Enantiospecific Solid Solution Formation Triggers the Propagation of Homochirality

Baglai, Iaroslav; Leeman, Michel; Wurst, Klaus; Kellogg, Richard M.; Noorduin, Wim L.

doi:10.1002/ange.202009719

Cited by 7 publications

(2 citation statements)

References 42 publications

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“…59,60 Compound 2 crystallizes as a conglomerate and also readily undergoes racemization in the presence of DBU in methanol. 39,48,61 To demonstrate that the chiral amplification is also independent of the racemization catalyst, we use the organic base 1,1,3,3-tetramethylguanidine (TMG), which we show racemizes 2 as well (Figure S1). As proof of generality, akin to the abrupt cooling experiments for 1, we create a supersaturated solution of (RS)-2 (30 mg/mL) in the presence of 100 μL/mL TMG at 20 °C.…”

Section: Journal Of Thementioning

confidence: 99%

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

et al. 2022

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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.

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Section: Journal Of Thementioning

confidence: 99%

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

et al. 2022

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“…29−36 However, there are no reports of conglomerates that can handle many additives in any scenario to control the chirality of crystal growth. 37 For example, in the preferential crystallization of asparagine and glutamine without dynamic racemization, there is a pioneering report in which the reversal effect controls mirror images in which several amino acids are preferentially obtained. 38 In dynamic crystallization, it has been reported that, of the many additives tested during optical resolution by crystallization of binaphthyl, only mandelic acid and tartaric acid could perform chirality control.…”

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confidence: 99%

Behavior of All Chiral Standard Amino Acids for Chiral Symmetry Breaking of p-Anisoin

Miyazaki

Sanada

Nakamura

et al. 2022

Crystal Growth & Design

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The asymmetric amplification of p-anisoin was studied by attrition-enhanced deracemization in the presence of chiral standard amino acids. In this reaction, p-anisoin crystallized as a conglomerate, and deracemization under basic conditions was efficiently performed in 99% ee by Viedma ripening. Although the handedness of the enantioselective crystallization cannot be controlled by spontaneous crystallization, it could be governed by the coexistence of a catalytic amount of 16 chiral amino acids except cysteine, serine, and threonine. l-Amino acids tilted the handedness of enantiomer crystals to (R)-anisoin, while d-amino acids tilted it toward (S)-isomer crystals. It was clarified that this is due to the asymmetric transformation of p-anisoin in the mother liquor by the enantiomeric amino acids. The same slight asymmetric transformation in the solution phase was observed in α-hydroxyketones such as acetoin. Though the Soai reaction for an autocatalytic and asymmetric amplification system in the presence of a variety of chiral sources is famous, the crystallization-induced dynamic deracemization of p-anisoin provides the first chirality control system to be tilted by the enantioselective crystallization derived from many chiral additives.

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Combining Incompatible Processes for Deracemization of a Praziquantel Derivative under Flow Conditions

Valenti

Tinnemans²,

Baglai

et al. 2021

Angewandte Chemie

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An efficient deracemization method for conversion of the racemate to the desirable (R)-enantiomer of Praziquantel has been developed by coupling incompatible racemization and crystallization processes. By a library approach, a derivative that crystallizes as a conglomerate has been identified. Racemization occurs via reversible hydrogenation over a palladium on carbon (Pd/C) packed column at 130 8C, whereas deracemization is achieved by alternating crystal growth/ dissolution steps with temperature cycling between 5-15 8C. These incompatible processes are combined by means of a flow system resulting in complete deracemization of the solid phase to the desired (R)-enantiomer (98 % ee). Such an unprecedented deracemization by a decoupled crystallization/racemization approach can readily be turned into a practical process and opens new opportunities for the development of essential enantiomerically pure building blocks that require harsh methods for racemization.

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Enantiospecific Solid Solution Formation Triggers the Propagation of Homochirality

Cited by 7 publications

References 42 publications

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

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

Behavior of All Chiral Standard Amino Acids for Chiral Symmetry Breaking of p-Anisoin

Combining Incompatible Processes for Deracemization of a Praziquantel Derivative under Flow Conditions

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