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Absolute configuration determination of small molecules with X-ray and electron diffraction

By Dr. Bo Wang, Ph.D.
Biogen, Cambridge, MA

Absolute configuration determination of an active pharmaceutic ingredient (API) is a crucial task in drug development. Tremendous scientific and technical progress has been made to diffraction method to enable experimental determination of chirality. Together with X-ray diffraction, microcrystal electron diffraction (MicroED) has been shown its unique capacity in crystal structure elucidation. The minimal specimen preparation in MicroED is very attractive for the pharmaceutical industry, especially in early drug development when the quantity of test substances is limited. Without extensive crystal growth effort and material quantity limitation, this approach offers a readily route to obtain reliable absolute configuration early in the drug development process. In this talk, we showcase three real-world examples where X-ray and MicroED data was utilized to determine the absolute configuration of light-atom only containing pharmaceuticals. Besides showcasing one interesting chirality case with X-ray diffraction, we also present the feasibility of absolute structure determination via MicroED by using chiral salt formation, and moreover, without chiral reference by running the cutting-edge dynamical refinement method directly. This talk provides an overview of the utility of the latest advance with diffraction to not only enable, but also unambiguously assign absolute configuration for hard-to-crystallize, complex, and quantity-limited pharmaceutics.
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