Recently, sodium glucose cotransporter 2 (SGLT2) inhibitors have been received a lot of attention for the treatment of diabetes. C-arylglucoside compounds have been shown to be potent SGLT2 inhibition. Reports on the synthesis of SGLT2 inhibitors have appeared. Several reviews have also been reported as so far. This review deals with SGLT2 inhibitors approved by 2019 and the synthetic methods of some of these compounds, which have appeared in academic journals, from view point of synthetic strategy. The reactions of several kind of sugar electrophiles with aryl carbanions generated from aryl halides by the halogen-metal exchange reactions have met success to form the desired carbon-carbon bond. Lactone derivatives, anhydro-sugars and glycosyl halides have been used as sugar electrophiles. More recently, by use of α-oxo-vinylsulfone, cross-coupling with aryl boronate have been proven to afford C-aryl glycal leading to C-glucoside. Construction of aromatic ring by [4+2] cycloaddition of tetrahydropyran bearing dienone-yne under aerobic conditions has led to C-glucoside.

The solvent of a reaction is an important element in the synthetic preparation of chemical and pharmaceutical products. The uses of green solvents that balance safety, health and environmental aspects are increasingly desirable these days, especially in pilot-scale syntheses. Due to ease of handling, good solubility and low reactivity with reactants, low-molecular-weight ethers such as diethyl ether (Et₂O), tetrahydrofuran (THF), and tert-butyl methyl ether (TBME) are often used in laboratory-scale syntheses. These solvents, however, are less than ideal for large-scale synthesis due to their high inflammability, non-recyclabilty, and aptitude to form peroxides as well as volatile organic compound (VOC) emissions. Herein, I showcase the applicability of two recently developed, recyclable ethereal solvents, cyclopentyl methyl ether (CPME) and 4-methyltetrahydropyran (4-MeTHP), in organic synthesis, and their potential as alternatives to not only conventional ethers but also harmful aromatic hydrocarbon and halogenated solvents. In addition, the basic chemical properties involving stability and reactivity against free-radical, organometallic, oxidation, and other conditions, as well as possible degradation pathways are reported. These comprehensive studies are expected to inform a broad range of synthetic chemists, from beginners to professional process chemists, who require green chemistry perspectives to be met in the advanced organic synthesis of the 21st century.

Glycosyl phosphate repeat structures are seen in bacterial- and protozoan-derived sugar chains and these sugar chains have ten or more glycosyl phosphate repeats in many cases. Chemical synthesis of glycosyl phosphate repeats and their analogues can contribute to reveal their biological functions and to develop novel glycoconjugate vaccines and drugs. However, there is no synthetic approach for such long repeats on demand and only few repeats could be synthesized by most conventional approaches. One of the major problems of this difficulty is derived from the instability of glycosyl phosphates and their synthetic intermediates especially under acidic conditions. We used fluorinated sugar analogues of glycosyl phosphates to overcome the instability and achieved a stepwise solid-phase synthesis of a compound containing five such repeating units using the phosphoramidite approach. In addition, we have developed a phosphorus atom modified analogues of glycosyl phosphate repeats by various strategies.

Phosphodiesterase 10A (PDE10A) inhibitors are expected as a novel treatment of schizophrenia with no or less adverse effects caused by typical and atypical antipsychotic drugs. In the pursue of developing a novel PDE10A inhibitor, a pyridazin-4(1H)-one derivative was identified as a hit compound by high throughput screening (HTS) and the X-ray co-crystal structure of the hit compound with PDE10A enabled us a rational structure-based drug design (SBDD) approach. Following optimization focusing on topological polar surface area (TPSA) to enhance the brain-penetration led to discovery of Balipodect, a highly potent, selective, and orally active PDE10A inhibitor (IC₅₀＝0.30 nM, 18,000-fold selectivity over other PDEs). Balipodect is being developed in clinical trials for the treatment of schizophrenia. This article describes the successful example of the structure- and property-based drug designs from the HTS hit to the clinical compound. The development of optimal synthetic routes depending on each stage of the drug discovery is also discussed.

Phosphodiesterase (PDE) 2A inhibitors have emerged as a novel mechanism with potential therapeutic option to ameliorate cognitive dysfunction in schizophrenia or Alzheimer’s disease through upregulation of cyclic nucleotides in the brain and thereby achieve potentiation of cyclic nucleotide signaling pathways. In the search for a potent, selective, in vivo active PDE2A inhibitor, pyrazolo［1,5-a］pyrimidine 2 was identified as a hit compound from high-throughput screening (HTS) campaign of our in-house compound library. The ligand-based lead generation efforts led to the discovery of the promising lead molecule 8a. Further optimization of this lead was guided by its X-ray co-crystal structure in complex with PDE2A, thus culminating in the identification of the clinical candidate (1, TAK-915), which demonstrates an appropriate combination of potency, PDE selectivity, and favorable pharmacokinetic (PK) properties, including brain penetration. This article details the expedited lead generation and ensuing optimization approaches leading to the discovery of clinical candidate, as well as the synthetic route of TAK-915 for 1-week toxicological studies.

The noncovalent interactions, such as hydrogen bonding and ion pairing interaction, are widely recognized as the powerful tools to control enantio- and regio-selectivity in synthetic chemistry. However, most reactions have been relied on using hydrogen bond. This review highlights recent progress in developing an ion pairing interaction-driven approach to control regioselectivity. In particular, the remote aromatic C(sp²)-H bond borylation, which is highly challenging and valuable, is focused on.