Crystallization-induced diastereomer transformation of thiohydantoin derivatives

State of the Art in Crystallization‐Induced Diastereomer Transformations

“…a switch in configuration of the crystallizing product can be induced by using a different solvent; [47] in the realms of classic resolutions, this phenomenon is sometimes called solvent‐induced chirality switching [152] or dielectrically‐induced resolution ; [153]…”

“…Many useful comments and recommendations on developing CIDT protocols can be found in the concluding parts of reviews from Anderson [21f] or Brands with Davies. [21g] Instead of duplicating these useful hints and along with comments provided herein, in this review, we would like to underline several additional important factors to keep in mind when designing or interpreting a CIDT experiment: a) if CIDT proceeds with a racemic auxiliary, it is not 100% certain that it would as well be operative when enantiomerically pure auxiliary is used instead; [46c,113] b) if CIDT is operative both with racemic and enantiomerically pure auxiliary of the same structure, it should be not taken for granted that stereochemical outcome of these two experiments is the same; since enantiomerically pure compounds and their racemates differ in solubilities and relative stabilities of their crystals, the stereochemical outcome of CIDT can be altered depending on enantiomeric purity of the starting material; [46c,112] c) a switch in configuration of the crystallizing product can be induced by using a different solvent; [47] in the realms of classic resolutions, this phenomenon is sometimes called solvent-induced chirality switching [152] or dielectrically-induced resolution; [153] d) even a subtle structural modification, e. g. a different counterion, [76e] an additional substituent [61b] or an excessive reagent [117] can be translated into the product's different stereochemistry.…”

“…The point can be illustrated on CIDT of thiohydantoin derivatives A and B, recently published by Sakamoto et al (Scheme 2). [47] Both in methanol and chloroform, solubility ratios and chemical equilibria favor formation of diastereomer A. And indeed, CIDT in methanol, catalyzed by 10 mol% DBU, provided crystalline A in quantitative yield and essentially pure.…”

“…Just within 2.5 h, the originally minor C25 epimer precipitated out of heptane/toluene (3:1 v/v) in 64% yield and 12:1 dr. Sakamoto et al observed that, under basic conditions, thiohydantoin derivatives 64 a-c underwent fast ring opening/closing reactions via intermediate 65 (Scheme 25). [47] For example, when chloroform solution of (5R,1'R)-64 a (0.05 M) and DBU (0.005 M ) was used, the half-life of epimerization was determined to be 540 s at 25 °C. Taking into account crystalline nature of 64 a-c, CIDT was examined in several solvents with success.…”

Stereochemical switch driven by crystallization: Interplay between stoichiometry and configuration of the products

“…Crystallization as a separation and purification process offers numerous advantages, often reflected in both faster and higher mass throughput and overall cost reduction (for recent reviews on crystallization in pharmaceutical manufacturing, see Cote et al 1 and Orehek et al 2 ). Precipitation or crystallization of product(s), if taking place already in the course of a reaction, might bring additional benefits, for example, a significant increase of the reaction yields in equilibrating systems (illustrative examples: Lennox and Lloyd‐Jones, 3 Li and Li, 4 and Ji et al 5 ) or an altered reaction outcome (illustrative examples: Kato et al, 6 Zhang and Barboiu, 7 and Uemura et al 8 ). In the realms of stereoselective synthesis, the option of driving a reaction equilibrium towards a selectively crystallizing stereoisomer appears to be particularly appealing.…”