Chemical protein synthesis offers a powerful platform for elucidating protein function and constructing engineered proteins with tailored properties. Despite its broad utility, several challenges remain in the synthesis and handling of peptides and proteins. In this account, we describe the development of a series of synthetic strategies that exploit the distinctive reactivity and versatility of peptide hydrazides. First, we established a method for the direct thioesterification of N-terminal thiazolidine-containing peptide hydrazides, effectively suppressing undesired thiazolidine ring-opening side reactions. Second, we introduced a late-stage solubilization technique based on reductive N-alkylation of hydrazides with hydrophilic tags, enabling improved purification and ligation of poorly soluble peptides. Third, we developed a solid-phase linker that generates alkyl hydrazides, dramatically enhancing HPLC peak resolution and purification yields. Finally, we synthesized aspartic acid hydrazides that suppress aspartimide formation during solid-phase synthesis, including under microwave-assisted conditions. Collectively, these hydrazide-based methodologies constitute a unified and practical toolkit for overcoming persistent bottlenecks in chemical peptide and protein synthesis.

Arynes are important synthetic intermediates containing a formal triple bond in the aromatic ring. Although an aryne is conventionally generated under basic conditions from various precursors, unfortunately, limited methods exist for generating arynes under non-basic conditions. In this context, we have recently developed o-triazenylarylboronic acids as practical aryne precursors. These aryne precursors are obtained as stable solids storable in air at ambient temperature. On the other hand, they generate arynes under various non-basic conditions, including treatment with neutral silica gel, or 1,2-diol and p-nitrophenol, or sulfonic acid. These reaction conditions are applicable to a wide range of reactions of the precursors and arynophiles bearing various functional groups or pharmaceutical cores. In addition, we have developed a precursor of novel 3-triazenylaryne species for the efficient preparation of functionalized o-triazenylarylboronic acids. This 3-triazenylaryne precursor is regarded as a novel 1,2-benzdiyne equivalent that allows for iterative transformations involving arynes via o-triazenyl-arylboronic acids as key intermediates.

Natural products have historically been evaluated for their biological activities in pharmaceutical development; however, their potential as asymmetric catalysts has been rarely explored. In this study, we screened our natural product library for catalytic activity and identified three naturally occurring alkaloids—gardnerine, spiradine A, and calycanthine—that effectively catalyze an asymmetric Michael reaction between oxindole and nitrostyrene. Among them, (+)-calycanthine, characterized by its unique aminal structure, was further investigated. Concise synthetic and extraction protocols were developed to access both enantiomers of calycanthine. Subsequent derivatization of this alkaloid led to improved enantioselectivity in the model reaction. Computational studies revealed that the aminal moiety of the catalyst activates both nucleophiles and electrophiles through multiple hydrogen-bonding interactions, including non-classical hydrogen bonds between the carboxylic acid group and the aminal C-H.

Carboxylic acids and esters, which are derived from naturally abundant fats, oils, or sugars, possess high oxidation states. Therefore, the catalytic reduction of carboxylic acids and esters plays a crucial role in their conversion into valuable chemical products. Considering operational advantages such as recovery and reusability of catalysts, the use of heterogeneous catalysts is essential for industrial applications. So far, significant efforts have been devoted to the development of heterogeneous catalysts for the hydrogenation of carboxylic acids and esters to alcohols. However, the development of catalysts that produce other value-added compounds remains an significant challenge. In this account paper, we summarize our recent works regarding the development of highly active heterogeneous Pt-Mo catalysts for the reductive transformations of carboxylic acids and esters: i) the direct hydrodeoxygenation of esters to unsymmetric ethers, ii) the reductive amination of carboxylic acids to alkylamines, and iii) the reductive amination of triglycerides to fatty amines. The Pt-Mo catalysts offer simple and clean approaches for reductive transformations of carboxylic acids and esters, contributing to future sustainable chemical processes.

Carboxylic acid derivatives such as acyl halides, acid anhydrides, esters, and amides have garnered significant attention as electrophilic coupling partners due to their low cost and ready availability. These derivatives offer distinct advantages in transition-metal-catalyzed decarbonylative transformations for the following reasons: 1) Unlike conventional aryl halides, carboxylic acid derivatives can be readily prepared from carboxylic acids in a single step, making them both economical and synthetically accessible; 2) The leaving group (X) can coordinate with the transition metal center, reducing the energy barrier for the rate-limiting step and other key reaction processes; and 3) When X is basic, cross-coupling reactions can proceed under base-free conditions. Since acyl chlorides are chemically unstable and esters and amides exhibit low reactivity, we have recently focused on acyl fluorides, which provide an optimal balance between stability and reactivity. In recent years, we have successfully developed a series of nickel- or palladium-catalyzed decarbonylative protocols, enabling efficient methodologies for constructing carbon-carbon, carbon-heteroatom, and carbon-halogen bonds. This systematic work broadens the scope of synthetic organic chemistry and catalysis, laying a strong foundation for future advancements in the field.