A Fluorinated Chaperone Gives X-ray Crystal Structures of Acyclic Natural Product Derivatives up to 338 Molecular Weight.

Crystallizing molecules with long flexible chains is a challenge, making it difficult to perform X-ray crystallography. Chaperones can assist in the crystallization of compounds that do not crystallize by themselves by producing solvate crystals that contain the analyte in their three-dimensional lattices. Among the most versatile chaperones for liquid analytes are tetraaryladamantanes (TAAs), but the size of the compounds that can be encapsulated is limited, and attempts to surpass this limit with known TAAs were unsuccessful. Here we report that 1,3,5,7-tetrakis(2-fluoro-4-methoxyphenyl)adamantane (TFM) is a crystallization chaperone for acyclic molecules up to the molecular weight of phytyl acetate (338 g/mol). Encapsulation of such a large acyclic compound was achieved when the analyte was esterified and when a two-step temperature protocol was used for crystallization. Exploratory work indicates that a drop to -20 °C allows for encapsulation of squalene (Mr 411 g/mol), albeit with positional disorder of the analyte. Our X-ray crystal structures of solvates with flexible analytes shed light on how crystalline order can be imposed on large acyclic analytes. The new, fluorinated TAA gives access to crystal structures that were inaccessible thus far.