Login
Register

Tag: Nagoya Institute of Technology

A fresh perspective on Picket-Spengler reaction with α-ketoesters as new carbonyl source

Posted on by NITech

The asymmetric Pictet-Spengler reaction is an efficient method to synthesize chiral tetrahydro-β-carbolines—biologically active molecular structures with pharmacological properties. The synthesis involves an acid-catalyzed reaction between a carbonyl group and tryptamine. However, most of the reactions have been carried out using aldehydes as carbonyl compounds.

Now researchers in Japan have successfully synthesized pharmaceutical products using acyclic α-ketoesters as carbonyl compounds. This method can be used to synthesize a wider range of pharmaceutical compounds.

Chiral tetrahydro-β-carbolines or tryptolines that contain a tetrasubstituted carbon center provides a framework for a variety of biologically active compounds. This basic structure is found in naturally occurring compounds and is a necessary component for pharmaceutical products. The synthesis of the bioactive structure and its derivatives begins with the asymmetric Pictet-Spengler reaction, an acid-catalyzed reaction between a carbonyl group and an amine (tryptamine).

However, the range of compounds that can be synthesized by this method is limited as the carbonyl groups have mainly been derived from aldehydes. Given the importance of the Pictet-Spengler reaction in pharmaceutical product development, expanding the scope of the reaction by substituting in other carbonyl-containing compounds remains an active research area.

Now in a study published online on January 26, 2022 and in the 2022 February issue of Organic Letters, Professor Shuichi Nakamura and his team from Nagoya Institute of Technology and Osaka University, Japan, have successfully demonstrated the Pictet-Spengler reaction with acyclic α-ketoesters as the carbonyl source. “We succeeded in demonstrating the first enantioselective Pictet–Spengler reaction of acyclic α-ketoesters with tryptamines, and have recorded excellent yields and enantioselectivity for the reaction using chiral imidazoline-phosphoric acid catalysts, which was developed by our group”, says Prof. Nakamura.

Organic compounds, especially pharmaceuticals that contain a chiral carbon atom can form enantiomers, which are a pair of molecular structures that are non-superimposable mirror images of each other. As these isomers have different biological activities, selecting a particular isomer over its mirror image, i.e., ‘enantioselective synthesis,’ is one of the key criteria for the production of pharmaceuticals.

To obtain a favorable enantiomer with a high yield, the researchers initially studied the reaction between tryptamine and α-ketoesters in the presence of various chiral catalysts. Using alkyl 2-oxopentanoates as α-ketoesters, the highest yield (99%) and enantioselectivity (78%) was obtained when tryptamine was combined with alkyl 2-oxopentanoates containing an ethyl group in the presence of a chiral phosphoric acid catalyst with imidazoline groups (chiral bis-(imidazoline)-phosphoric acid catalysts).

After determining the optimal catalyst and the α-ketoester reactant, the researchers proceeded to synthesize a variety of tryptolines using tryptamines containing electron-donating or withdrawing groups. The reactions they carried out resulted in high yields and enantioselectivity, proving the validity of their method. “These results are the first examples of the enantioselective Pictet−Spengler reaction of acyclic α-ketoesters with tryptamines,” comments Prof. Nakamura.

The imidazoline group in the chiral catalyst was found to play a key role in the reaction, especially with the selection of the enantiomer and the activation of the tryptamine reactant. According to the researchers, the reaction occurs through the formation of two intermediates as a result of the interaction between the catalyst and the reactants. The initial reaction is proposed to occur between the catalyst and tryptamine to form an ammonium salt of tryptamine (the first intermediate). In turn, this compound is thought to react with the carbonyl group of the α-ketoester and produce a second ketimine intermediate, which ultimately results in the Pictet-Spengler product. Using density functional theory to study the transition states, the researchers found that the stereoselectivity or enantioselectivity of the final product resulted due to the formation of a sterically less-hindered (R)-isomer from the ketimine intermediate.

The results of the study could lead to the development of new pharmaceutical products with potentially significant impacts on improving human health. “We will be able to synthesize medicines that have been difficult to synthesize, which may improve the quality of our lives. It may also be possible to synthesize inexpensive agricultural chemicals, which may increase production of safe and secure food,” observes an optimistic Prof. Nakamura.

***

Reference

Title of original paper: Enantioselective Pictet−Spengler Reaction of Acyclic α‑Ketoesters

Using Chiral Imidazoline-Phosphoric Acid Catalysts

Journal: Organic Letters

DOI: https://doi.org/10.1021/acs.orglett.1c04316

Plumbing the Depths: Defect Distribution in Ion-Implanted SiC Diodes

Posted on by NITech

Researchers reveal that aluminum implantation doping in p-type bipolar semiconductors creates defects many layers deeper than the implantation site

Introducing a vertical arrangement of n and p layers into the drift layer of semiconductors to enable bipolar operation is a way around the ‘unipolar limit’ problem in semiconductors. But defect generation during the fabrication of such devices is a matter of concern. Researchers have examined the depth and distribution of defects formed by aluminum ion implantation in silicon carbide bipolar diodes to identify ways to induce efficient conductivity modulation.

Silicon carbide (SiC) unipolar semiconductors are in wide commercial use, but their operations are limited by a trade-off relationship between breakdown voltage and specific resistance of the drift layer, or specific on-resistance. Including a super junction structure, which refers to an arrangement of n and p layers in trenches in the drift layer, or enabling bipolar operation in the device, provides a way to overcome this unipolar limit. Bipolar operation brings about a large decrease in on-resistance by inducing a conductivity modulation in the drift layer. But bipolar operation is not without its disadvantages. Conduction and switching losses in bipolar devices need to be carefully balanced.

P-type contact layers in semiconductors are generally formed via aluminum (Al) doping. Al doping can be achieved in two ways – epitaxial or ion implantation. Epitaxial growth involves the layer by layer deposition of semiconductor materials on a substrate, whereas ion implantation entails bombarding the semiconductor layers with high energy charged particles. But ion implantation leads to the formation of defects deep in the semiconductor layers, which could have a critical effect on conductivity modulation.

In a recent study published in Physica Status Solidi (b), researchers from Japan investigated the depth distribution of defects in SiC bipolar diodes that were formed by Al doping. “Our findings will help with the optimum design of SiC power devices, which will soon be employed in electric vehicles, trains etc. These results will ultimately help improve the performance, as well as the size and energy consumption of traction systems in vehicles and trains,” says Associate Professor Dr. Masashi Kato of Nagoya Institute of Technology, who led the study.

To study the depth distribution of defects, the research team fabricated two SiC PiN diodes with Al doped p-layers, one through epitaxial growth and the other through ion implantation. They then studied the distribution of defects in both diodes using conventional ‘deep level transient spectroscopy’ (DLTS) and characterized its properties using cathodoluminescence (CL). They found that p-type layer deposition by epitaxial growth did not cause damage in the adjacent n-type layers, but that the growth showed slight instability that led to the formation of deep level defects. The specific on-resistance of this diode was also low, thanks to the effects of conductivity modulation.

For the diode formed by ion implantation, however, the researchers found that Al doping achieved a high specific on-resistance without influencing conductivity modulation. Moreover, the researchers observed that the defects in the semiconductor device penetrated to a minimum of 20 µm from the implantation region. “Our study shows that the ion implantation in SiC bipolar devices need to be processed at least 20 µm away from the active regions,” explains Dr. Kato.

The low power consumption of SiC power devices mean that they will be essential in the future as climate change increases and the fossil fuel energy crisis worsens. Improving semiconductor technology rapidly so that it can take its rightful place on the world stage is of paramount importance. With strong results like this to inform future research and manufacturing, we may realize this future sooner than expected!

Researchers determine the mechanisms of ion diffusion in phosphate glass 

Posted on by NITech

Phosphate glasses are expected to have applications in a variety of fields. To improve their functionality, it is necessary to determine the association between their structure and ion diffusion characteristics. Recently, using first-principles molecular dynamic simulations, researchers from Nagoya Institute of Technology, Japan, have provided novel insights into the ion diffusion mechanisms of phosphate glass, suggesting that ionic conductivity and glass solubility can be manipulated by controlling the morphology of the material.

Recently, a team of researchers from Nagoya Institute of Technology, Japan, led by Dr. Tomoyuki Tamura, has theoretically deciphered the ion diffusion mechanism involved in the hydration reaction process of phosphate glasses. Their study has been published in the Physical Chemistry Chemical Physics journal.

In fully connected P2O5-based phosphate glass, three of the oxygen atoms in each phosphate unit are bonded to neighboring phosphorous atoms. To study the dynamics of ions in the phosphate glass during the hydration process, the researchers used a model made of phosphates with QP2 and QP3 morphologies, that contain two and three bridging oxygens per PO4 tetrahedron, respectively, along with six coordinated silicon structures.

The researchers implemented a theoretical computational approach known as “first-principles molecular dynamic (MD) simulation” to investigate the diffusion of proton and sodium ions into the glass.

Explaining the rationale for their unconventional approach, Dr. Tamura says, “First-principles MD simulation enabled us to assume the initial stage of water infiltrating and diffusing into silicophosphate glass and elucidate the diffusion of protons and inorganic ions for the first time.”

Based on their observation, the researchers proposed a mechanism where the protons “hop” and are adsorbed onto the non-bridging oxygen or “dangling” oxygen atom of nearby phosphates through hydrogen bonds. However, in the phosphate glass model they used, the QP2 phosphate units contributed more strongly to the diffusion of protons than the QP3 phosphate units. Thus, they found that the morphology of the phosphate network structure, or the “skeleton” of the glass, greatly affects the diffusion of ions.

They also noticed that when a sodium ion was present in the vicinity, the adsorption of a proton onto a QP2 phosphate unit weakened the electrostatic interaction between sodium and oxygen ions, inducing the chain diffusion of sodium ions.

The demand for new biomaterials for effective prevention and treatment is on the rise, and phosphate glasses are well-poised to fulfil this growing need. A large proportion of the population, comprising both elderly and younger people, suffers from diseases related to bone and muscle weaknesses.

As Dr. Tamura surmises, “Water-soluble silicophosphate glass is a promising candidate for supplying drugs or inorganic ions that promote tissue regeneration, and our study takes the research in glass technology one step nearer towards realizing the goal.”

Scientists find a way to use visible light to decompose CO2 with high efficiency

Posted on by NITech

To tackle the challenge of global warming, scientists have been looking into green and sustainable methods of breaking down carbon dioxide in emissions and in the atmosphere. Now, a group of researchers from Nagoya Institute of Technology, Japan, have developed a novel, easy to synthesize composite compound that enables the efficient use of solar energy to reduce carbon dioxide, taking us one step closer to achieving a green economy.

A team of scientists led by Drs. Shinji Kawasaki and Yosuke Ishii from Nagoya Institute of Technology, Japan, has been at the forefront of efforts to achieve efficient solar-energy-assisted CO2 reduction. Their recent breakthrough is published in Nature’s Scientific
Reports.

Their research began with the need to solve the limited applicability problem of silver iodate (AgIO3), a photocatalyst that has attracted considerable attention for being useful for the CO2 reduction reaction. The problem is that AgIO3 needs much higher energy than that which visible light can provide to function as an efficient photocatalyst, and visible light is the majority of solar
radiation.

Scientists have attempted to work around this efficiency problem by combining AgIO3 with
silver iodide (AgI), which can efficiently absorb and utilize visible light. However, AgIO3–AgI composites have complicated synthesis processes, making their large-scale manufacturing impractical. Further, they don’t have structures that offer efficient pathways for the transfer of photoexcited electrons (electrons energized by light absorption) from AgI to AgIO3, which is key to the composite’s catalytic activity.

“We have now developed a new photocatalyst that incorporates single-walled carbon nanotubes (SWCNTs) with AgIO3 and AgI to form a three-component composite catalyst,” says Dr. Kawasaki, “The role of the SWCNTs is multimodal. It solves both the synthesis and
the electron transfer pathway problems.”

The three-component composite’s synthesis process is simple and involves just two steps: 1. Encapsulating iodine molecules within the SWCNT using an electrochemical oxidation method; and 2. Preparing the composite by immersing the resultant of the previous step in an aqueous solution of silver nitrate (AgNO3).

Spectroscopic observations using the composite showed that during the synthesis process, the encapsulated iodine molecules received charge from the SWCNT and converted into specific ions. These then reacted with AgNO3 to form AgI and AgIO3 microcrystals, which, due to the initial positions of the encapsulated iodine molecules, were deposited on all the SWCNTs uniformly. Experimental analysis with simulated solar light revealed that the SWCNTs also acted as the conductive pathway through which photoexcited electrons moved from AgI to AgIO3,  enabling the efficient reduction of CO2
to carbon monoxide (CO).

The incorporation of SWCNTs also allowed for the composite dispersion to be easily spray-coated on a thin film polymer to yield flexible photocatalytic electrodes that are versatile and can be used in various applications.

Dr Ishii is hopeful about their photocatalyst’s potential. “It can make the solar reduction of industrial CO2 emissions and atmospheric CO2 an easy-to-scale and sustainable renewable energy-based solution tackling global warming and climate change, making people’s lives safer and healthier,” he says.

The next step, the team says, is to explore the possibility of using their photocatalyst for solar hydrogen generation. Perhaps, humanity’s future is bright after all!

Researchers from Japan develop a model to explore the dynamics of movement in cheetahs

Posted on by NITech

In a new study, a team of researchers from Japan propose and validate an analytical model for studying cheetah galloping by comparing its predictions with cheetah data. While improving upon the current understanding of cheetah’s locomotion, their findings pave the way for designing legged robots!

“All animal running constitutes a flight phase and a stance phase, with different dynamics governing each phase,” explains Dr. Tomoya Kamimura from Nagoya Institute of Technology, Japan, who specializes in intelligent mechanics and locomotion.

During the flight phase, all feet are in the air and the center of mass (COM) of the whole body exhibits ballistic motion. Conversely, during the stance phase, the body receives ground reaction forces through the feet.

“Due to such complex and hybrid dynamics, observations can only get us so far in unravelling the mechanisms underlying the running dynamics of animals,” Dr. Kamimura says.

Consequently, researchers have turned to computer modelling to gain a better dynamic perspective of the animal gait and spine movement during running and have had remarkable success using fairly simple models. However, few studies so far have explored the types of flight and spine motion during galloping (as seen in a cheetah).

Against this backdrop, Dr. Kamimura and his colleagues from Japan have now addressed this issue in a recent study published in Scientific Reports, using a simple model emulating vertical and spine movement.

The team, in their study, employed a two-dimensional model comprising two rigid bodies and two massless bars (representing the cheetah’s legs), with the bodies connected by a joint to replicate the bending motion of the spine and a torsional spring. Additionally, they assumed an anterior-posterior symmetry, assigning identical dynamical roles to the fore and hind legs.

By solving the simplified equations of motion governing this model, the team obtained six possible periodic solutions, with two of them resembling two different flight types
(like cheetah galloping) and four, only one flight type (unlike cheetah galloping), based on the criteria related to the ground reaction forces provided by the solutions themselves. Researchers then verified these criteria with measured cheetah data, revealing that cheetah galloping in the real world indeed satisfied the criterion for two flight types through spine bending.

Additionally, the periodic solutions also revealed that horse galloping only involves gathered flight due to restricted spine motion, suggesting that the additional extended flight in
cheetahs combined with spine bending allowed them to achieve such great speeds!

“While the mechanism underlying this difference in flight types between animal species still remains unclear, our findings extend the understanding of the dynamic mechanisms underlying high-speed locomotion in cheetahs. Furthermore, they can be applied to the mechanical and control design of legged robots in the future,” speculates an optimistic Dr Kamimura.

Mineral found in human bone can help fight toxic organic compounds

Posted on by NITech

Many industrial processes emit volatile organic compounds (VOCs) that are hazardous to human health. In a new study, scientists from NITech, Japan, tailor the catalytic activity of hydroxyapatite, a mineral contained in human bones, using mechanical stress. This method was inexpensive and resulted in a 100% VOC conversion, potentially opening doors to effective climate control.

A team of scientists led by Prof. Takashi Shirai from Nagoya Institute of Technology (NITech), Japan, reported a complete catalytic decomposition of VOC using an inorganic compound called “hydroxyapatite” (HAp), a naturally occurring form of the mineral calcium phosphate that makes up most of the human bone structure.

“HAp is made of elements abundant in nature, is non-toxic and exhibits high biocompatibility. Our results, thus, opened up a new possibility for designing cheap, noble-metal-free catalysts for VOC control,” says Prof. Shirai. 

In a new study published in Scientific Reports, Prof. Shirai and his colleague Yunzi Xin from NITech now take things further by tailoring the “active surface” of HAp using a mechanochemical treatment under ambient conditions that leads to a highly efficient catalytic oxidation of VOC with 100% conversion to harmless compounds.

Specifically, they mixed initial HAp with ceramic balls in a vessel and conducted “planetary ball milling” at room temperature and ambient pressure. This essentially altered the chemical structure of HAp and allowed for its selective tailoring by simply changing the ball size.

By using different ball sizes (3, 10, and 15 mm) to systematically vary the morphology, crystallinity, surface defects/oxygen vacancy, acidity/basicity, and VOC affinity of HAps, the
scientists carried out their characterization using various techniques such as scanning electron microscopy, powder X-ray diffraction, Fourier transform infrared spectrometry, X-ray photoelectron spectroscopy, electron spin resonance analysis, surface acidity/basicity evaluation, and gas-flowing diffuse reflectance infrared Fourier transform spectroscopy. 

They observed a predominance of oxygen vacancy formation in the PO43- (triply charged
PO4) site along with an enhanced basic site population caused by selective mechanochemical activation of the c-plane (plane perpendicular to the symmetry axis) of the hexagonal HAp crystal and attributed it to the excellent catalytic conversion of VOC to CO2/CO. 

Moreover, they found that HAps treated with 3 mm balls showed superior catalytic activity over that treated with 10- and 15-mm balls, even though larger balls caused more defects and basicity. By looking at the surface absorption of a VOC, ethyl acetate, scientists attributed this anomaly to the inhibited absorption of ethyl acetate in HAp treated with larger balls, leading to suppressed catalysis. 

The results have excited scientists about the future prospects of HAps. “We expect that our catalyst will contribute significantly to VOC controlling and environmental cleaning all over the world by next decade, achieving the sustainable goals of clean air and water, affordable energy, and climate action,” comments Prof. Shirai, excited. 

A new algae-based switch is lighting up biological research

Posted on by NITech

A group of scientists from the Nagoya Institute of Technology, Japan, have discovered a novel ion channel protein that can be controlled by light, in a species of terrestrial alga. These channels respond to the shorter indigo blue wavelength of light, the first discovery of its kind. Subsequent light-based manipulations of the channel find potential applications in the modulations of specific functions of nerves, muscles, and more, for biological research.

Scientists from the Nagoya Institute of Technology, Japan, and Jawaharlal Nehru University, India, have identified a channelrhodopsin that responds to an even shorter indigo blue wavelength of light.

In their study published in Nature’s Communications Biology, the group of researchers,
led by Professor Hideki Kandori and Associate Professor Satoshi P. Tsunoda, identified a novel channelrhodopsin, which they named KnChR, from a species of terrestrial alga called Klebsormidium nitens.

“We chose this alga because it is known to be responsive to light, but its photoreceptor domain has not been established,” reports Prof. Kandori. Unlike other discovered channelrhodopsins, KnChR was found to respond to indigo blue light.

It is known that KnChR is made up of a seven-cell membrane-spanning region, which forms the pore that allows the entry and exit of different ions. This region is followed by a protein moiety including a peptidoglycan binding domain.

In order to investigate the properties of KnChR, the researchers performed extensive genetic and electrophysiological experiments.

What was perhaps the most exciting result was that they could identify the role of the “cytoplasmic domain.” All known channelrhodopsins have a large “cytoplasmic domain,” or the region that is located in the internal area of the cell. As Prof. Kandori explains, “All currently known channelrhodopsins comprise a large cytoplasmic domain, whose function is elusive. We found that the cytoplasmic domain of KnChR modulates the ion channel properties.”

Accordingly, the results of the experiments showed that changing the lengths of the cytoplasmic domain caused changes in ion channel closure. Particularly, the shortening of the domain resulted in increased channel ‘open time’ by more than ten-fold.

In addition, the researchers also identified two arginine amino acid residues, namely R287 and R291, in the same region, which played an important role in the properties of generated light currents. They found that KnChR exhibited maximal sensitivity at 430 nm and 460 nm, making it the ‘bluest’ channelrhodopsin.

Overall, the researchers have faith in the KnChR being helpful in biological systems requiring specific excitation parameters. When asked about the implications of these findings, Prof. Tsunoda, who is the corresponding author of the study suggests, “KnChR would expand the optogenetics tool kit, especially for dual light applications when short-wavelength excitation is required.”

What this means is that the light-operated property of KnChR can be applied in targeted manipulation of an organism’s biological functions, in a research setting. A few examples would include manipulation of neuronal and myocyte activities.

It is hoped that the scope of this discovery would expand beyond the laboratory into real-world applications. These real-world applications could include a cure for Alzheimer’s disease and heart diseases, light therapy for recovery from depression, and visual restoration.

Asymmetric synthesis of Aziridine with a new catalyst can help develop novel medicines

Posted on by NITech

Aziridine structures are an important component of several medicines and pharmaceutical drugs, due to which reactions yielding desirable aziridine structures with high purity have received much interest. In a new study, scientists from Japan have reported a high yield of aziridines with high purity from oxazolones using a novel catalyst and look into the underlying mechanism, paving the way for future development of novel drugs and medicines.

“Oxazolones are well-known for their versatility in affording biologically active compounds,” explains Professor Shuichi Nakamura from Nagoya Institute of Technology (NITech), Japan, who studies asymmetric reactions.

“However, the enantioselective reactions of 2H-azirines with oxazolones have not been very fruitful, despite being touted as one of the most efficient methods to synthesize aziridines.”

In a new study recently published in Organic Letters, Prof. Nakamura along with his colleagues from NITech and Osaka University, Japan, explored this issue and, in a significant breakthrough, managed to obtain aziridine-oxazolone compounds in high yields (99%) as well as high enantioselectivity or purity (98%). In addition, the team used an original catalyst they developed to catalyze the reactions they studied.

The team started off by heating α-azideacrylates at 150°C in an organic solvent tetrahydrofuran (THF) to prepare 2H-azirines and then reacted them with oxazolones in presence of various organocatalysts to produce different aziridine-oxazolone compounds.

In particular, the team examined the effect of the catalyst cinchonine and various heteroarenecarbonyl and heteroarenesulfonyl groups in organocatalysts derived from cinchona alkaloids and found that reactions using catalysts with either a 2-pyridinesulfonyl group or an 8-quinolinesulfonyl group gave both a high yield (81-99%) as well high enantiopurity (93-98%).

In addition, scientists observed that the reaction between a 2H-azirine containing an ethyl ester group and an oxazolone with a 3, 5-dimethoxyphenyl group in presence of the catalyst with 8-quinolinesulfonyl group also gave high yields (98-99%) as well as enantiopurity (97-98%).

The team then moved on to exploring the reaction between 2H-azirine with ethyl ester group and a wider variety of oxazolones in presence of the catalyst with 8-quinolinesulfonyl group.

In all of the reactions, they observed high yields (77-99%) and enantiopurities (94-99%) except one for the case of an oxazolone bearing a benzyl group and the catalyst with a 2-pyridylsulfonyl group that only produced a moderate yield (61%) and purity (86%). Moreover, they were able to convert the obtained aziridines into various other enantiomers without any loss of purity.

Finally, the team proposed a catalytic mechanism and a transition state for the reaction of 2H-azirines with oxazolones in which the catalyst activates both the oxazolone and the 2H-azirine, which then react to give an “addition product” that, in turn, yields the aziridine with the regeneration of the catalyst.

While the detailed mechanism is yet to be clarified, scientists are excited by their findings and look forward to the method’s application in medicine and pharmacology.

“It has the potential to provide people with new medicines and create new drugs as well as drug candidates that are currently difficult to synthesize. Moreover, the catalyst used in this study can be used for many other stereoselective synthetic reactions,” observes an
optimistic Prof. Nakamura.