Herein we report our recent efforts on the greener catalytic synthetic methods of nitrogen-containing compounds using N-unprotected ketimines. We found that alkynylation of N-unprotected trifluoromethyl ketimines proceeded in the presence of zinc catalysts, providing the products in good yield with broad functional group tolerance and unique chemoselectivity. Next, we extended the methodology to catalytic stereoselective addition reactions and found that a direct Mannich-type reaction, a Friedel-Crafts-type alkylation reaction, a decarboxylative Mannich-type reaction, and an arylation reaction proceeded in the presence of appropriate metal or organocatalysts to give α-tetrasubstituted amines in high yield and stereoselectivity. The detailed scope and some mechanistic insights of these reactions are also presented.

Carbometalation of a carbon-carbon multiple bond is the most powerful synthetic tool for organometallic compounds because the corresponding organometallics are produced with the formation of a new carbon-carbon bond. Many transition metal-catalyzed carbometalations have been established. Recently, transition metal catalyst-free carbometalation has attracted much attention because potentially toxic and expensive transition metals are not required. Generally, highly reactive organometallic compounds such as organolithiums and Grignard reagents are needed for the addition to non-activated alkynes and alkenes. However, the high nucleophilicity of the organometallics led to a lack of functional group tolerance. In this study, group-13 heavy metal Lewis acids such as indium trihalides and gallium trihalides have been focused on developing a novel carbometalation system. The Ga(III) and In(III) centers possess moderate Lewis acidity and high π-electron affinity due to the large ionic radius, which leads to compatibility with functional groups and to the activation of carbon-carbon multiple bonds. Therefore, mild organometallic reagents such as organosilicon compounds can be used to avoid undesired overreactions. In addition, organogalliums and -indiums produced by carbometalation are applicable to sequential reactions due to their high-chemoselectivity. Regio- and stereoselective carbometalation of alkynes and alkenes with mild carbon-nucleophiles such as silyl ketene acetals and silyl ketene imines was accomplished by using heavy main-group metal salts such as indium, gallium, and bismuth halides to afford highly-functionalized organometallic compounds possessing carbonyl and cyano groups, respectively. By extending this concept to oxymetalation, new synthetic methods for organometallic compounds with heterocyclic skeletons were also established. In addition, the catalytic cycle involving the present carbometalation realized the cross-coupling between enol derivatives with organosilicon reagents.

The development of aerobic oxidative transformations is a central, highly rewarding challenge in modern organic chemistry, because those reactions utilize molecular oxygen which is recognized as an ideal oxidant with many advantages such as sustainable abundance, cost-effectiveness, atom-economy, and minimal pollution. Recently, we have developed a novel strategy for the green oxidative transformations by combining iodine catalyst and riboflavin-derived organocatalyst which enables the efficient activation of molecular oxygen. The flavin-iodine-coupled organocatalytic system successfully promotes diverse oxidative transformations requiring molecular oxygen as the only sacrificial reagent, thus provides atom- and step-economical syntheses that fulfill the recent demands of green and sustainable chemistry. In addition, inspired by the photochemical mechanism of a plant blue-light receptor, we have developed a flavin-based photocatalytic system for chemoselective heterocoupling of thiols.

In recent years, the development of peptide chemistry has facilitated the synthesis of peptide libraries with diverse sequences. Along with this, peptides are widely used as probe molecules for elucidating biological functions and as tools for chemical biology research. However, there are limits to peptides consisting of only 20 types of proteinogenic α-amino acids. Such peptides are hydrolyzed by peptidases and proteases that are abundant in the body, and then, easily inactivate their functions. In addition, the secondary structure of short peptides is greatly fluctuated in the body, and thus, it is difficult to adopt a stable conformation. Against such background, the synthesis of non-proteinogenic amino acids (unnatural amino acids), the synthesis of peptide mimetics, and the techniques for controlling peptide secondary structures have been actively developed based on the synthetic organic chemistry approaches. We have been engaged in the design and synthesis of unnatural amino acids, the conformational analysis of their peptides, and research on their functionalization. This article describes unnatural amino acids that can change their side chain structures not only in amino acids themselves but also in peptides and control peptides secondary structures in response to the external environment. Furthermore, as an application study to the functional peptides using unnatural amino acids, I introduce cell-penetrating peptides and drug delivery peptides.

To determine of the position of oxidative nucleoside in DNA, the selective detection of 8-oxo-2’-deoxyguanosine (8-oxo-dG) without chemical or enzymatic treatment is an attractive tool for genomic research. Here, I described the summary of our resent study which designed and synthesized the non-natural nucleoside analogue, the adenosine-1,3-diazaphenoxazine derivative (Adap), for selective recognition of 8-oxo-dG in DNA. This study has clearly shown that Adap has stabilizing effect of the duplex including the Adap-8-oxodG base pair with high selectivity. Furthermore, the fluorescent quenching property of Adap has been shown to detect of 8-oxo-dG in DNA. And also, the triphosphate of Adap (dAdapTP) was synthesized and tested for single nucleotide incorporation reaction to primer strand using DNA polymerase. The efficiency of dAdapTP incorporation into 8-oxo-dG-containing templates was better than with dG-containing templates. Then the detection of 8-oxo-dG in human telomeric DNA sequences extracted from H₂O₂-treated HeLa cells and in genome DNA extracted from small intestine of transgenic mice were successful. Furthermore, I will introduce the development of Adap derivatives, which are expected to be applied to sequencing technology in this review.

Specialized medicine is now expanding from low-molecular drugs to recombinant proteins, antibodies, and nucleic acids(i.e., mRNA and plasmid DNA). Especially, in parallel with the rapid progress in post-genome-related “-omics” technologies, gene- or nucleic acid-based therapeutics are now recognized as an attractive approach for developing personalized medications. Especially, the concept of RNA therapy is now widely growing worldwide as an alternative gene complement approach. In the case of conventional gene therapy, the cargo DNA must enter the nucleus for transcription by overcoming a severe nuclear membrane barrier. Also, the nucleus-delivered DNA is potentially integrated to the genomic DNA to induce oncogenesis. In contrast, in the case of mRNA, the target organelle is the cytoplasm. Thus, a higher protein production would be expected, and would also be theoretically safer than DNA owing to the absence of a risk of genetic integration. Furthermore, short nucleic acids (i.e., short interference RNA; siRNA and micro RNA; miRNA) can be used to knock-down or down-regulate disease-related genes. siRNA against transthyretin familial amyloid (ATTR), and antisense oligonucleotides for muscular dystrophy have currently been approved by FDA and EMA. Since, the RNA molecule per se is quite hydrophobic molecule, and readily degradable, especially in the body, to realize RNA-based therapeutics, an innovative Drug Delivery System (DDS) is, in turn, essential. We have developed a lipid-like material: SS-cleavable and pH-Activated Lipid-like Material (ssPalm) as a material for the RNAs and nucleic acids. In this article the design and function of ssPalm is summarized.

Protein interaction networks and localization hold the key to understand all signaling processes in living cells. Proximity-dependent labeling (PL) is an innovative method to unveil them by using chemical probes. Chemical PL methods which do not require genetic engneering have been attracting attention in recent years. This review summarizes the PL by using energy transfer processes between photocatalysts and chemical probes.