Support of academic synthetic chemistry using separation technologies from the pharmaceutical industry

Abstract

The use of state-of-the-art separation tools from the pharmaceutical industry for addressing intractable separation problems from academic synthetic chemistry is evaluated, showing fast and useful results for the resolution of complex mixtures, separation of closely related components, visualization of difficult to detect compounds and purification of synthetic intermediates. Some recommendations for potential near term deployment of separation tools within academia and the evolution of next generation separation technologies are discussed.

Transition Metal-Mediated and Metal-Catalyzed Carbon–Fluorine Bond Formation

“…The fluorination of aryl triflates displays a broad substrate scope and tolerates nucleophilic functional groups not often tolerated in electrophilic fluorination reactions because of competing side reactions (vide infra). Reduction of the aryl triflate substrates to form C-H (rather than C-F) bonds was sometimes observed as an undesired minor side reaction; separation of fluoroarenes from reduced arene side products is typically challenging using standard chromatographic methods [107]. Protic functional groups are not tolerated due to the strongly basic anhydrous fluoride used.…”

Search for improved fluorinated stationary phases for separation of fluorine-containing pharmaceuticals from their desfluoro analogs

“…Fluorinated stationary phases have gained increasing importance in LC separations because they offer selectivity that is orthogonal to traditional alkyl phases, which operate predominately by hydrophobic interaction mechanisms. Fluorinated adsorbents afford retention by different mechanisms, providing an alternative and complementary selectivity for separation of isomers, halogenated, aromatic and/or polar compounds [15][16][17][18][19][20]. A number of perfluorophenyl and perfluoroalkyl stationary phases are commercially available, with the pentafluorophenyl, propyl-pentafluophenyl, perfluorododecyl, perfluoroctyl, perfluorohexyl and perfluoroalkyl branched chain stationary phases being the most popular.…”

Chirality imprinting and direct asymmetric reaction screening using a stereodynamic Brønsted/Lewis acid receptor

“…The overall pace of the discovery process, however, is still limited by the considerable amount of time that is required for the determination of the yield and the stereochemical outcome (enantiomeric excess and sense of asymmetric induction)—in particular when hundreds of reactions each performed on the milligram scale need to be analysed. This remaining bottleneck has pointed increasing attention to fast chromatographic methods5, mass spectrometry678, fluorescence91011 and ultraviolet (UV)1213 spectroscopy, infrared (IR) thermography14, NMR spectroscopy1516, electrochemistry17, and biochemical assays181920, all of which share the potential for high-throughput screening (HTS) of asymmetric reactions. The exceptional prospect of chiroptical sensing2122 has encouraged the development of a variety of circular dichroism probes by Berova23, Anslyn2425, Borhan26, Canary27, us2829 and others3031.…”