Identifying a Hidden Conglomerate Chiral Pool in the CSD

Abstract

Conglomerate crystallization is the spontaneous generation of individually enantioenriched crystals from a nonenantioenriched material. This behavior is responsible for spontaneous resolution and the discovery of molecular chirality by Pasteur. The phenomenon of conglomerate crystallization of chiral organic molecules has been left largely undocumented, with no actively curated list available in the literature. While other crystallographic behaviors can be interrogated by automated searching, conglomerate crystallizations are not identified within the Cambridge Structural Database (CSD) and are therefore not accessible by conventional automated searching. By conducting a manual search of the CSD and literature, a list of over 1800 chiral species capable of conglomerate crystallization was curated by inspection of the racemic synthetic routes described in each publication. The majority of chiral conglomerate crystals are produced and published by synthetic chemists who seldom note and rarely exploit the implications this phenomenon can have on the enantiopurity of their crystalline materials. With their structures revealed, we propose that this list of compounds represents a new chiral pool which is not tied to biological sources of chirality.

Conglomerate Crystallization in the CSD (2020–2021)

“…Publishing trends. The trend noted in our previous study 13 -that synthetic chemists are the primary generators of chiral conglomerate crystals within the CSD -has only strengthened between 2020-2021. Only 7.5% of chiral conglomerate crystals discovered in the CSD between 2020-2021 were published in crystallographic focused journals, as displayed in Figure 1.…”

“…Spacegroup frequency. The frequency of the Sohncke space groups of the conglomerate crystallizations reported in 2020-2021 could be compared to both the previously unearthed conglomerate crystallizations 13 and the overall frequency of Sohncke space groups for enantioenriched species in the CSD. 8 Unsurprisingly, the overall distribution of the space groups of the current cohort of chiral conglomerate crystals reported in this work matches those of our previous conglomerate search and the distribution of Sohncke space groups in the CSD.…”

“…The implications of this behavior and how to implement a conglomerate crystallization as a strategy for resolution and asymmetric synthesis have been discussed previously. 13 This conglomerate crystallization behavior is not being actively tracked within crystallographic databases because it is not standard practice to include the necessary metadata within a CIF. Without the inclusion of the relevant information which would identify a crystal as a conglomerate upon deposition of the CIF to a crystallographic database, chiral conglomerate crystals will be indistinguishable from other enantioenriched crystals which have originated from non-spontaneous asymmetric synthesis or have been isolated from natural sources when searched by automated means.…”

Conglomerate Crystallization in the Cambridge Structural Database (2020–2021)

“…33 EYEMIH, 34 OXACEY, 35 TUDVAS, 36 CUGXEK, 37 UWOBUG, 38 CUYREW, 39 BUHZEM, 40 SUNKUK, 41 PUGQEQ, 42 UHECUI, 43 OMEXAI, 44 Space Group Frequency. The frequency of the Sohncke space groups of the conglomerate crystallizations reported in 2020−2021 could be compared to both the previously unearthed conglomerate crystallizations 13 and the overall frequency of Sohncke space groups for enantioenriched species in the CSD. 8 Unsurprisingly, the overall distribution of the space groups of the current cohort of chiral conglomerate crystals reported in this work matches those of our previous conglomerate search and the distribution of Sohncke space groups in the CSD.…”

Chiral Amplification through the Interplay of Racemizing Conditions and Asymmetric Crystal Growth

“…Moreover, they offer practical routes for synthesis of essential molecules such as agricultural compounds and pharmaceuticals. − Amplification has been observed in catalysis, in which the chiral product exhibits a larger enantiomeric excess (ee) than the enantiopurity of the catalysts. , In the unique case of the Soai reaction, the reaction product even feeds back to catalyze its own formation, thus resulting in autocatalytic amplification . In contrast, amplification of ee is routinely observed during crystallization processes when enantiomers undergo racemization in solution while crystallizing in separate crystals (so-called conglomerates). ,− In particular, slurries of left- and right-handed enantiomorphic crystals can convert into an enantiopure phase via continuous growth and dissolution using, for instance, temperature gradient deracemization, temperature cycling-induced deracemization (TCID), − or attrition-enhanced deracemization (Viedma ripening). ,,,− Already, these deracemization processes have been demonstrated for a wide range of molecules, including precursors of agricultural compounds and blockbuster pharmaceuticals. ,,,− Even though there is still debate over the details of the underlying mechanism in these remarkable processes, there is a general consensus that the interplay between growth and dissolution is essential for achieving enantioenrichment through crystallization. ,,,− …”