α-Alkylation of carbonyl compounds using a Brønsted base is a fundamental carbon-carbon bond-forming reaction for constructing basic molecular skeletons. Among these transformations, the alkylation using alkenes as electrophiles (hydroalkylation) is more desirable than traditional alkylation with alkyl halides due to its superior atom economy (i.e., no salt waste). However, while activated alkenes such as α,β-unsaturated carbonyl compounds are commonly used, nonactivated alkenes like 1-hexene remain challenging due to their low electrophilicity. Despite this limitation, nonactivated alkenes are attractive electrophiles, offering access to a diverse range of alkyl substituents and functional groups. Here, we report efficient α-alkylation of active methylene and methine compounds with nonactivated alkenes. This method employs an organophotocatalyst (4CzIPN or its derivative) and lithium thiophenoxide (LiSPh) as a multifunctional catalyst system, enabling Lewis acid/Brønsted base/hydrogen atom transfer (HAT) catalysis under blue LED irradiation. The reactions proceed smoothly under ambient conditions with low catalyst loadings, affording the desired alkylated products in high yields using only a slight excess of the carbonyl compound and without by-product formation. This represents a practical and atom-economical alkylation strategy. Furthermore, we found that magnesium thiophenoxide (Mg(SPh)₂) exhibits higher catalytic activity than LiSPh, allowing for further reduction in catalyst loading. In addition, a metal Lewis acid/amine/PhSH system proved effective for the alkylation of active methine compounds, and even a metal-free simple amine/PhSH system was effective for the alkylation of malononitrile.

Organofluorine compounds constitute a valuable class in the fields of pharmaceuticals and agrochemicals, because biological activity and physicochemical properties, such as bioavailability, lipophilicity, and metabolic stability, can be improved by the introduction of fluorine atom(s). Therefore, efficient methods for the synthesis of organofluorine compounds have been intensively studied. Development of practical fluorinating reagents is indispensable for this purpose. In this paper, the author reports the synthesis of novel electrophilic fluorinating reagents (N-F reagents) as substitutes for NFSI (N-fluorobenzenesulfonimide) with N-F covalent bond and their application to reactions. The paper describes three main topics: First, selective mono- and difluorination in the α-position of carbonyl compounds are demonstrated by exploiting the fluorinating activity of the tuned N-F reagents. Second, the selective difluorination in the benzylic C-H bonds of N-heterocycles is achieved by using N-F reagent, which readily enables the interaction with N-heterocycles. Third, the aminofluorination of alkenes in the presence of palladium catalyst is also developed by using N-F reagents containing easily transformable substituents.

Our recent research results on a diaminomethylenemalononitrile (DMM) organocatalyst will be introduced. DMM organocatalysts efficiently promoted the asymmetric conjugate additions of some nucleophiles such as α-cyanoketones, α-angerica lactones, and β-keto esters to benzoyl acrylonitriles as Michael acceptor to afford the corresponding addition products in high yields with excellent enantioselectivities. We demonstrated that benzoyl acrylonitriles are good Michael acceptor for asymmetric reactions using organocatalysts. In addition, N,N-dibenzyl DMM organocatalysts efficiently promoted the asymmetric Henry reaction of trifluoromethyl enones with nitromethane and the asymmetric 5-exo selective bromolactonization of stilbene-type carboxylic acids, resulting in the corresponding 1,2-adducts and phthalide derivatives with high stereoselectivities. We demonstrated that the molecules bearing both DMM motif as hydrogen-bond donor and chiral amine are good organocatalysts for some valuable stereoselective reactions.

Conical intersections (CIs), which indicate the crossing of two or more adiabatic electronic states, are crucial in the mechanisms of photophysical, photochemical, and photobiological processes; including cis-trans photoisomerization of the primary events in vision and signals, excited-state proton transfer, and photodamage to deoxyribonucleic acid. In photo processes, information on the minimum-energy CIs (MECIs) between the ground state and the first singlet electronic excited state (S₀/S₁-MECI) is essential for investigating the energetically preferred internal conversion. Quntum chemical calculation is a powerful tool for atomic-level analysis in photo processes. Although various geometries and energy levels have been reported using quantum chemical calculations, systematic interpretation of the MECI geometries is unclear. It is because MECI geometries, unlike equilibrium geometries, are difficult to predict due to their complex structures with ring strain, ring opening, π-bond rotation, and σ-bond dissociation. We systematically investigated the S₀/S₁-MECI geometries of organic molecules using frozen orbital analysis (FZOA), which decomposes the energy difference of two electronic states into several excitation energy components for the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO). The investigation revealed two important controlling factors related to S₀/S₁-MECIs: the HOMO-LUMO exchange integral approximately vanishes and the HOMO-LUMO gap becomes close to the HOMO-LUMO Coulomb integral. This article describes the overview of FZOA and the controlling factors using several organic molecules. In addition, its application to the elucidation of internal conversion processes for bithiophene-fused isoquinoline is reported.

DS55980254 (1) is a potent and selective PTDSS1 inhibitor discovered by Daiichi Sankyo. This study addresses the significant challenge of efficiently synthesizing the active pharmaceutical ingredient (API) with high enantiomeric excess by developing a practical and unique optical resolution method. Utilizing a diastereomeric salt crystallization of 2,3-pyrrolidinedione and chiral amine facilitates the large-scale production of the API. Through optimization of the entire synthesis method from the perspective of process chemistry, enhancement in yields, complete elimination of chromatographic purification, and reduction in the number of unit operations were achieved. This new process demonstrated a remarkable enhancement in productivity compared to the original synthesis route, resulting in an overall yield that increased approximately threefold. This method consistently yielded high-quality products at each step, enabling efficient and robust synthesis of the PTDSS1 inhibitor. Additionally, efforts to minimize impurities in each intermediate ensured the quality of the API throughout the entire manufacturing process, allowing for timely delivery on multi-kilogram scale. Notably, the quality of all intermediates was greater than 99.7% in all cases, indicating that this synthetic strategy was appropriate. In fact, the synthesis of 18.7 kg of the PTDSS1 inhibitor was successfully achieved using the developed method and the product quality met all specification requirements.