Indole and related skeletons are ubiquitous structural motifs often found in pharmaceuticals and natural compounds, and their arylated species have attracted attention because of their diverse biological activities. Among them, much synthetic effort has been made to obtain 3-arylindoles. Palladium-catalyzed direct arylation of N-unsubstituted indole is a powerful tool for 3-arylated indole synthesis, though achieving high C3-selectivity over C2- and N1-selectivity is still challenging. A palladium-dihydroxyterphenylphosphine (DHTP) catalyst was successfully applied to the direct C3-arylation of N-nonsubstituted indoles with aryl chlorides, triflates, and nonaflates. This catalyst showed C3-selectivity, whereas catalysts with other structurally related phosphine ligands exhibited N1-selectivity. Complex formation between the lithium salts of the ligand and the indole is assumed to promote the selective arylation at the C3-position of the indole ring. In the case of 3-alkylindoles, dearomative C3-arylation proceeded to afford 3,3-disubstituted indolenines, which can be further converted to the corresponding indoline derivatives. This methodology was further applied to tryptamine derivatives, and the dearomative C3-arylation followed by intramolecular cyclization of the resulting 3,3-disubstituted indolenines afforded C3a-arylated pyrroloindolines in one-pot. Furthermore, reactions using homotryptamine derivatives successfully provided C4a-arylated pyridoindolines.

Because structural development studies have conventionally been conducted based on frameworks consisting of C, N, O, and S functionalities, the development of new structural options utilizing a wide variety of elements can dramatically expand the chemical space of medicinal chemistry. In order to explore the “elements-based chemical space” in medicinal chemistry and propose new methodologies for molecular design, the development of biologically active compounds using various multi-element structures was investigated. As a novel design methodology, structural development using silicon and phosphorus functionalities, as well as three-dimensional structural development using boron clusters and ferrocene, was explored. In the case of silicon functionalities, the correlation between the biological activity and changes in the physical properties induced by Si/C-exchange was quantitatively analyzed, revealing that differences in the atomic radii on the order of picometers resulted in large differences in the biological activity. Structural development methods using silyl alcohols and silanol structures were also developed. In the case of phosphorus functionalities, the P-B bond in phosphine boranes was found to be a versatile option for structural development. Boron clusters and ferrocenes are useful hydrophobic anchors for biologically active compounds, and developments in their three-dimensional structures have led to the development of highly potent compounds. The proposed expansion of the “elements-based chemical space” in medicinal chemistry is a promising approach for developing novel and distinctive drug candidates.

Natural products are a group of structurally diverse compounds that exhibit various biological activities using their three-dimensional chemical space. Total synthesis studies have been conducted for many years, and synthetic methods and strategies have advanced. However, some compounds, such as complex or large natural products, are still challenging to synthesize. In this article, the author focuses on fused natural products and introduces the total synthesis of aplysiasecosterols and nemorosonols. Aplysiasecosterol A (1) has a unique tricyclic γ-diketone skeleton, and nemorosonol (41) has a tricyclo[4.3.1.0^3,7]decane skeleton, making it a challenging synthetic target for synthetic organic chemistry. The author’ s strategy for the total synthesis of aplysiasecosterols used the Suzuki-Miyaura coupling reaction for the late-stage bond formation of the C8-C14 bond as a common key reaction. This late-stage convergent synthesis rarely reported in secosteroid synthesis, is adaptable to many 9,11-secosteroids. The author also has established a strategy for constructing a tricyclo[4.3.1.0^3,7]decane skeleton, which is common to many polycyclic polyprenylated acylphloroglucinols (PPAPs). In this tandem reaction, it is possible to introduce a benzoyl group at the C8 position and adjust the degree of oxidation at the C9 position at the same time. Furthermore, the author achieved the total synthesis of nemorosonol (41) in 12 steps from commercially available cyclopentanone 67 by using the established synthetic strategy.

Nitriles are useful synthetic intermediates because the cyano group is a versatile functional group that can be easily converted to nitrogen or oxygen functional groups. We have found that boron Lewis acids can effectively activate umpolung-type (electrophilic) cyanating reagents through the coordination of their cyano group to the boron center and have achieved various types of electrophilic cyanation reactions. For example, Lewis acidic activation of a hypervalent iodine reagent containing a transferable cyano group with tris(pentafluorophenyl)borane (B(C₆F₅)₃) enabled the electrophilic cyanation of silyl enol ethers to provide β-ketonitriles. In addition, boron enolates derived from 9-borabicyclo[3.3.1]nonane (9-BBN) were found to undergo highly efficient electrophilic cyanation with N-cyano-N-phenyl-p-toluenesulfonamide (NCTS) and p-toluenesulfonyl cyanide (TsCN), which would proceed through a six-membered ring transition state. This approach was extended to the electrophilic cyanation of allylic boranes to provide β,γ-unsaturated nitriles, a process that is applicable to the construction of allylic quaternary carbon centers. Furthermore, the stereospecific intermolecular cyanofunctionalization of alkenes by boron Lewis acid activation of suitable bifunctional electrophilic cyanating reagents has also been realized. The use of TsCN and cyanogen bromide (BrCN) allows for bromocyanation and oxycyanation, respectively. The methods developed have significantly expanded the scope of application of the electrophilic cyanation method, allowing for the synthesis of unique nitriles that are difficult to synthesize by existing methods.

Peptides, which are composed of a wide variety of amino acids, have attracted considerable attention particularly in the pharmaceutical industry. Ever since the pioneering works of Curtius and Fischer more than a century ago, efficient methodologies for forming peptide bonds have been developed and reported. While most of these methods involve reagent-controlled additive-based reactions, we have established several substrate-controlled reactions that show enormous potential for practical use because they do not require excess amounts of additives and enable selective reactions to proceed at specific positions. And, the conventional peptide synthesis employs condensation of N- and C-terminal protected amino acids and deprotection. Protective groups are important to suppress side reactions and carry out the desired reaction selectively, but there are concerns about an increase the amount of waste and a decrease in total yield due to increase of steps. We developed novel methods for forming peptide bonds using substrate-controlled systems, that include: 1) Catalytic peptide bond formation using silyl esters, 2) remote condensation reaction of dipeptides, 3) peptide bond formation in unprotected amino acids, 4) silacyclic dipeptide synthesis, 5) peptide elongating both termini of a silacyclic dipeptide. In this paper, we present these novel substrate-controlled reactions that we have developed and the history and current techniques of peptide bond formation.

In recent years, N,N,O-trisubstituted hydroxylamine motif is gradually asserting its potentials as a novel structural element for drug discovery because of its multiple features, including low basicity, good stability, and an inherent lack of reactivity toward enzymes, which confer mutagenicity on less-substituted hydroxylamines. However, the broad application of this moiety for drug discovery purposes is limited by the paucity of synthetic methods for a series of complex hydroxylamine derivatives. This short review focuses on recent advances in the synthesis of N,N,O-trisubstituted hydroxylamines suitable for fragment-based drug design in medicinal chemistry.