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

Abstract

Amplification of enantiomeric excesses (ee) is routinely observed during chiral crystallization of conglomerate crystals for which the enantiomers undergo racemization in solution. Although routes comprising a combination of crystal growth and dissolution are frequently used to obtain enantiopure molecules, crystal growth by itself has rather been considered as a source of enantiomeric erosion and discounted as a potential source of enantiomeric amplification. Counterintuitively, we here demonstrate striking enantiomeric amplification during crystal growth for clopidogrel and tert-leucine precursors. Based on a mechanistic framework, we identify that the interplay between racemization and crystal growth rates elicits this surprising effect. The asymmetric amplification of the solid-phase ee can be enhanced by increasing the mass of grown material relative to the product such that small amounts of seeds of only 60% ee already result in virtually exclusive growth of the majority phase. These results impact our understanding of asymmetric amplification mechanisms during crystallization and offer a tangible basis for practical production of enantiopure molecules.

Rapid deracemization through solvent cycling: proof-of-concept using a racemizable conglomerate clopidogrel precursor

“…Specifically, we recently showed that slow growth and deep cooling result in large asymmetric crystallization with virtually exclusive growth of the majority phase. 16 In contrast, we here realize that fast heating should be favourable to keep the overall cycle time short. Hence, we hypothesize that a process combining slow crystal growth and fast dissolution would be ideal to achieve rapid deracemization.…”

“…Finally, the supersaturation increases rapidly at high temperatures, leading to undesired primary nucleation and fast growth with low chiral enrichment by asymmetric crystal growth. 16 These considerations highlight the importance of solvent choice for solvent cycling-induced deracemization.…”

“…17 Since 1 has been studied extensively in various crystallization-induced deracemizations, this is an ideal model compound to demonstrate the proof-of-principle and benchmark the performance with previously developed methods. 6,11,16,17 To realize solvent cycling-induced deracemization experimentally, we repurpose a Soxhlet apparatus (Fig. 2b).…”

Nonclassical Crystallization Causes Dendritic and Band‐Like Microscale Patterns in Inorganic Precipitates

“…[1,2] However, systems deviating from this conventional mechanism have questioned the comprehensiveness of this framework, sparking vigorous experimental and theoretical investigations into nonclassical crystallization (NCC). [3][4][5][6] The primary objective of NCC studies is to understand and regulate growth processes driven by particle attachment, encompassing nanoparticles, clusters, and liquid precursor phase droplets. [7][8][9] Achieving even partial success in these pursuits holds not only the potential for a more profound understanding of diverse geochemical and biomineralization processes but also for the development of advanced synthesis techniques for materials unconstrained by the geometric limitations of crystal unit cells.…”

“…The emergence of these solids from a homogeneous phase typically relies on the stochastic and dynamic addition of atoms, ions, or molecules [1,2] . However, systems deviating from this conventional mechanism have questioned the comprehensiveness of this framework, sparking vigorous experimental and theoretical investigations into nonclassical crystallization (NCC) [3–6] . The primary objective of NCC studies is to understand and regulate growth processes driven by particle attachment, encompassing nanoparticles, clusters, and liquid precursor phase droplets [7–9] .…”