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Visible light-driven photocatalytic deracemization is highly esteemed as an ideal tool for organic synthesis due to its exceptional atom economy and synthetic efficiency. Consequently, successful instances of deracemization of allenes have been established, where the activated energy of photosensitizer should surpass that of the substrates, representing an intrinsic requirement. Accordingly, this method is not applicable for axially chiral molecules with significantly high triplet energies. In this study, we present a photoredox catalytic deracemization approach that enables the efficient synthesis of valuable yet challenging-to-access axially chiral 2-azaarene-functionalized quinazolinones. The substrate scope is extensive, allowing for both 3-axis and unmet 1-axis assembly through facile oxidation of diverse central chiral 2,3-dihydroquinazolin-4(1H)-ones that can be easily prepared and achieve enantiomer enrichment via deracemization. Mechanistic studies reveal the importance of photosensitizer selection in attaining excellent chemoselectivity and highlight the indispensability of a chiral Brønsted acid in enabling highly enantioselective protonation to accomplish efficient deracemization.

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The bioderacemization of racemic phosphinothricin (D, L-PPT) is a promising route for the synthesis of l-phosphinothricin (L-PPT). However, the low activity and tolerance of wild-type enzymes restrict their industrial applications. Two stereocomplementary aminotransferases with high activity and substrate tolerance were identified in a metagenomic library, and a one-pot, two-stage artificial cascade biocatalytic system was developed to produce L-PPT through kinetic resolution and asymmetric amination. We observed that 500 mM D, L-PPT (100 g/L) could be converted into L-PPT with 94% final conversion and >99.9% enantiomeric excess (e.e.) within 24 h, with only 0.02 eq amino acceptor pyruvate and 1.2 eq amino donor l-aspartate required. The process could be scaled up to 10 L under sufficient oxygen and stirring. The superior catalytic performance of this system provides an eco-friendly and sustainable approach to the industrial deracemization of D, L-PPT to L-PPT.

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Multi-enzyme cascade catalysis has become an important technique for chemical reactions used in manufacturing and scientific study. In this research, we designed a four-enzyme integrated catalyst and used it to catalyse the deracemization reaction of cyclic chiral amines, where monoamine oxidase (MAO) catalyses the enantioselective oxidation of 1-methyl-1,2,3,4-tetrahydroisoquinoline (MTQ), imine reductase (IRED) catalyses the stereo selective reduction of 1-methyl-3,4-dihydroisoquinoline (MDQ), formate dehydrogenase (FDH) is used for the cyclic regeneration of cofactors, and catalase (CAT) is used for decomposition of oxidative reactions. The four enzymes were immobilized via polydopamine (PDA)-encapsulated dendritic organosilica nanoparticles (DONs) as carriers, resulting in the amphiphilic core-shell catalysts. The hydrophilic PDA shell ensures the dispersion of the catalyst in water, and the hydrophobic DON core creates a microenvironment with the spatial confinement effect of the organic substrate and the preconcentration effect to enhance the stability of the enzymes and the catalytic efficiency. The core-shell structure improves the stability and reusability of the catalyst and rationally arranges the position of different enzymes according to the reaction sequence to improve the cascade catalytic performance and cofactor recovery efficiency.

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A fundamental question associated with chirality is how mixtures containing equal amounts of interconverting enantiomers can spontaneously convert to systems enriched in only one of them. Enantiomers typically have similar chemical properties, but can exhibit distinct reactivity under specific conditions, and these differences can be used to bias the system's composition in favor of one enantiomer. Transport properties are also expected to differ for enantiomers in chiral solvents, but the role of such differences in chiral symmetry breaking has not been clarified yet. In this work, we develop a theoretical framework to show that asymmetry in diffusion properties can trigger a spontaneous and selective symmetry breaking in mixtures of enantiomers. We derive a generic evolution equation for the enantiomeric excess in a chiral solvent. This equation shows that the relative stability of homochiral domains is dictated by the difference of diffusion coefficients of the two enantiomers. Consequently, deracemization toward a specific enantiomeric excess can be achieved when this difference is large enough. These results hold significant implications for our understanding of chiral symmetry breaking.

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A novel one-pot deracemization method using a bifunctional chiral agent (BCA) is proposed for the first time to convert a racemate to the desired enantiomer. Specifically, chiral α, (α-diphenyl-2-pyrrolidinemethanol) formed enantiospecific cocrystals with racemic dihydromyricetin, and used its own alkaline catalysis to catalyze the racemization between the (2R,3R)-enantiomer and (2S,3S)-enantiomer in solution, achieving a one-pot spontaneous deracemization. This strategy was also successfully extended to the deracemization of three other racemic compound drugs: (R,S)-carprofen, (R,S)-indoprofen, and (R,S)-indobufen. The one-pot deracemization method based on the BCA strategy provides a feasible approach to address the incompatibility between cocrystallization and racemization reactions that are commonly encountered in the cocrystallization-induced deracemization process and opens a new window to develop essential enantiomerically pure pharmaceutical products with atom economy.

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Enantiomerically pure D-amino acids hold significant potential as precursors for synthesizing various fine chemicals, including peptide-based drugs and other pharmaceuticals. This study focuses on establishing an enzymatic cascade system capable of converting various L-amino acids into their D-isomers. The system integrates four enzymes: ancestral L-amino acid oxidase (AncLAAO-N4), D-amino acid dehydrogenase (DAADH), D-glucose dehydrogenase (GDH), and catalase. AncLAAO-N4 initiates the process by converting L-amino acids to corresponding keto acids, which are then stereo-selectively aminated to D-amino acids by DAADH using NADPH and NH4Cl. Concurrently, any generated H2O2 is decomposed into O2 and H2O by catalase, while GDH regenerates NADPH from D-glucose. Optimization of reaction conditions and substrate concentrations enabled the successful synthesis of five D-amino acids, including a D-Phe derivative, three D-Trp derivatives, and D-phenylglycine, all with high enantiopurity (>99 % ee) at a preparative scale (>100 mg). This system demonstrates a versatile approach for producing a diverse array of D-amino acids.

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Transaminase (TA) is a crucial biocatalyst for enantioselective production of the herbicide L-phosphinothricin (L-PPT). The use of enzymatic cascades has been shown to effectively overcome the unfavorable thermodynamic equilibrium of TA-catalyzed transamination reaction, also increasing demand for TA stability. In this work, a novel thermostable transaminase (PtTA) from Pseudomonas thermotolerans was mined and characterized. The PtTA showed a high specific activity (28.63 U/mg) towards 2-oxo-4-[(hydroxy)(methyl)phosphinoyl]butyric acid (PPO), with excellent thermostability and substrate tolerance. Two cascade systems driven by PtTA were developed for L-PPT biosynthesis, including asymmetric synthesis of L-PPT from PPO and deracemization of D, L-PPT. For the asymmetric synthesis of L-PPT from PPO, a three-enzyme cascade was constructed as a recombinant Escherichia coli (E. coli G), by co-expressing PtTA, glutamate dehydrogenase (GluDH) and D-glucose dehydrogenase (GDH). Complete conversion of 400 mM PPO was achieved using only 40 mM amino donor L-glutamate. Furthermore, by coupling D-amino acid aminotransferase (Ym DAAT) from Bacillus sp. YM-1 and PtTA, a two-transaminase cascade was developed for the one-pot deracemization of D, L-PPT. Under the highest reported substrate concentration (800 mM D, L-PPT), a 90.43% L-PPT yield was realized. The superior catalytic performance of the PtTA-driven cascade demonstrated that the thermodynamic limitation was overcome, highlighting its application prospect for L-PPT biosynthesis. KEY POINTS: • A novel thermostable transaminase was mined for L-phosphinothricin biosynthesis. • The asymmetric synthesis of L-phosphinothricin was achieved via a three-enzyme cascade. • Development of a two-transaminase cascade for D, L-phosphinothricin deracemization.

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Attrition-enhanced chiral symmetry breaking in crystals, known as Viedma deracemization, is a promising method for converting racemic solid phases into enantiomerically pure ones under non-equilibrium conditions. However, many aspects of this process remain unclear. In this study, we present a new investigation into Viedma deracemization using a comprehensive kinetic rate equation continuous model based on classical primary nucleation theory, crystal growth, and Ostwald ripening. Our approach employs a fully microreversible kinetic scheme with a size-dependent solubility following the Gibbs-Thomson rule. To validate our model, we use data from a real NaClO3 deracemization experiment. After parametrization, the model shows spontaneous mirror symmetry breaking (SMSB) under grinding. Additionally, we identify a bifurcation scenario with a lower and upper limit of the grinding intensity that leads to deracemization, including a minimum deracemization time within this window. Furthermore, this model uncovers that SMSB is caused by multiple instances of concealed high-order autocatalysis. Our findings provide new insights into attrition-enhanced deracemization and its potential applications in chiral molecule synthesis and understanding biological homochirality.

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Substituted derivatives of the DOTA framework are of general interest to alter chelate properties and facilitate the conjugation of chelates to other molecular structures. However, the scope of substituents that can be introduced into the α-position has traditionally been limited by the availability of a suitable enantiopure starting materials to facilitate a stereoselective synthesis. Tetra-substituted DOTA derivatives with phenyl and benzoate substituents in the α-position have been prepared. Initial syntheses used enantiopure starting materials but did not afford enantiopure products. This indicates that the integrity of the stereocenters was not preserved during synthesis, despite the homo-chiral diastereoisomer being the major reaction product. The homochiral diastereoisomer could be produced as the major or sole reaction product when starting from racemic or even achiral materials. Deracemization was found to occur during chelation through the formation of an enolate stabilized by the aryl substituent. This general ability of aryl groups to enable deracemization greatly increases the range of substituents that can be introduced into DOTA-type ligands with diastereochemical selectivity.

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d-pantolactone is an intermediate in the synthesis of d-pantothenic acid, which is known as vitamin B5. The commercial synthesis of d-pantolactone is carried out through the selective resolution of dl-pantolactone catalyzed by lactone hydrolase. In contrast to a kinetic resolution approach, the deracemization of dl-pantolactone is a simpler, greener, and more sustainable way to obtain d-pantolactone with high optical purity. Herein, an efficient three-enzyme cascade was developed for the deracemization of dl-pantolactone, using l-pantolactone dehydrogenase from Amycolatopsis methanolica (AmeLPLDH), conjugated polyketone reductase from Zygosaccharomyces parabailii (ZpaCPR), and glucose dehydrogenase from Bacillus subtilis (BsGDH). The AmeLPLDH was used to catalyze the dehydrogenated l-pantolactone into ketopantolactone; the ZpaCPR was used to further catalyze the ketopantolactone into d-pantolactone; and glucose dehydrogenase together with glucose fulfilled the function of coenzyme regeneration. All three enzymes were co-expressed in E. coli strain BL21(DE3), which served as the whole-cell biocatalyst. Under optimized conditions, 36 h deracemization of 1.25 M dl-pantolactone d-pantolactone led to an e.e.p value of 98.6%, corresponding to productivity of 107.7 g/(l·d).

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Biocatalytic processes are increasingly used in organic synthesis for the preparation of targeted molecules or the generation of molecular diversity. The search for the biocatalyst is often the bottleneck in the development of the process. We described a combinatorial approach for the selection of active strains from a library of microorganisms. In order to show the potential of the method we applied it to a mixture of substrates. We were able to select yeast strains capable of producing enantiopure alcohol from corresponding ketones with very few tests and highlight tandem reaction sequences involving several microorganisms. We demonstrate an interest in the kinetic study and the importance of incubation conditions. This approach is a promising tool for generating new products.

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A series of poly(biarylylacetylene)s (PBAs) bearing axially-chiral (S)-and (R)-pyridyl-N-oxide residues with a methoxy, propoxy, or acetyloxy substituent at the 3-position of the biaryl units was synthesized. All the PBAs formed a preferred-handed helix, while the helical sense preference was varied depending on the substituents despite the same twist-sense of the biaryl units. Among them, the propoxy-bound helical PBA showed an exceptionally high chiral recognition ability as a chiral stationary phase (CSP) for high-performance liquid chromatography (HPLC) and efficiently resolved not only various chiral aromatic alcohols, but also a variety of chiral aliphatic alcohols; the latter still remains difficult to resolve by commercially-available CSPs in HPLC. Such practically-useful both handed helical PBA-based CSPs can be produced from the racemic PBA composed of fully racemic monomer units through deracemization of the biaryl units with a chiral alcohol.

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We report the first case of mechanochemical deracemization by using liquid-assisted abrasive grinding. The target molecule is a precursor of Paclobutrazol, an important fungicide and plant growth inhibitor. Using mechanochemical deracemization, we are even able to transform a 10 % ee scalemic mixture of this latter in an enantioenriched product of 97 % ee in a couple of hours. This is substantially shorter compared to solution-based deracemization methodologies. The present paper thus introduces an efficient and greener process to enantiopure material.

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In this work we review research activities on a few of the most relevant structural aspects of bilirubin (BR) and biliverdin (BV). Special attention is paid to the exocyclic C=C bonds being in mostly Z rather than E configurations, and to the overall conformation being essentially different for BR and BV due to the presence or absence of the double C=C bond at C-10. In both cases, racemic mixtures of each compound of either M or P configuration are present in achiral solutions; however, imbalance between the two configurations may be easily achieved. In particular, results based on chiroptical spectroscopies, both electronic and vibrational circular dichroism (ECD and VCD) methods, are presented for chirally derivatized BR and BV molecules. Finally, we review deracemization experiments monitored with ECD data from our lab for BR in the presence of serum albumin and anesthetic compounds.

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Asymmetric catalysis has long been recognized as a powerful tool for the synthesis of enantioenriched molecules. In addition to precise enantiocontrol, high-atom economy, which is crucial for practicality, has always been pursued by chemists in the development of methodologies. Consequently, deracemization, the direct conversion of a racemic compound to one of its enantiomers, and thus characterized by a 100 % atom efficiency, has attracted increasing interest. Recently, visible-light-driven photocatalysis has been demonstrated to be a promising platform for the development of deracemization. Central to its success is its ability to efficiently overcome the prevailing kinetic issues in chemical transformations and the intrinsic thermodynamic challenges, which typically require the use of additional stoichiometric reagents, thus undermining the original advantages. In this review, the advances in this attractive area are systematically summarized and discussed, with examples organized according to the different modalities of energy transfer and single-electron transfer in photocatalysis.

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Deracemization extended to racemic-compound-forming systems is demonstrated. We present here the first results of an alternative for the resolution of systems that exhibit a stable racemic compound but also a closely related conglomerate-forming system. If the couples of enantiomers forming the racemic compound and the enantiomers of the stable conglomerate can syncrystallize in mirror-related partial solid solutions, it is possible to deracemize the racemic mixture of mixed crystals to access to a single handedness. The evidence for this possibility is given in three examples by using temperature-cycling-induced deracemization.

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Stereochemical editing has recently risen to prominence, allowing the direct editing of organic molecules with stereocenter(s) to adjust their relative stereochemistry at a late-stage. Several seminal light-driven stereochemical editing reactions such as deracemization and epimerization have been successively developed. Recently, Wendlandt and co-workers reported a versatile photochemical epimerization of unactivated tertiary stereogenic centers to rapidly prepare the stereoisomers that were previously challenging to access.

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Catalytic deracemization is an ideal synthetic strategy due to its formally perfect atom utilization. Asymmetric photocatalysis has been appreciated as a promising tool to accomplish this attractive reaction pattern in an economical fashion, but it remains underdeveloped. Here, we report a new platform based on photoredox-neutral catalysis, allowing efficient and modular optical enrichment of α-amino esters and other valuable analogues. Two single-electron transfer processes between the photocatalyst and the substrates serve to provide the key prochiral intermediates, and the chiral Brønsted acid catalyst mediates enantioselective protonation to reconstitute a stereogenic C-H bond. The efficiency of deracemization is determined by the enantiofacial differentiation effect during the stereocentre-forming step.

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Optically pure sulfoxides are noteworthy compounds applied in a wide range of industrial fields; however, the biocatalytic deracemization of racemic sulfoxides is challenging. Herein, a high-enantioselective methionine sulfoxide reductase A (MsrA) was combined with a low-enantioselective styrene monooxygenase (SMO) for the cyclic deracemization of sulfoxides. Enantiopure sulfoxides were obtained in >90 % yield and with >90 % enantiomeric excess (ee) through dynamic "selective reduction and non-selective oxidation" cycles. The cofactors of MsrA and SMO were subsequently regenerated by the cascade catalysis of three auxiliary enzymes through the consumption of low-cost D-glucose. Moreover, this "one-pot, one-step" cyclic deracemization strategy exhibited a wide substrate scope toward various aromatic, heteroaromatic, alkyl and thio-alkyl sulfoxides. This system proposed an efficient strategy for the green synthesis of chiral sulfoxide.

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Crystallization is one of the largest and most economical bulk purification techniques used in industry today. There has been an increase in demand for enantiomerically pure compound production for research, organic synthesis, pharmaceutical drug production, and other applications. Even after asymmetric synthesis, chiral purification will always be necessary. The focus of this review is on recent advances in chiral crystallization for the purification of enantiomers. A comprehensive discussion of three techniques and their mechanisms is provided, namely: attrition-enhanced deracemization, cocrystallization, and inorganic ionic cocrystallization. Several examples of attrition-enhanced deracemization are discussed. The key advantage of this technique is that it eliminates enantiomeric waste and can be used to produce enantiomeric excesses of greater than 99% from racemic mixtures. Chiral cocrystallization is examined, with over 60 cocrystallizing compounds, as an excellent means for enantiomeric enrichment. Selective chiral inclusion complexation was shown to be a novel approach for the formation of cocrystals. Chiral inorganic ionic cocrystallization is a new technique involving the formation of cocrystals between chiral ligands and certain metal salts in order to produce conglomerate crystal behavior in otherwise racemic compounds.

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