Kohei Matsuzaki

Bio: Kohei Matsuzaki is an academic researcher from Nagoya Institute of Technology. The author has contributed to research in topics: Trifluoromethylation & Enantioselective synthesis. The author has an hindex of 10, co-authored 18 publications receiving 972 citations.

Importance of a Fluorine Substituent for the Preparation of meta- and para-Pentafluoro-λ6-sulfanyl-Substituted Pyridines

Abstract: Although there are ways to synthesize ortho-pentafluoro-λ6-sulfanyl (SF5) pyridines, meta- and para-SF5-substituted pyridines are rare. We disclose herein a general route for their synthesis. The fundamental synthetic approach is the same as reported methods for ortho-SF5-substituted pyridines and SF5-substituted arenes, that is, oxidative chlorotetrafluorination of the corresponding disulfides to give pyridylsulfur chlorotetrafluorides (SF4Cl-pyridines), followed by chloride/fluoride exchange with fluorides. However, the trick in this case is the presence on the pyridine ring of at least one fluorine atom, which is essential for the successful transformation of the disulfides into m-and p-SF5-pyridines. After enabling the synthesis of an SF5-substituted pyridine, ortho-F groups can be efficiently substituted by C, N, S, and O nucleophiles through an SNAr pathway. This methodology provides access to a variety of previously unavailable SF5-substituted pyridine building blocks.

Advances in catalytic enantioselective fluorination, mono-, di-, and trifluoromethylation, and trifluoromethylthiolation reactions.

Abstract: Despite being largely absent from natural products and biological processes, fluorine plays a conspicuous and increasingly important role within pharmaceuticals and agrochemicals, as well as in materials science.1a−1c Indeed, as many as 35% of agrochemicals and 20% of pharmaceuticals on the market contain fluorine.1d Fluorine is the most electronegative element in the periodic table, and the introduction of one or more fluorine atoms into a molecule can result in greatly perturbed properties. Fluorine substituents can potentially impact a number of variables, such as the acidity or basicity of neighboring groups, dipole moment, and properties such as lipophilicity, metabolic stability, and bioavailability. The multitude of effects that can arise from the introduction of fluorine in small molecules in the context of medicinal chemistry has been extensively discussed elsewhere.2 For these reasons, methods to introduce fluorine into small organic molecules have been actively investigated for many years by specialists in the field of fluorine chemistry. However, particularly in the past decade, a combination of the increasing importance of fluorine-containing molecules and the successful development of bench stable, commercially available fluorine sources has brought the expansion of fluorine chemistry into the mainstream organic synthesis community. This has resulted in an acceleration in the development of new fluorination methods and consequently in methods for the asymmetric introduction of fluorine.3 Catalytic asymmetric fluorination methods have inevitably lagged somewhat behind their nonasymmetric counterparts as understanding of the modes of reactivity of new fluorinating reagents must generally be developed and understood before they can be extended to enantioselective catalysis.3b Indeed, the last special issue of Chemical Reviews dedicated to fluorine chemistry, in 1996, contained no articles addressing asymmetric fluorine chemistry, and the editor of the issue noted that “although fluorine chemistry is much less abstruse now than when I entered the field a generation ago, it remains a specialized topic and most chemists are unfamiliar, or at least uncomfortable, with the synthesis and behavior of organofluorine compounds.”4 The field has undoubtedly undergone great change within the last two decades. As with the incorporation of the fluorine atom, the introduction of the trifluoromethyl (CF3) group into organic molecules can substantially alter their properties. As with fluorine, the prevalence of CF3 groups in pharmaceuticals and agrochemicals coupled with the development of new trifluoromethylating reagents also has led to a recent surge in the development of asymmetric trifluoromethylation and perfluoroalkylation. Although the fluorine and trifluoromethyl moieties are often found on the aromatic rings of many pharmaceutical and agrochemicals rather than in aliphatic regions, this may be a result of the lack of efficient methods for the asymmetric introduction of C–F and C–CF3 bonds into molecules; it could be the case that lack of chemical methods is restricting useful exploration of such molecules. However, there are still encouraging examples of drug candidates containing chiral fluorine and trifluoromethyl-bearing carbons (Figure ​(Figure11). Figure 1 Molecules of medicinal interest bearing C–F and C–CF3 stereocenters.

Contribution of Organofluorine Compounds to Pharmaceuticals.

Abstract: Inspired by the success of fluorinated corticosteroids in the 1950s and fluoroquinolones in the 1980s, fluorine-containing pharmaceuticals, which are also known as fluoro-pharmaceuticals, have been attracting attention for more than half of a century. Presently, about 20% of the commercial pharmaceuticals are fluoro-pharmaceuticals. In this mini-review, we analyze the prevalence of fluoro-pharmaceuticals in the market and categorize them into several groups based on the chemotype of the fluoro-functional groups, their therapeutic purpose, and the presence of heterocycles and/or chirality to highlight the structural motifs, patterns, and promising trends in fluorine-based drug design. Our database contains 340 fluoro-pharmaceuticals, from the first fluoro-pharmaceutical, Florinef, to the latest fluoro-pharmaceuticals registered in 2019 and drugs that have been withdrawn. The names and chemical structures of all the 340 fluorinated drugs discussed are provided in the Supporting Information.

Modern Approaches for Asymmetric Construction of Carbon–Fluorine Quaternary Stereogenic Centers: Synthetic Challenges and Pharmaceutical Needs

Abstract: New methods for preparation of tailor-made fluorine-containing compounds are in extremely high demand in nearly every sector of chemical industry. The asymmetric construction of quaternary C–F stereogenic centers is the most synthetically challenging and, consequently, the least developed area of research. As a reflection of this apparent methodological deficit, pharmaceutical drugs featuring C–F stereogenic centers constitute less than 1% of all fluorine-containing medicines currently on the market or in clinical development. Here we provide a comprehensive review of current research activity in this area, including such general directions as asymmetric electrophilic fluorination via organocatalytic and transition-metal catalyzed reactions, asymmetric elaboration of fluorine-containing substrates via alkylations, Mannich, Michael, and aldol additions, cross-coupling reactions, and biocatalytic approaches.