Frontispiece: Fluorine‐Containing Drugs Approved by the FDA in 2018

Recent progress in the application of fluorinated chiral sulfinimine reagents

Abstract The development of synthetic methodology allowing for a strategic incorporation of fluorine into target compounds is in a high demand in many areas of the chemical and pharmaceutical industries. In this regard, application of fluorinated chiral sulfinimine reagents, in particularly, N-tert-butylsulfinyl-3,3,3-trifluoroacetaldimine, is one of the most general and practical approaches for preparation of compounds containing pharmacophoric fluoro-amino-keto/hydroxy moieties. This article provides a timely and comprehensive overview of the recent synthetic applications of fluorinated chiral sulfinimine reagents for asymmetric synthesis of fluoro-containing polyfunctional amino-compound…

Chemistry of detrifluoroacetylativelyin situgenerated fluoro-enolates

This review article comprehensively profiles all literature reports (2015-2018) related to the detrifluoroacetylative in situ generation of fluorine-containing enolates and their reactions with electrophilic reagents. The innovative facets of this unconventional methodology and its synthetic generality for the preparation of fluorine-containing compounds of high medicinal value are highlighted.

The Ruthenium‐Catalyzed Domino Cross Enyne Metathesis/Ring‐Closing Metathesis in the Synthesis of Enantioenriched Nitrogen‐Containing Heterocycles

Fluorine-containing drugs approved by the FDA in 2019

Abstract Eleven new fluorine-containing FDA-approved drugs have been profiled and details of their discovery and preparation are discussed. Therapeutic areas include schizophrenia, migraine, multiple sclerosis, insomnia, rheumatoid arthritis, anti-tuberculosis, breast cancer, lymphoma kinase inhibitor, serotonin receptor antagonist. New pharmaceuticals feature four examples of aromatic fluorine, three aromatic CF3 group, three aliphatic CF3 and one compound with aromatic CF3O group. Furthermore, among the new compounds, six are chiral and seven are derived from tailor-made amino acids.

Recent Advances on the Halo- and Cyano-Trifluoromethylation of Alkenes and Alkynes

Incorporation of fluorine into organic molecules is a well-established strategy in the design of advanced materials, agrochemicals, and pharmaceuticals. Among numerous modern synthetic approaches, functionalization of unsaturated bonds with simultaneous addition of trifluoromethyl group along with other substituents is currently one of the most attractive methods undergoing wide-ranging development. In this review article, we discuss the most significant contributions made in this area during the last decade (2012−2021). The reactions reviewed in this work include chloro-, bromo-, iodo-, fluoro- and cyano-trifluoromethylation of alkenes and alkynes.

Asymmetric Michael Addition in Synthesis of β-Substituted GABA Derivatives

γ-Aminobutyric acid (GABA) represents one of the most prolific structural units widely used in the design of modern pharmaceuticals. For example, β-substituted GABA derivatives are found in numerous neurological drugs, such as baclofen, phenibut, tolibut, pregabalin, phenylpiracetam, brivaracetam, and rolipram, to mention just a few. In this review, we critically discuss the literature data reported on the preparation of substituted GABA derivatives using the Michael addition reaction as a key synthetic transformation. Special attention is paid to asymmetric methods featuring synthetically useful stereochemical outcomes and operational simplicity. This research was funded by the National Na…

Fluorine in pharmaceutical industry: fluorine-containing drugs introduced to the market in the last decade (2001-2011).

Tailor‐Made Amino Acids and Fluorinated Motifs as Prominent Traits in Modern Pharmaceuticals

Structural analysis of modern pharmaceutical practices allows for the identification of two rapidly growing trends: the introduction of tailor-made amino acids and the exploitation of fluorinated motifs. Curiously, the former represents one of the most ubiquitous classes of naturally occurring compounds, whereas the latter is the most xenobiotic and comprised virtually entirely of man-made derivatives. Herein, 39 selected compounds, featuring both of these traits in the same molecule, are profiled. The total synthesis, source of the corresponding amino acids and fluorinated residues, and medicinal chemistry aspects and biological properties of the molecules are discussed.

Asymmetric Synthesis of Fluorinated Monoterpenic Alkaloid Derivatives from Chiral Fluoroalkyl Aldimines via the Pauson‐Khand Reaction

Asymmetric Vinylogous Mukaiyama‐Mannich Reactions of Heterocyclic Siloxy Dienes with Ellman's Fluorinated Aldimines

Asymmetric Vinylogous Mannich-Type Addition of α,α-Dicyanoalkenes to α-Fluoroalkyl Sulfinyl Imines

Abstract. The asymmetric vinylogous Mannich reaction (AVMR) of alfa,alfa-dicyanoalkenes with alfa-fluoroalkyl sulfinyl imines has been successfully accomplished. This transformation is unprecedented with fluorinated imines at the same time as the use of dicyanoalkenes in AVMR has been scarcely reported. Several fluorinated sulfinyl imines are compatible with the process, which gaves access to a family of chiral fluorinated amines with excellent level of stereocontrol. Interestingly, the selectivity found in our protocol is reverse to that encountered in analogous AVMR previously reported. Additionally, the synthetic applicability of the addition products has been exemplified with several tr…

Fluorine-Containing Drugs Approved by the FDA in 2018

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.

Chemical Aspects of Human and Environmental Overload with Fluorine

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 an…

Stereoselective Synthesis of Fluorine-Containing β-Amino Acids

Frontispiece: Tailor‐Made Amino Acids and Fluorinated Motifs as Prominent Traits in Modern Pharmaceuticals

CCDC 1578271: Experimental Crystal Structure Determination

Related Article: Álvaro Sanz-Vidal, Javier Torres, Vadim A. Soloshonok, Yi Zhu, Jianlin Han, Santos Fustero, Carlos del Pozo|2018|Adv.Synth.Catal.|360|366|doi:10.1002/adsc.201701284

CCDC 1972570: Experimental Crystal Structure Determination

Related Article: Alberto Llobat, Jorge Escorihuela, Daniel M. Sedgwick, Miriam Rodenes, Raquel Román, Vadim A. Soloshonok, Jianlin Han, Mercedes Medio-Simón, Santos Fustero|2020|Eur.J.Org.Chem.|2020|4193|doi:10.1002/ejoc.202000598

CCDC 1908613: Experimental Crystal Structure Determination

Related Article: Santos Fustero, Miriam Rodenes, Raquel Román, Daniel M. Sedgwick, José Enrique Aguado, Vadim A. Soloshonok, Jianlin Han, Haibo Mei, Mercedes Medio‐Simon, Pablo Barrio|2019|Adv.Synth.Catal.|361|3860|doi:10.1002/adsc.201900464

CCDC 1578275: Experimental Crystal Structure Determination

Related Article: Álvaro Sanz-Vidal, Javier Torres, Vadim A. Soloshonok, Yi Zhu, Jianlin Han, Santos Fustero, Carlos del Pozo|2018|Adv.Synth.Catal.|360|366|doi:10.1002/adsc.201701284

CCDC 1908615: Experimental Crystal Structure Determination

Related Article: Santos Fustero, Miriam Rodenes, Raquel Román, Daniel M. Sedgwick, José Enrique Aguado, Vadim A. Soloshonok, Jianlin Han, Haibo Mei, Mercedes Medio‐Simon, Pablo Barrio|2019|Adv.Synth.Catal.|361|3860|doi:10.1002/adsc.201900464

CCDC 1908614: Experimental Crystal Structure Determination

Related Article: Santos Fustero, Miriam Rodenes, Raquel Román, Daniel M. Sedgwick, José Enrique Aguado, Vadim A. Soloshonok, Jianlin Han, Haibo Mei, Mercedes Medio‐Simon, Pablo Barrio|2019|Adv.Synth.Catal.|361|3860|doi:10.1002/adsc.201900464

CCDC 1578276: Experimental Crystal Structure Determination

Related Article: Álvaro Sanz-Vidal, Javier Torres, Vadim A. Soloshonok, Yi Zhu, Jianlin Han, Santos Fustero, Carlos del Pozo|2018|Adv.Synth.Catal.|360|366|doi:10.1002/adsc.201701284