Umpolung strategies are of considerable interest to oragnic chemists because they provided alternative synthetic routes to those imposed by the natural polarity of classic synthons. In recent years, umpolung of enamines has received much attention as a novel strategy to access α-substituted ketones. We focused on the synergistic effect of N-alkoxyenamines and organoaluminum reagents and found that the N-O bond cleavage and introduction of nucleophiles at the β-position of N-alkoxyenamine can be achieved in a S_N2′-type reaction manner. This approach is amenable to the synthesis of α-substituted ketones by incorporating various C (sp³) and C (sp²) units, such as alkyl, aryl, heteroaryl, and alkenyl groups. We applied this method to aldehydes, vicinal functionalization to double bond of enamines is possible, allowing the double introduction of nucleophiles at both the α- and β-positions of the enamine. Moreover, this method can also be applied to O-silyl-N,O-keteneacetals derived from isoxazolidine amides, affording α-substituted amides via nucleophilic β-phenylation of O-silyl-N,O-keteneacetals. Furthermore, polarity inversion of amides was achieved, enabling the introduction of nucleophiles at the α-position as well as the γ-position. In this review, we want to describe the details of our endevours to develop the novel enamine chemistry through an umpolung startegy.

Dehydration condensation and hydrolysis reactions are fundamental to both organic synthesis and biological processes. Controlling these opposing reactions under various conditions, especially in the presence of water, remains a significant challenge. In particular, the use of chemical dehydrating agents in aqueous or moisture-containing systems—common in life sciences—requires a precise understanding of their hydrolytic stability and kinetic behavior.

In this study, we present a detailed kinetic and mechanistic analysis of esterification reactions using 2-methyl-6-nitrobenzoic anhydride (MNBA), a representative dehydrating agent known for its high efficiency and functional group compatibility. We investigate the impact of water on the reaction pathway, identify hydrolysis-prone species, and evaluate strategies to maintain high coupling efficiency under partially aqueous conditions. These findings provide new insights into the practical use of MNBA-mediated dehydration condensation in complex and biologically relevant environments, opening the way for broader applications in the life sciences.

We recently discovered that acrolein is produced at high concentrations in various cancer cells. We then developed an efficient in-cell reaction with acrolein in cancer; thus, the aryl azides undergo a metal-free 1,3-dipolar cycloaddition reaction with acrolein in a highly selective manner, resulting in the formation of α-diazocarbonyl derivatives. In this paper, we describe our recent trials of this in-cell reaction toward medical applications, i.e., cancer diagnosis and therapy. Our in-cell reaction strategy led to the clinical application and constitutes a new modality for cancer medicine.

Optimization of reaction conditions is indispensable yet time-consuming in developing new reactions. Advanced modalities such as flow and electrochemical reactions often require substantially more experiments to identify optimal conditions compared to conventional batch processes. While machine learning approaches can efficiently predict suitable conditions, they typically rely on specialized informatics expertise and large, carefully curated datasets. In this review, we highlight the application of data-driven multiparameter screening with small datasets-more accessible to experimental chemists-to the exploration of conditions in flow and electrochemical reactions. Yield mapping with Gaussian process regression enabled the visualization of predicted yields across the design space for an organocatalytic flow domino reaction, allowing the identification of high-yielding conditions with only ten experiments. Similarly, Bayesian optimization (BO)-based multiparameter screening of electrooxidation conditions successfully identified optimal high-yielding conditions within twelve experiments. Categorical BO incorporating one-hot encoding identified six key parameters-including mixer selection-for an organocatalytic flow biaryl synthesis, achieving substantial yield improvement in fifteen experiments. In addition, constrained BO applied to the electrochemical flow synthesis of amino acids accomplished two simultaneous objectives-high yield and reduced energy consumption-with only nine experiments.

Deuterium (D) is a stable and nonradioactive isotope of hydrogen (H), and deuterated compounds have broad applications. Especially, the deuterium kinetic isotope effect, attributed from the higher dissociation energy of the carbon-deuterium (C-D) bond compared with that of carbon-hydrogen (C-H) bond, has attracted considerable attention in recent drug discovery studies. The deuterium switch (replacement of C-H bonds with C-D bonds) at the metabolic sites (the α-position to heteroatoms etc.) of drugs improves the bioavailability of mother drugs (H forms) owing to the deuterium kinetic isotope effect (KIE). Therefore, the development of efficient synthetic method of deuterated drugs (heavy drugs) is eagerly desired. We have recently synthesized the deuterated alkyl reagents (d_n-alkyl diphenylsulfonium salts and d_n-alkyl thianthrenium salts) aimed at development of heavy drugs, possessing high deuterium contents at the adequate positions. Additionally, photocatalytic site-selective deuteration of α-thio C(sp³)-H bonds and polyethylene glycol derivatives were also successfully accomplished. In this review, we explain the approved heavy drugs and their characters, and our recent results of deuteration are introduced.