Natural products (secondary metabolites) pose a unique problem in molecular structure solution, being both complex in form and typically only available in milligram quantities following laborious isolation protocols. The structural diversity of such natural products, and the need to determine absolute stereochemistry, means that single crystal X-ray diffraction (SCXRD) analysis is typically the go-to method in this field. However, sample limitations (typically &lt; 10 mg) means that the extensive experimental screening required for single crystal growth of a new molecule, the prerequisite of SCXRD analysis, becomes a significant limiting factor in progressing such a project.<br/>Herein we will present our work on the development of a high throughput Encapsulated Nanodroplet Crystallisation (ENaCt) method, that allows for the screening of hundreds of crystallisation conditions with minimal sample requirements. Through the use of nanolitre scale liquid handling robotics and multi-well plates, a few milligrams of isolated natural product is sufficient to test several hundred individual crystallisation experiments from both single and multiple solvent systems, each of which can provide a crystal suitable for SCXRD. We also show that initial crystallisation “hits” are amenable to follow-up experiments, from which higher quality crystals can be can obtained. This has allowed us to solve the structures of many previously uncrystallised natural products, from a wide range of biological sources. This approach has the potential to become a main-stay of future natural products research, as well as providing solutions in related sample limited structural elucidation problems.

High throughput encapsulated nanodroplet crystallisation (ENaCt) for the structural solution of complex natural products by X-ray diffraction

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