Structural Elucidation and Absolute Stereochemistry for Pharma Compounds Using MicroED

Abstract

Microcrystal electron diffraction (microED) is an emerging technique for rapid crystallographic analysis of small molecule micro- and nanocrystals. In this report, we evaluate the applicability of microED to pharmaceutical compounds through the analysis of 30 samples obtained from the process and medicinal chemistry groups at Amgen Inc. Using only 40 h of microscope time, 15 of 30 crystal structures were elucidated. From these crystal structures, all chiral compounds had the correct absolute stereochemistry assigned by dynamical refinement of continuous rotation electron diffraction data, confirming dynamical refinement as a promising tool for the absolute stereochemistry determination of pharmaceutically relevant compounds.

Figure 1

Structures solved by microED where a preliminary solution was obtained in under 1 h each. Partial view of the asymmetric unit shown for samples 1 and 3 (Z′ = 2). Hydrogen atoms have been omitted for clarity.

Figure 2

Structures solved by microED where a preliminary solution was obtained (a) at cryogenic temperatures and in under 3 h each and (b) by extensive screening time and recrystallization trials. Partial view of the asymmetric unit shown for samples 7 (Z′ = 2), 11, 13, and 15 (Z′ = 4). Hydrogen atoms omitted for clarity.