First synthesis of (±)-halichonadins A-D.

Described herein is the first total synthesis of a marine isocyanide terpene, (±)-halichonadin C. Our synthetic strategy features nitrile-to-isocyanide interconversion utilizing hypervalent iodine-promoted Hofmann rearrangement. This approach led to successful construction of an isocyanide group at the stereochemically encumbered C-6 position in (±)-halichonadin C. Furthermore, in accord with a scenario we propose for the biosynthesis of halichonadins A-D, (±)-halichonadin C was transformed to halichonadins A and B via the missing link intermediate, halichonadin isocyanate.

Continuous-flow electrorotation (cROT): improved throughput characterization for dielectric properties of cancer cells.

This paper presents the concept of a newly developed high-throughput measurement device for determining the dielectric properties of cancer cells. The proposed continuous-flow electrorotation (cROT) device can induce electrorotation (ROT) with vertical rotation using two sets of interdigitated electrodes on the top and bottom substrates to torque the cells. In the developed device, multiple rotating cells flowing in a microchannel are aligned between electrodes using dielectrophoresis. This allows for the measurement of the rotational behavior of the cells with continuous flow, resulting in a significant improvement in throughput compared to the conventional ROT devices reported previously. The dielectric properties, permittivity of the cell membrane and conductivity of the cell cytoplasm, of HeLa cells obtained by simultaneous measurements using the developed cROT device were 9.13 ± 1.02 and 0.93 ± 0.10 S m-1, respectively. Moreover, the measurement throughput was successfully increased to 2700 cells per h using the cROT technique.

Bioinspired total synthesis of boneratamides A-C.

We disclose the first synthesis of the marine natural product, (+)-boneratamide A, whose structure is composed of a terpene unit linked via an amide bond to a pyroglutamic acid moiety. The key step in this route is a bioinspired Ugi reaction of (+)-axisonitrile-3 with acetone as the carbonyl component and L-glutamic acid. This reaction brings about a remarkably efficient, one-pot assembly of reaction components concomitant with γ-lactam ring formation to produce (+)-boneratamide A in 70% yield. (+)-Boneratamide B and (-)-boneratamide C methyl esters were also synthesized using a similar bioinspired strategy, and the relative stereochemistries at the stereogenic centers in these substances were elucidated using X-ray analysis.

Development of a Flexible MEMS Sensor for Subsonic Flow.

Detection and control of flow separation is a key to improving the efficiency of fluid machinery. In this study, we developed a flexible MEMS (microelectromechanical systems) sensor for measuring the wall shear stress and flow angle in subsonic airflow. The developed sensor is made of a flexible polyimide film and a microheater surrounded by three temperature sensor pairs. The sensor measures the wall shear stress from the heater output and the flow angle from the temperature gradient around the heater. The geometry and design of the heater and temperature sensors were determined based on numerical simulations. To evaluate the validity of the sensor, we conducted an experiment to measure the wall shear stress and the flow angle in a wind tunnel in different velocities ranging from 30 m/s to 170 m/s, equivalent to Mach numbers from 0.1 to 0.5. The heater output was proportional to one-third power of the wall shear stress. Additionally, the bridge output correlating the temperature difference between two opposing temperature sensors showed sinusoidal variation depending on the flow angle. Consequently, we have clarified that the developed sensor can measure both the wall shear stress and flow direction in subsonic flow.

Efficient nanoparticle focusing utilizing cascade AC electroosmotic flow.

This study presents on-chip continuous accumulation and concentration of nanoscale samples using a cascade alternating current electroosmosis (cACEO) flow. ACEO can generate flow motion caused by ion movement due to interactions between the AC electric field and the induced charge layer on the electrode surface, with the potential to accumulate particles, especially in low-conductive liquid. However, the intrinsic particle diffusive motion, which is sensitive to particle size, is an essential element influencing accumulation efficiency. In this study, an electrode combining chevron and double-gap geometry embedded in a microfluidic channel was developed to perform efficient three-dimensional (3D) nanoparticle focusing using ACEO. The chevron electrode pattern was introduced upstream of the focusing zone to overcome particle accumulation in scattering zones near the channel sidewall. To demonstrate the efficiency of the proposed device for particle accumulation, three nanoparticle types were used: latex, metal, and biomaterial. Continuous 3D concentration of 50-nm polystyrene particles was confirmed. The concentration factor, determined based on image processing, became quite high when 50-nm gold nanoparticles were used. Moreover, nanoparticles with a 20-nm diameter were accumulated using cACEO. Finally, we used the concentrator chip to accumulate 50-nm liposome particles, confirming that the device could also successfully concentrate biomaterials.

Gap Effect on Electric Field Enhancement and Photothermal Conversion in Gold Nanostructures.

Plasmonic optical tweezers and thermophoresis are promising tools for nanomaterial manipulation. When a gold nanostructure is irradiated with laser light, an electric field around the nanostructure is enhanced because of the localized surface plasmon resonance, which increases the optical radiation pressure applied to the nanomaterials. In addition, a temperature gradient is also generated by the photothermal conversion, and thermophoretic force is then generated. This study numerically evaluated the electric and temperature fields induced by the localized surface plasmon resonance between two gold nanostructures. Here, we focused on the effect of the gap width between nanostructures on the optical radiation pressure and thermophoretic force. The simulation results show that the electric field is locally enhanced according to the gap width, but the effect on the temperature rise due to the photothermal heating is small. This fact suggests that the gap effect between the nanostructures is particularly dominant in nanomanipulation using optical force, whereas it has little effect in nanomanipulation using thermophoresis.

Determining particle depth positions and evaluating dispersion using astigmatism PTV with a neural network.

Herein, a calibration procedure to determine the depth positions of particles in a microfluidic channel via astigmatism particle tracking velocimetry (APTV) has been described. A neural network model focusing on the geometrical parameters of distorted particle images was developed to calibrate APTV. To demonstrate the efficiency of this procedure, the Poiseuille flow and depth of the particles, and dispersions in the microchannel were studied. The depth positions were determined with an uncertainty of ±1µm. The present results suggest that the particle position dispersion could be a result of the degree of particle image deformation and its deviation.

Protecting group-free method for synthesis of N-glycosyl carbamates and an assessment of the anomeric effect of nitrogen in the carbamate group.

The first protecting group-free synthesis of N-glycosyl carbamates has been developed through reaction of d-glucose with n-butyl carbamate in acidic aqueous media. The structures of the N-glucosyl carbamates were unambiguously determined by comparison with authentic samples, prepared using the isocyanide method. With this protective group-free method for synthesis of N-glycosyl carbamates in hand, an anomeric pair of N-xylopyranosyl carbamates were prepared and used to assess the anomeric effect of nitrogen in the carbamate group.

Total synthesis of exigurin: the Ugi reaction in a hypothetical biosynthesis of natural products.

The first total synthesis of a marine natural product, exigurin, has been accomplished in 13 steps starting from (+)-menthone. The key intermediate (-)-10-epi-axisonitrile-3 was prepared by stereoselective intramolecular cyclopropanation followed by a cyclopropane ring opening reaction by the azide anion. The bioinspired Ugi reaction of (-)-10-epi-axisonitrile-3, formaldehyde, sarcosine and methanol successfully constructed the target exigurin in which its terpene and amino acid units were linked through an amide bond.

Asymmetric organocatalytic desymmetrization of 4,4-disubstituted cyclohexadienones at high pressure: a new powerful strategy for the synthesis of highly congested chiral cyclohexenones.

A highly diastereoselective and enantioselective method for the asymmetric desymmetrization of 4,4-disubstituted cyclohexadienones using the Michael addition reaction of malonates under catalysis with the primary amine-thiourea conjugate catalyst and PPY at high pressure was developed.

Protecting group free synthesis of urea-linked glycoconjugates: efficient synthesis of ß-urea glycosides in aqueous solution.

A method for the protecting group free synthesis of ß-urea-linked glycoconjugates has been developed. The one step process, involving reactions between urea and D-glucose, N-acetyl-D-glucosamine or D-xylose in acidic aqueous solution, furnishes the corresponding ß-urea glycosides in modest yields. This simple and efficient procedure is applicable to the synthesis of ß-urea tethered amino acid-carbohydrate conjugates.

Aminohydroxyacetone synthons: versatile intermediates for the organocatalytic asymmetric aldol reaction.

A practical method for the synthesis of 1,3-aminohydroxyacetone synthons was developed, and their utility in the organocatalytic asymmetric aldol reaction was demonstrated in a short synthesis of aza-sugars.

Synthesis of manzacidin A and C: efficient construction of quaternary carbon stereocenters bearing nitrogen substituents.

An efficient synthetic method for stereoselective construction of asymmetric quaternary carbon stereocenters, bearing nitrogen in the form of Boc-protected allyl amines, has been developed. This methodology is employed in the synthesis of marine alkaloids, manzacidin A and C.

Asymmetric synthesis of (+)-geranyllinaloisocyanide: assignment of absolute stereochemistry.

The first nonracemic synthesis of (+)-geranyllinaloisocyanide, starting with (-)-lactic acid methyl ester, has been accomplished by exploiting a [3.3] sigmatropic rearrangement of allyl cyanate. The synthesis enables assignment of the S configuration of the C(3) isocyano substituted, quaternary stereogenic center in natural geranyllinaloisocyanide.

A new powerful strategy for the organocatalytic asymmetric construction of a quaternary carbon stereogenic center.

A new method for chiral diamine-catalyzed Robinson-type annulation was developed to construct cyclohexenone derivatives bearing a quaternary carbon stereogenic center at the 4-position in high enantiomeric excess. This method was successfully applied to the short synthesis of (+)-sporochnol A.

Synthesis of glycocinnasperimicin D.

The first total synthesis of amino sugar antibiotic glycocinnasperimicin D (1) has been achieved by a convergent, three-component coupling strategy. The key steps involve the Heck-Mizoroki reaction by using the iodophenyl glycoside 50 and acryl amide 32 to furnish the right core structure of 1, and the construction of the urea glycoside employing the reaction of glycosyl isocyanate 8 with amino sugar 9. Glycosyl isocyanate 8 was prepared by the oxidation of isonitrile 10, which displayed excellent reactivity in the coupling event. Synthetic roadblocks, encountered during this synthetic effort, have led to the development of the alpha-selective, Lewis acid catalyzed phenyl glycosylation process with 2-amino-hexopyranose and a procedure for acetonide deprotection without affecting the silyl ethers.

Synthesis of (-)-agelastatin A by [3.3] sigmatropic rearrangement of allyl cyanate.

Total synthesis of (-)-agelastatin A has been achieved starting from l-arabitol. The highlights in our synthesis include the preparation of vicinal diamine moiety by [3.3] sigmatropic rearrangement of allyl cyanate and construction of central ring-C with ring-closing metathesis.

Stereocontrolled route to vicinal diamines by [3.3] sigmatropic rearrangement of allyl cyanate: asymmetric synthesis of anti-(2R,3R)- and syn-(2R,3S)-2,3-diaminobutanoic acids.

A stereocontrolled route via allyl 1,2-diols to vicinal diamines based on the [3.3] sigmatropic rearrangement of allyl cyanate has been developed. Our approach consists of two consecutive steps: stereoselective construction of allyl anti- and syn-1,2-diols followed by [1,3]-chirality transfer by sigmatropic rearrangement, which allow an access to anti-(2R,3R)- and syn-(2R,3S)-2,3-diaminobutanoic acids. [reaction: see text]

A new approach to the neoglycopeptides: synthesis of urea- and carbamate-tethered N-acetyl-D-glucosamine amino acid conjugates.

A novel approach to the synthesis of Fmoc-protected neoglycopeptide building blocks is described. Oxidation of N-acetyl-D-glucosamine isonitrile afforded the corresponding highly reactive glycopyranosyl isocyanate, which reacted with amino acid derivatives to furnish the corresponding urea- and carbamate-tethered Fmoc-protected N-acetyl-D-glucosamine amino acid conjugates in good yields. [reaction: see text]

Synthesis of urea-tethered neoglycoconjugates and pseudooligosaccharides in water.

A novel approach to the synthesis of urea glycosides in aqueous media has been explored. Steyermark's glucopyranosyl oxazolidinone was found to be a good synthon for anchoring glucosyl moieties onto amines and thiols. The present method was successfully applied to establish a new route for the synthesis of urea-tethered neoglycoconjugates and pseudooligosaccharides in water.