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.
CONTENTS
Over the last two decades, fluorine substitution has become one of the essential structural traits in modern pharmaceuticals. Thus, about half of the most successful drugs (blockbuster drugs) contain fluorine atoms. In this review, we profile 17 fluorine‐containing drugs approved by the food and drug administration (FDA) in 2018. The newly approved pharmaceuticals feature several types of aromatic F and CF3, as well as aliphatic (CF2) substitution, offering advances in the treatment of various diseases, including cancer, HIV, malarial and smallpox infections.
Over
the last 100–120 years, due to the ever-increasing
importance of fluorine-containing compounds in modern technology and
daily life, the explosive development of the fluorochemical industry
led to an enormous increase of emission of fluoride ions into the
biosphere. This made it more and more important to understand the
biological activities, metabolism, degradation, and possible environmental
hazards of such substances. This comprehensive and critical review
focuses on the effects of fluoride ions and organofluorine compounds
(mainly pharmaceuticals and agrochemicals) on human health and the
environment. To give a better overview, various connected topics are
also discussed: reasons and trends of the advance of fluorine-containing
pharmaceuticals and agrochemicals, metabolism of fluorinated drugs,
withdrawn fluorinated drugs, natural sources of organic and inorganic
fluorine compounds in the environment (including the biosphere), sources
of fluoride intake, and finally biomarkers of fluoride exposure.
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