Absolute Configuration of Small Molecules by Co‐Crystallization

Abstract

The most reliable method to determine the absolute configuration of chiral molecules is X‐ray crystallography, but small molecules can be difficult to crystallize. We report rapid co‐crystallization of tetraaryladamantanes with small molecules as different as n‐decane to nicotine to produce crystals for X‐ray analysis and the assignment of absolute configuration when the molecules are chiral. A screen of 52 diverse compounds gave inclusion in co‐crystals for 88 % of all cases and a high‐resolution structure in 77 % of cases. Furthermore, starting from three milligrams of analyte, a combination of NMR spectroscopy and X‐ray crystallography produced a full structure in less than three days using an adamantane crystallization chaperone that encapsulates the analyte at room temperature.

Absolute Configuration of Small Molecules by Co‐Crystallization

“…As our data shows, there are many more such mutually acceptable arrangements than for rigid, preformed lattices. [29] In conclusion, we report a method for structure elucidation of small molecules by using tetraaryladamantanes as crystallization chaperones. One-step crystallization occurs without the need for covalent bonds or strong directional interactions.…”

Structure and absolute configuration of liquid molecules based on adamantane derivative cocrystallization

“…To resolve this conict, it is necessary to introduce particular treatments according to previous reports. 18 Compared to the above reports, the homochiral natures of chiral compounds were further conrmed by solid CD spectrum.…”

“…Recently, another particularly signicant method using "crystallization chaperones" was presented. These crystallization chaperones, including tetraaryladamantanes [8][9][10][11][12][13][14][15][16][17][18][19] and trimesic acid, [20][21][22][23][24][25][26][27] readily form crystalline inclusion complexes with a range of guest molecules and provide accurate structural information on difficult-to-crystallize small molecules. Meanwhile, the high-throughput nanoscale crystallization of organicsoluble small molecules (encapsulated nanodroplet crystallization) was reported.…”

Absolute configuration determination of pharmaceutical crystalline powders by MicroED via chiral salt formation

“…As crystallography produces only one pair of possible structures regardless of the number of chiral centers, knowledge of the configuration of one chiral center allows the assignment of the remaining chiral centers (relative configuration). It is therefore possible to assign the absolute configuration of an API molecule by introducing a chiral standard using salt and/or cocrystal formation, a well-known strategy used in scXRD 9 , 22 , 23 and powder X-ray diffraction (PXRD). 24 , 25 Adopting the same methodology, we expect that the absolute configuration of an API can be readily determined by MicroED using internally referenced chiral salt or cocrystal powders.…”