During the past few years, considerable attention has been devoted to the functional-group-directed functionalization of C-H bonds through nearby heteroatom coordination to the metal center of the catalyst. We found that 1,1,1,3,5,5,5-heptamethyltrisiloxane promoted the Ru-catalyzed intermolecular dehydrogenative coupling. The C(sp²)-H silylation of aromatic compounds, such as aryloxazolines, arylimines, arylpyridines, and benzamides, took place at ortho-positions of the benzene ring. In the case of 2-alkyloxazolines, the C(sp³)-H silylation took place site-selectively at methyl C(sp³)-H bonds located γ to the nitrogen atom of oxazolyl groups. Based on DFT calculations and KIE experiments, we proposed a catalytic cycle involving the rate-determining C(sp³)-Si bond formation step. Also, we have developed a Ru-catalyzed N(sp²)-directed C(sp²)-H borylation using pinacolborane. DFT calculations and KIE experiments suggest that the catalytic cycle should involve oxidative addition of the C(sp²)-H bond, the rate-determining σ-bond metathesis of pinacolborane with the ruthenium hydride complex, and reductive elimination of the C(sp²)-B bond.

Fluoroarenes are widely found in molecules involving pharmaceuticals, agrochemicals, and organic functional materials. The fluoro group is often installed to the molecules to provide favorable characteristics that rest on unique properties of fluorine. The increasing availability of fluoroarenes has stimulated considerable interest in their late-stage transformation via C-F bond cleavage, which is a challenging issue to achieve due to high stability of the C-F bond. Particularly, defluoroborylation of fluoroarenes has been attracting much attention owing to the reliable and versatile organoboron chemistries that enable facile diversification for obtaining valuable compounds such as drug candidates and molecular probes that promote researches in drug discovery and life science. In this article is reviewed the recent progress made on this challenging issue. These include borylation of perfluoroarenes having a fluoro group with relatively high leaving ability, low-valent transition metal-catalyzed defluoroborylation of fluoroarenes bearing an inert C-F bond, and promising photochemical defluoroborylation of fluoroarenes.

In the development of drugs, the structural diversity of natural compounds plays a pivotal role and is extensive but not unlimited. Semisynthetic compounds produced by diversification of a natural product through the chemical transformation was valuable as new medicinal seeds. Chemically Engineered Extracts (CEEs) are an ideal tool for obtaining semisynthetic natural compounds. CEEs are natural crude extracts directly derivatized by chemical reactions and thus can yield various novel compounds at once. Coumarins and coumarin dimers (including the unprecedented tetracyclic coumarin derivatives) were isolated from CEEs of the marine-derived fungus Eurotium rubrum. The structures of these compounds were established using NMR, MS and IR methods. The absolute configuration of tetracyclic coumarin structure was determined by Electronic Circular Dichroism (ECD) calculations. Isolated coumarins and coumarin dimers showed stronger activity for anti-melanogenesis. These results showed that chemically engineered extract generated medicinal seeds for new drugs.

In drug discovery, various biologically active peptides have been discovered, characterized and modified for medicinal chemistry. However, the utilization of peptides as therapeutics has some limitation owing to several factors, including low metabolic stability towards proteolysis and undesired interactions with multiple receptors. Hence, the development of “peptidomimetc”, in which a part or whole of a molecule is modified, is an important strategy with which to enhance the stability or bioactivity of peptide-based drugs. In this situation, we have designed and developed a synthetic method for chloroalkene dipeptide isosteres (CADIs), which involves replacement of an amide bond in peptides with a chloroalkene structure, toward the peptidomimetc. By a developed synthetic method, an N-tert-butylsulfonyl protected CADI was obtained utilizing diastereoselective allylic alkylation with organocopper reagents as a key reaction. This CADI was also transformed into an N-Fmoc protected CADI in a few steps. In addition, The CADI could be used in Fmoc-based solid-phase peptide synthesis and applied to introduce for a bioactive peptide.

Biosynthesis of cyclic structures of natural products is important for generating their structural diversity. In some cases, these cyclic structures are responsible for their bioactivities (e.g., a β-lactam ring in β-lactam antibiotics and an aziridine ring in antitumor antibiotics). Therefore, cyclization reaction is among the most important steps in the biosynthesis of natural products. In these steps, chemical reactions important for organic synthesis are often used for synthesizing cyclic structures. For example, the Diels-Alder reaction is used to biosynthesize the decaline structure in mevastatin and lovastatin, which are known for HMG-CoA reductase inhibitors. Another example is the phenol radical coupling reaction, which is used for biosynthesizing the macrocyclic structures of glycopeptide antibiotics. Although cyclic structure biosynthesis has been studied extensively, the biosynthetic pathways of many cyclic structures have not been elucidated. In this review, we focus on benzastatins, the biosynthetic pathway of which our group has analyzed by heterologous expression and in vitro assays using recombinant enzymes. Most importantly, the indoline and tetrahydroquinoline structures of benzastatin derivatives were revealed to be synthesized by an unusual cytochrome P450, BezE. Instead of oxygenation, which most cytochrome P450s catalyze, BezE catalyzes nitrene formation, its addition to a double bond to yield aziridine, and nucleophilic substitution to open the aziridine ring and form a 5- or 6-membered ring.

The construction of polycyclic aromatic hydrocarbons (PAHs) via alkyne benzannulation reactions has become an increasingly utilized method over the past few years. High energy of an alkyne bond is capable of the rapid synthesis of condensed polycyclic sp²-frameworks. Much efforts have been devoted to the design of the substrates containing multiple alkyne bonds and the control of the streoselectivity of the reaction. The short review will describe recent works of alkyne benzannulations mediated by Lewis acid catalysts and radical initiators, to produce various PAHs scaffolds.