Dolutegravir sodium, a potent inhibitor of Human Immunodeficiency Virus type-1 (HIV-1) integrase, is a promising drug for the treatment of HIV infectious disease. Dolutegravir sodium has a highly-functionalized tricyclic core structure, thus it has been a challenge to establish practical synthetic methods. The synthetic route at the medicinal chemistry stage required numerous synthetic steps along with chromatographic purification operations, leading to a low total yield and difficult application to practical scale production. To solve these problems, we have developed two practical synthetic methods for the preparation of dolutegravir sodium; (i) a practical method starting from readily accessible material maltol and (ii) a more efficient method through the key intermediate pyrone diester. The first method includes scalable oxidation process of methyl moiety of maltol and palladium-catalyzed carbonylation for introduction of amide moiety, leading to a practical manufacturing method in less synthetic steps and enabling multikilogram scale manufacturing. The second method includes an efficient and practical synthetic method of the pyrone diester intermediate from readily accessible starting materials, and the obtained pyrone diester can easily be transformed to dolutegravir sodium, leading to a more efficient and atom-economical method for preparation of the potent anti-HIV agent.

Sodium hypochlorite pentahydrate (NaOCl·5H₂O) has recently become commercially available and is one of the promising oxidants for environmentally benign organic syntheses, because the postoxidation waste is “table salt”(NaCl). NaOCl·5H₂O has succeeded in overcoming many disadvantages of the conventional aqueous solution of sodium hypochlorite (aq. NaOCl, the concentration is up to 13%). NaOCl·5H₂O contains 44% NaOCl and minimal amounts of sodium hydroxide and NaCl. The aq. NaOCl is prepared from NaOCl·5H₂O and water, and has a lower pH value (ca. 11) than that of the conventional aq. NaOCl (ca. 13). NaOCl·5H₂O is more stable than the conventional aq. NaOCl below 7 °C. This review summarizes the organic synthetic reactions using NaOCl·5H₂O. The oxidation of primary or secondary alcohols (including sterically-hindered alcohols) can be efficiently carried out by using NaOCl·5H₂O in the presence of TEMPO (2,2,6,6-tetramethylpiperidin-1-oxyl) and tetrabutylammonium hydrogen sulfate as catalysts without pH adjustment. Even in the absence of catalysts, NaOCl·5H₂O selectively oxidizes allylic, benzylic, and secondary alcohols using acetonitrile as the solvent. Aliphatic primary alcohols are hard to oxidize under this reaction condition. NaOCl·5H₂O is applicable to glycol cleavage, and this reagent can easily cleave trans-cyclic glycols which are difficult to react with conventional “glycol cleavage” reagents. The oxidation of sulfides with an equimolar amount of NaOCl·5H₂O in aqueous acetonitrile selectively produces the corresponding sulfoxides in high yields under a catalyst-free condition. Sulfones are efficiently obtained by the oxidation of sulfides with 2.4 eq. of aqueous NaOCl prepared from NaOCl·5H₂O in toluene. This reaction is also catalyst-free. The reaction of disulfides or thiols with NaOCl·5H₂O in acetic acid produces sulfonyl chloride. The reaction of NaOCl·5H₂O with NaBr in acetic acid gives HOBr, and the resulting HOBr reacted with disulfides or thiols to afford the corresponding sulfonyl bromides. N-Sulfonyloxaziridines (Davis’ oxaziridines) can be synthesized by reacting the corresponding N-sulfonylimines with aqueous NaOCl in acetonitrile without any catalyst. The reaction of phenols with NaOCl·5H₂O in the presence of water causes oxidative dearomatization. (Diacetoxyiodo)arenes can be easily prepared from the reaction of iodoarenes with NaOCl·5H₂O in acetic acid.

Ferrocene, a prototypical sandwich compound, has attracted the attention of chemists since its discovery in 1951. The application of its unique structure as chiral phosphine ligand in transition metal catalysis is one of the most successful examples of ferrocene chemistry. Concurrent with these developments, N-heterocyclic carbene (NHC) ligands, which have characteristics different from phosphine ligands, have emerged as an indispensable tool in transition metal catalysis. What kind of ligand would be generated by combining a ferrocene and an NHC in one molecule? This review summarizes advances in this field that has started at the beginning of this century, focusing on planar-chiral, ferrocene-based NHC ligands.

Photopolymer materials have been widely used in some advanced industries owing to their practicability, low-cost and ecological advantage. One of the key components of these photopolymer materials is a molecule that releases acidic species upon a photon trigger (known as photo-acid generators, PAGs). Recently, PAGs have attracted much attention with the advent of novel technologies such as near-infrared CTP imaging, 3D printing and EUV lithography, and are required to have various functions and sophisticated features.

This review article describes recent advances in the molecular design and function of PAGs, which are required to respond to the increasing applications of the photopolymer materials in advanced industries.

Natural products have been regarded as a pivotal source for biological active compounds. In addition, structural modification of natural products has been simultaneously received much attention because these modified natural products would show not only enhanced activity and selectivity, but possibly also an entirely distinct bioactivity from those of the parent natural products. We describe herein a series of study on structual modification of ageladine A for exploring new biological activity. Ageladine A was isolated from the marine sponge Agelas nakamurai as an antiangiogenic compound. Based on total syntheses of this alkalod, its structual modifications were caried out as a part of SAR study, which revealed that a pyridine derivative shows a more potent activity. More recently, we have developed an efficient bio-inspired cascade reaction for the synthesis of ageladine A. The cascade reaction involves an aza-electrocyclization and a novel 2-aminoimidazole formation that is modeled after a post-translational modification of arginine residue in protein. Employing the cascade reaction, ageladine A and its N1-substituted analogues were efficiently synthesized in one-pot fashion from anilines or guanidines. In addition, it was found that some analogs showed significant activity on modulating neuronal differentiation. Namely, these analogs selectively activate or inhibit the differentiation of neural stem cells to neurons, while negligible in astrocyte differentiation. The series of study represent a successful case in altering native bioactivity of natural products by structural modification.

Carbocation chemistry is one of the most fundamental fields in organic chemistry. However, the use of carbocations as intermediates in asymmetric synthesis has remained an underdeveloped area due to the difficulty of controlling the enantiofacial selectivity of the carbocation. This article overviews recent synthetic strategies for enantiocontrol over tertiary carbocations.