Visualizing stereochemistry with electron diffraction

Using the diffraction of electrons, rather than X-rays, to determine the structure of small molecules has gained popularity among organic chemists because it allows them to get structural information from nanoscale crystals instead of much larger, high-quality crystals. But the technique hasn’t been able to provide them with a key piece of information—a molecule’s absolute stereochemistry—until now. Researchers led by Petr Brázda of the Czech Academy of Sciences report a method for determining the absolute stereochemistry of the molecules in a cocrystal of the hepatitis C therapy sofosbuvir and L-proline (shown). Scientists have previously used electron diffraction to determine the absolute stereochemistry of inorganic compounds, but doing the same analysis on compounds that contain only light atoms, like many drug molecules, was problematic because the electron beam destroys the nanocrystals. Brázda’s team managed to get around the problem by studying the electron diffraction patterns taken from different spots on four nanocrystals. The absolute stereochemistry was established by evaluating multiple scattering effects, also known as dynamical diffraction effects (Science 2019, DOI: 10.1126/science.aaw2560). The technique could become a tool for determining the absolute stereochemistry of small-molecule drug candidates, which is required for approval from the US Food and Drug Administration.