Chemists Give Peptidomimetics An F

Organofluorine chemists have long appreciated that fluorinated alkene groups can serve as stand-ins for amide groups in modified natural peptides or synthetic peptides being explored as drugs. Fluorine provides distinct properties, such as decreased hydrogen-bonding abilities, which can improve the stability and bioactivity of the peptidomimetics. Ming-Hsiu Yang, Siddharth S. Matikonda, and Ryan A. Altman of the University of Kansas, Lawrence, have now come up with a convenient strategy for introducing fluoroalkene groups into peptide building blocks, steroids, and other bioactive molecules at a late stage in the synthesis (Org. Lett. 2013, DOI: 10.1021/ol401637n). The team went after the fluoroalkenes by altering the Shapiro reaction, which is widely used in natural product synthesis. This reaction typically involves condensing an N-sulfonyl hydrazide with a ketone, creating a vinyllithium intermediate, and then trapping the vinyl anion with H⁺ to obtain the alkene product. In the Altman group’s fluorination scheme, the researchers used N-fluoro­benzenesulfonimide as a source of F⁺ to trap the fluoroalkene product. Given the number of ketone functional groups in natural products and pharmaceutically important building blocks, the researchers believe there’s a rich variety of substrates awaiting the new transformation.