On Solute Recovery and Productivity in Chiral Resolution through Solid-State Deracemization by Temperature Cycling.

Temperature cycling represents an effective means for the deracemization of chiral compounds that crystallize as conglomerates and racemize in solution. In such a process, a suspension enriched in the desired enantiomer is converted into an enantiopure one through periodic cycles of crystal dissolution and crystal growth. We show that performing temperature cycling at higher temperatures leads to faster deracemization and, consequently, higher productivity. However, this comes at the cost of lower recovery, as the solution contains potentially relevant amounts of solute due to the higher solubility at an elevated temperature. In this work, we introduce and compare two process variants that mitigate this issue. The first involves temperature cycling, followed by linear cooling, whereas the second is based on merging the temperature cycles and cooling crystallization. Experiments carried out with the chiral compound N-(2-methylbenzylidene)-phenylglycine amide show that the former variant is faster than the latter, and it is easier to design and implement. In this process, the choice of an appropriate cooling rate is essential to avoid nucleation of the undesired enantiomer.

Exact and Ubiquitous Condition for Solid-State Deracemization in Vitro and in Nature.

Solid-state deracemization is the amplification of an enantiomeric excess in suspensions of conglomerate-forming chiral compounds. Although numerous chemical and biochemical compounds deracemize, its governing mechanism has remained elusive. We introduce a novel formulation of the classical population-based model of deracemization through temperature cycles to prove that suspensions deracemize whenever a simple and ubiquitous condition is met: crystal dissolution must be faster than crystal growth. Such asymmetry is a known principle of crystallization, hence explaining the generality of deracemization. Through both experiments and a theoretical analysis, we demonstrate that this condition applies even for very small temperature cycles and for random temperature fluctuations. These findings establish solid-state deracemization as an attractive route to the manufacture of enantiopure products and as a plausible pathway toward the emergence of homochirality in nature.