for a variety of substrates. The system could also be applied to deprotection reactions. We could achieve an effective interaction between hydrogen, substrates, and a palladium catalyst using extremely large interfacial areas and the short path required for molecular diffusion in the very narrow channel space. This concept could be extended to other multiphase reactions that use gas-phase reagents such as oxygen and carbon dioxide.


Air-stable, storable, and highly efficient chiral zirconium catalysts for enantioselective Mannich-type, aza Diels-Alder, aldol, and hetero Diels-Alder reactions.

For the synthesis of optically active compounds, chiral catalysts have attracted much attention because large quantities of optically active molecules can be prepared from a small amount of a chiral source. However, many chiral catalysts are often unstable in air (oxygen) and/or in the presence of water. This is especially the case in chiral Lewis acid catalysis, because most Lewis acids are air- and moisture-sensitive. Therefore, many catalysts are prepared in situ in an appropriate solvent just before use, and they cannot be stored for extended periods. We have developed air-stable, storable, and highly efficient chiral zirconium Lewis acids. The catalysts promoted asymmetric Mannich-type, aza Diels-Alder, aldol, and hetero Diels-Alder reactions efficiently with high enantioselectivities. A key to stabilizing the catalysts is an appropriate combination of chiral zirconium Lewis acids with molecular sieves, and the zirconium-molecular sieves-combined catalysts can be stored for extended periods in air at room temperature without loss of activity. Moreover, it has been demonstrated that the catalysts can be recovered and reused.

Proceedings of the National Academy of Sciences of the United States of America


An air-stable, storable chiral zirconium catalyst for asymmetric aldol reactions.

Asymmetric aldol reactions of ketene silyl acetals with aldehydes using an air-stable, storable chiral zirconium catalyst, which could be stored for at least 13 weeks at room temperature, proceeded smoothly to afford the desired adducts in high yields with high selectivity.


Phase-transfer alkylation reactions using microreactors.

Phase-transfer alkylation in a microreactor proceeds smoothly, and the reaction has been found to be more efficient than that in a round-bottomed flask with vigorous stirring; we have observed by an optical microscope study that an interfacial area provided by organic and aqueous phases is more extended in a microreactor.


Catalytic Asymmetric Mannich-Type Reactions Using a Novel Chiral Iron Complex


Catalytic Enantioselective Addition of Propionate Units to Imines: An Efficient Synthesis of anti--Methyl--Amino Acid Derivatives


Air-Stable, Storable, and Highly Selective chiral Lewis Acid Catalyst


A Novel Inhibitor of Ceramide Trafficking from the Endoplasmic Reticulum to the Site of Sphingomyelin Synthesis

Ceramide produced at the endoplasmic reticulum (ER) is transported to the lumen of the Golgi apparatus for conversion to sphingomyelin (SM). N-(3-Hydroxy-1-hydroxymethyl-3-phenylpropyl)dodecanamide (HPA-12) is a novel analog of ceramide. Metabolic labeling experiments showed that HPA-12 inhibits conversion of ceramide to SM, but not to glucosylceramide, in Chinese hamster ovary cells. Cultivation of cells with HPA-12 significantly reduced the content of SM. HPA-12 did not inhibit the activity of SM synthase. The inhibition of SM formation by HPA-12 was abrogated when the Golgi apparatus was made to merge with the ER by brefeldin A. Moreover, HPA-12 inhibited redistribution of a fluorescent analog of ceramide, N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-pentanoyl)-d-erythro-sphingosine (C(5)-DMB-Cer), from intracellular membranes to the Golgi region. Among four stereoisomers of the drug, (1R,3S)-HPA-12, [corrected] which resembles natural ceramide stereochemically, was found to be the most active, although (1R,3S)-HPA-12 [corrected] did not affect ER-to-Golgi trafficking of protein. Interestingly, (1R,3S)-HPA-12 [corrected] inhibited conversion of ceramide to SM little in mutant cells defective in an ATP- and cytosol-dependent pathway of ceramide transport. These results indicated that (1R,3S)-HPA-12 [corrected] inhibits ceramide trafficking from the ER to the site of SM synthesis, possibly due to an antagonistic interaction with a ceramide-recognizing factor(s) involved in the ATP- and cytosol-dependent pathway.


Catalytic enantioselective synthesis of a novel inhibitor of ceramide trafficking, (1R,3R)-N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl)dodecanamide (HPA-12)


A novel chiral zirconium catalyst for enantioselective aldol and Mannich-type reactions. Catalytic activation of both aldehydes and imines using a similar chiral Lewis acid


Enantioselective Mannich-Type Reactions Using a Novel Chiral Zirconium Catalyst for the Synthesis of Optically Active -Amino Acid Derivatives

Journal of the American Chemical Society


Catalytic Asymmetric Synthesis of Antimalarial Alkaloids Febrifugine and Isofebrifugine and Their Biological Activity.

Antimalarial alkaloids febrifugine (1) and isofebrifugine (2) were efficiently synthesized from simple achiral starting materials on the basis of the catalytic asymmetric synthesis. The first key reaction was performed using the tin(II)-mediated catalytic asymmetric aldol protocol to afford chiral aldehyde 3 in high yield with high diastereo- and enantioselectivities. The second key step, a Mannich-type reaction, did not give satisfactory results according to the conventional methods. We then developed a novel aqueous Mannich-type three-component reaction of an aldehyde, an amine, and a vinyl ether using a Lewis acid-surfactant combined catalyst (LASC), and the key intermediates 16 and 17 were obtained in high yields. The final coupling reactions of bromoacetone 14 with 4-hydroxyquinazoline were carried out using basic conditions, and successive deprotection gave 1 and 2, respectively, without any isomerization. These unambiguous total asymmetric syntheses revealed that the absolute configurations of febrifugine and isofebrifugine were not (2'S,3'R) and (2'R,3'R) as reported previously but (2'R,3'S) and (2'S,3'S), respectively (1' and 2'). Finally, antimalarial activities of the synthesized febrifugine and isofebrifugine, and their antipodes, were examined. It was revealed that the activities and selectivities of natural febrifugine and isofebrifugine were much higher than those of the antipodes.


Catalytic asymmetric synthesis of febrifugine and isofebrifugine


Catalytic Asymmetric Synthesis of Both Syn- and Anti--Amino Alcohols


Facile Synthesis of -Amino Nitriles Using Lanthanide Triflate as a Lewis Acid Catalyst


Catalytic Enantioselective Mannich-Type Reactions Using a Novel Chiral Zirconium Catalyst