Asymmetric Methods for Carbon‐Fluorine Bond Formation

Abstract

In memory of Ferenc FülöpAs a consequence of the ever-increasing relevance of fluorinated drugs in medicinal chemistry, organofluorine chemistry has become a hot topic research area during the last decade. Asymmetric carbon-fluorine bond-forming reactions have enormously developed in recent years with considerable findings related to novel reactions and synthetic approaches. These new synthetic efforts have contributed to the access to a growing number of fluorinated molecules and complex natural or synthetic products of high relevance in medicinal chemistry and drug research. Illustrative examples of novel synthetic methodologies, including organocatalytic processes, asymmetric syntheses or phase-transfer catalytic methods for the enantioselective incorporation of fluorine atom(s) into versatile molecular entities, are covered in the current Review, focusing on main contributions of the last ten years.

Fast, highly enantioselective, and sustainable fluorination of 4-substituted pyrazolones catalyzed by amide-based phase-transfer catalysts

“…3 Among them, direct enantioselective fluorination is undoubtedly one of the most profitable ways to obtain chiral fluorinated compounds. 4 Since the pioneering work on catalytic asymmetric fluorination by Togni 5 and Shibata, 6 numerous chiral metal complex-catalyzed 7 and organo-catalyzed systems 8 have been developed to afford highly substituted enantiomerically enriched fluorinated building blocks. Therefore, it is highly desirable to develop green and practical strategies and expand the substrate classes for asymmetric fluorination reaction.…”

Diastereoselective Synthesis, Glycosidase Inhibition, and Docking Study of C-7-Fluorinated Casuarine and Australine Derivatives

“…Of the small-molecule drugs approved by the FDA in the recent 5 years, approximately 40% of them contain fluorine, and a fair number of them contain fluorosugars. Therefore, the formation of carbon–fluorine bonds has attracted much research interest. , However, in many cases, especially for carbohydrates, regioselective and enantioselective fluorination has remained a significant challenge, and fluorination processes are frequently accompanied by elimination and rearrangement …”

Enantioenriched γ-Aminoalcohols, β-Amino Acids, β-Lactams, and Azetidines Featuring Tetrasubstituted Fluorinated Stereocenters via Palladacycle-Catalyzed Asymmetric Fluorination of Isoxazolinones

“…Fluorinated organic compounds have found widespread application, e.g., in the health, food, and energy industries. , For instance, in the pharmaceutical industry, around 35% of all active pharmaceutical ingredients (APIs) in clinical studies contain C–F bonds . More than half of the multibillion dollar drugs are organofluorine compounds …”

“…In strong contrast, less than 1% of all F-containing drugs or clinical candidates possess a F-substituted stereocenter, , although there are important drugs such as Fluticasone (treatment of asthma) and Solithromycin (treatment of pneumonia) featuring this structural motif. This situation is at least partially caused by the scarcity of general methods for catalytic asymmetric fluorination.…”

“…This situation is at least partially caused by the scarcity of general methods for catalytic asymmetric fluorination. Typical substrates for electrophilic fluorinations are pronucleophiles capable of two-point coordination to a Lewis acid, thus forming rigid metal enolates. , …”