High Optical Purity Research Articles

Enantioselective Synthesis of vic-Aminoalcohol Derivatives by Nickel-Catalyzed Reductive Coupling of Aldehydes with Protected Amino-pentadienoates.

A VAPOL-derived phosphoramidite ligand is uniquely effective at reverting the regiochemical course of nickel-catalyzed reactions of aldehydes with carbamate-protected 5-amino-2,4-pentadienoates as "push/pull" dienes; the ensuing carbonyl α-amino-homoallylation reaction affords anti-configured vic-aminoalcohol derivatives in good yields with high optical purity. The reductive coupling is conveniently performed with a bench-stable Ni(0) precatalyst and Et3B as the promoter.

Catalytic Asymmetric Synthesis of Chiral Fluorenes: Recent Developments and Future Perspectives

The chiral fluorene fragment constitutes one of the most important scaffolds frequently found in numerous bioactive molecules, ligands, and advanced functional materials due to its unique physical properties. In this context, various transition metal‐ and organo‐catalyzed asymmetric reactions have been developed to prepare chiral fluorenes with high optical purity. In the present mini‐review, we summarize fifteen years of achievements in the catalytic asymmetric synthesis of chiral fluorenes and their derivatives. Particular attention is given to the strategies used and mechanistic aspects of some significant reactions. Moreover, the cutting‐edge developments in the catalytic asymmetric synthesis of silafluorenes are also highlighted.

Catalytic Asymmetric Reductive Amination for Axially Chiral Aryl Aldehydes via Desymmetrization/Kinetic Resolution Cascade.

Herein we present an efficient chiral phosphoric-acid-catalyzed atropoenantioselective asymmetric reductive amination of biaryl dialdehydes. The process involves desymmetrization and the following kinetic resolution, with a wide range of axially chiral aryl aldehydes obtained with high optical purities.

Synthesis, enantiomeric separation and (chir)optical properties of [7]helicene derivatives for OLED applications. A comprehensive experimental and computational investigation

A two–step photochemical process was employed to synthesize new racemic [7]helicenes with appropriate functional groups, resulting in an overall yield of 61 % to 74 %. These helical species showed good solubility in common solvents and confirmed structurally through various spectroscopic methods. In solution, they exhibited strong absorption (λabs = 250–500 nm) and blue light emission with a fluorescence quantum yield (Φ) ranging from 7 % to 26 %. Experimental analysis of their HOMO and LUMO energy levels highlighted an irreversible electrochemical behavior and a band gap (Eg–el) of 2.60 eV to 2.64 eV. The helicenes were successfully separated by chiral HPLC, yielding P and M–enantiomers in high optical purity (>98.5 % up to >99.5 % ee) that demonstrated substantial optical rotations (e.g., +3700–5000 for the P–enantiomer at λ = 589 nm) and notable electronic circular dichroism (ECD) signals. Density functional theory (DFT) was undertaken to establish connections between diverse structure-properties relationships and precisely replicate the experimental findings. Ultimately, these helical species, with notable performance in emission, electrochemical behavior, and thermal stability, can effectively serve as blue-emitting chiral dopants in OLED devices and as hole-transport units.

Application of Asymmetric Catalysis in Chiral Pesticide Active Molecule Synthesis.

The different configurations of chiral pesticides generally have significant influence on their biological activities. Chiral agrochemicals with high optical purities have become a prominent topic in the research field of new pesticides due to their advantages including lower toxicity, higher efficiency, and reduced residue levels. However, most commercially available pesticides that possess chiral elements are still used in their racemic forms. To date, asymmetric catalysis has emerged as a versatile tool for the enantioselective synthesis of various chiral agrochemicals and novel chiral pesticide active molecules. This perspective provides a comprehensive overview of the applications of diverse asymmetric catalytic approaches in the facile preparation of numerous novel pesticide active molecules, and our own outlook on the future development of this highly active research direction is also presented at the end of this review.

Catalytic Investigation of ε-caprolactone Polymerization through Schiff BaseTitanium (IV) Complexes

Background: The ring-opening polymerization (ROP) reaction has provided an efficient and convenient route to prepare polyesters of high molecular weight, low polydispersity index, and high optical purity. The poly(ε-caprolactone) (PCL) and poly(lactide) (PLA) were prepared through ROP reaction of ε-caprolactone and D, L-lactide, respectively. These compounds have a huge industrial demand and become an interest among the scientific community to develop more economically and eco-friendly catalysts for ROP reactions. Methods: Three Schiff base ligands, 2-((benzo[d]thiazole-2-ylimino)methyl)phenol, L1; 2-(1-benzo[d]thiazole-2-ylimino)ethyl)phenol, L2; and 2- ((benzo[d]thiazole-2-ylimino)methyl)-5-methoxyphenol, L3; were prepared by the reaction of 2-aminobenzothiazole with 2-hydroxybenzaldehyde, 2-hydroxyacetophenone and 2-hydroxy-4-methoxybenzaldehyde in 1:1 molar ratio. In anticipation of interesting stereochemistry, reactivity, and catalytic potential against ε-caprolactone polymerization, three Titanium(IV) complexes (1 – 3) of these Schiff base ligands were synthesized. All the prepared compounds were characterized by elemental analysis, molar conductance, FT-IR, UV-Vis, 1H-NMR, 13C{1H}-NMR and FAB-Mass spectroscopic technique. Geometry was optimized with the help of DFT. Results: Complex 3 gives a much higher yield (87.7%) in comparison to 1 and 2. The order of catalytic efficiency for complexes is 3>1>2. With the increase in temperature, the % yield was found to decrease, and results are in support of moderate to good potency of synthesized catalysts. Conclusion: Complexes were screened for catalytic potency against ε-Caprolactone polymerization reaction. A most plausible mechanism for the polymerization was also proposed.

Photoexcited Palladium-Catalyzed Deracemization of Allenes.

The different enantiomers of specific chiral molecules frequently exhibit disparate biological, physiological, or pharmacological properties. Therefore, the efficient synthesis of single enantiomers is of particular importance not only to the pharmaceutical sector but also to other industrial sectors, such as agrochemical and fine chemical industries. Deracemization, a process during which a racemic mixture is converted into a nonracemic product with 100% atom economy and theoretical yield, is the most straightforward method to access enantioenriched molecules but a challenging task due to a decrease in entropy and microscopic reversibility. Axially chiral allenes bear a distinctive structure of two orthogonal cumulative π-systems and are acknowledged as synthetically versatile synthons in organic synthesis. The selective creation of axially chiral allenes with high optical purity under mild reaction conditions has always been a very popular and hot topic in organic synthesis but remains challenging. Herein, a photoexcited palladium-catalyzed deracemization of nonprefunctionalized disubstituted allenes is disclosed. This method provides an efficient and economical strategy to accommodate a broad scope of allenes with good enantioselectivities and yields (53 examples, up to 96% yield and 95% ee). The use of a suitable chiral palladium complex with visible light irradiation is an essential factor in achieving this transformation. A metal-to-ligand charge transfer mechanism was proposed based on control experiments and density functional theory calculations. Quantum mechanical studies implicate dual modes of asymmetric induction behind our new protocol: (1) sterically controlled stereoselective binding of one allene enantiomer under the ground-state and (2) facile, noncovalent interaction-driven excited-state isomerization toward the opposite enantiomer. The success of this newly established photochemical deracemization strategy should provide inspiration for expansion to other multisubstituted allenes and will open up a new mode for enantioselective excited-state palladium catalysis.

Asymmetric total synthesis of polycyclic xanthenes and discovery of a WalK activator active against MRSA

The development of new antibiotics continues to pose challenges, particularly considering the growing threat of multidrug-resistant Staphylococcus aureus. Structurally diverse natural products provide a promising source of antibiotics. Herein, we outline a concise approach for the collective asymmetric total synthesis of polycyclic xanthene myrtucommulone D and five related congeners. The strategy involves rapid assembly of the challenging benzopyrano[2,3-a]xanthene core, highly diastereoselective establishment of three contiguous stereocenters through a retro-hemiketalization/double Michael cascade reaction, and a Mitsunobu-mediated chiral resolution approach with high optical purity and broad substrate scope. Quantum mechanical calculations provide insight into stereoselective construction mechanism of the three contiguous stereocenters. Additionally, this work leads to the discovery of an antibacterial agent against both drug-sensitive and drug-resistant S. aureus. This compound operates through a unique mechanism that promotes bacterial autolysis by activating the two-component sensory histidine kinase WalK. Our research holds potential for future antibacterial drug development.

A Practical Method for Synthesizing Iptacopan.

Iptacopan, the first orally available small-molecule complement factor B inhibitor, was developed by Novartis AG of Switzerland. Iptacopan for the treatment of PNH was just approved by the FDA in December 2023. Other indications for treatment are still in phase III clinical trials. Iptacopan is a small-molecule inhibitor targeting complement factor B, showing positive therapeutic effects in the treatment of PNH, C3 glomerulonephritis, and other diseases. Although Iptacopan is already on the market, there has been no detailed synthesis process or specific parameter report on the intermediates during the synthesis of its compounds except for the original research patent. In this study, a practical synthesis route for Iptacopan was obtained through incremental improvement while a biosynthesis method for ketoreductase was used for the synthesis of the pivotal intermediate 12. Moreover, by screening the existing enzyme library of our research group on the basis of random as well as site-directed mutagenesis methods, an enzyme (M8) proven to be of high optical purity with a high yield for biocatalectic reduction was obtained. This enzyme was used to prepare the compound benzyl (2S,4S)-4-hydroxy-2-(4-(methoxycarbonyl)-phenyl)-piperidine-1-carboxylate) white powder (36.8 g HPLC purity: 98%, ee value: 99%). In the synthesis of intermediate 15, the reaction was improved from two-step to one-step, which indicated that the risk of chiral allosterism was reduced while the scale was expanded. Finally, Iptacopan was synthesized in a seven-step reaction with a total yield of 29%. Since three chiral intermediate impurities were synthesized directionally, this paper lays a solid foundation for the future of pharmaceutical manufacturing.

Turning noncovalent interactions via halogen substituents for improving activity and enantioselectivity of Candida antarctica lipase B

Noncovalent interactions associated with the enzyme, enzyme-substrate complexes, and transition states have profound influences on varying the biocatalytical activity and enantioselectivity. The recent rediscovery of halogen bonds incorporating in biocatalysis has induced our motivation on introducing halogen substituents into the substrate for improving the enzyme performance. By selecting Candida antarctica lipase B (CALB)-catalyzed kinetic hydrolysis (or butanolysis) of trans-2-(p-halophenyl)cyclopropyl 1,2,4-triazolide in methyl tert-butyl ether (MTBE) as the model reaction system, (R, R)-2-(p-halophenyl)cyclopropane-1-carboxylic acid (or ester) of high-optical purity that acts as the key building block for synthesizing the corresponding (1 R, 2S)-2-(p-halophenyl)cyclopropylamine derivatives was obtainable. The thermodynamic and kinetic analysis was then employed for elucidating effects of the halogen substituent and acyl acceptor on enhancing the noncovalent interactions of the rate-limiting tetrahedral intermediate and hence CALB activity and enantioselectivity. A putative model was moreover proposed for interpreting the possible hydrogen and halogen bonding involving the halogen substituent in turning the noncovalent interactions.

Chemoenzymatic Asymmetric Synthesis of Chiral Triazole Fungicide (R)-Tebuconazole in High Optical Purity Mediated by an Epoxide Hydrolase from Rhodotorula paludigensis.

Tebuconazole is a chiral triazole fungicide used globally in agriculture as a racemic mixture, but its enantiomers exhibit significant enantioselective dissimilarities in bioactivity and environmental behaviors. The steric hindrance caused by the tert-butyl group makes it a great challenge to synthesize tebuconazole enantiomers. Here, we designed a simple chemoenzymatic approach for the asymmetric synthesis of (R)-tebuconazole, which includes the biocatalytic resolution of racemic epoxy-precursor (2-tert-butyl-2-[2-(4-chlorophenyl)ethyl] oxirane, rac-1a) by Escherichia coli/Rpeh whole cells expressed epoxide hydrolase from Rhodotorula paludigensis (RpEH), followed by a one-step chemocatalytic synthesis of (R)-tebuconazole. It was observed that (S)-1a was preferentially hydrolyzed by E. coli/Rpeh, whereas (R)-1a was retained with a specific activity of 103.8 U/g wet cells and a moderate enantiomeric ratio (E value) of 13.4, which was remarkably improved to 43.8 after optimizing the reaction conditions. Additionally, a gram-scale resolution of 200 mM rac-1a was performed using 150 mg/mL E. coli/Rpeh wet cells, resulting in the retention of (R)-1a in a 97.0% ees, a 42.5% yields, and a 40.5 g/L/d space-time yield. Subsequently, the synthesis of highly optical purity (R)-tebuconazole (>99% ee) was easily achieved through the chemocatalytic ring-opening of the epoxy-precursor (R)-1a with 1,2,4-triazole. To elucidate insight into the enantioselectivity, molecular docking simulations revealed that the unique L-shaped substrate-binding pocket of RpEH plays a crucial role in the enantioselective recognition of bulky 2,2-disubstituted oxirane 1a.

Synthesis of new [6]helicene derivatives for OLED applications. Experimental photophysical and chiroptical properties and theoretical investigation

Six-membered helicenes with specific functionalities were synthesized in good overall yields (40 %-73 %) through a concise photochemical method, allowing for their comprehensive characterization. The racemic mixtures were effectively resolved into their P- and M-enantiomers with high optical purity (97.56 %-100 % ee) by using chiral HPLC. This separation showcased remarkable optical activity, revealing substantial optical rotations (e.g., +2500–3000 for the (P)-enantiomer at λ = 589 nm) and notable electronic circular dichroism (ECD) signals. The organic helical species showed a strong absorption in the UV region and exhibited a red shifted emission, resulting in a quantum yield of 0.12–0.21. Moreover, they demonstrated irreversible one-electron oxidation and reduction processes, and their HOMO and LUMO energy levels were estimated via electrochemical methods. Utilizing DFT and TD–DFT computational approaches, we accurately predicted the electronic absorption and ECD spectra, as well as the frontier molecular orbitals (FMOs), aligning closely with experimental observations. Furthermore, in-depth analyses of absorption and ECD spectra, molecular electrostatic potential (MEP), and reduced density gradient (RDG) through quantum chemical calculations offered insights into the fundamental characteristics of these materials. The collective properties strongly indicate the potential application of these helicenes in electroluminescent and OLED devices, underscoring their promise as candidates in optoelectronic applications.

Palladium-Catalyzed Atroposelective Suzuki-Miyaura Coupling to Construct Axially Chiral Tetra-Substituted α-Boryl Styrenes.

Palladium-catalyzed Suzuki-Miyaura (SM) coupling is a valuable method for forming C─C bonds, including those between aryl moieties. However, achieving atroposelective synthesis of axially chiral styrenes via SM coupling remains challenging. In this study, a palladium-catalyzed atroposelective Suzuki-Miyaura coupling between gem-diborylalkenes and aryl halides is presented. Using the monophosphine ligand Me-BI-DIME (L2), a range of axially chiral tetra-substituted acyclic styrenes with high yields and excellent enantioselectivities are successfully synthesized. Control experiments reveal that the gem-diboryl group significantly influences the product enantioselectivities and the coupling prefers to occur at sites with lower steric hindrance. Additionally, the alkenyl boronate group in the products proves versatile, allowing for various transformations while maintaining high optical purities.

Selective Stereoretention of Carbohydrates upon C−C Cleavage Enabling D‐Glyceric Acid Production with High Optical Purity over a Ag/γ‐Al2O3 Catalyst

AbstractChiral carboxylic acid production from renewable biomass by chemocatalysis is vitally important for reducing our carbon footprint, but remains underdeveloped. We herein establish a strategy that make use of a stereogenic center of biomass to achieve a rare example of D‐glyceric acid production with the highest yield (86.8 %) reported to date as well as an excellent ee value (>99 %). Unlike traditional asymmetric catalysis, chiral catalysts/additives are not required. Ample experiments combined with quantum chemical calculations established the origins of the stereogenic center and catalyst performance. The chirality at C4 in D‐xylose was proved to be retained and successfully delivered to C2 in D‐glyceric acid during C−C cleavage. The remarkable cooperative‐roles of Ag+ and Ag0 in the constructed Ag/γ‐Al2O3 catalyst are disclosed as the crucial contributors. Ag+ was responsible for low‐temperature activation of D‐xylose, while Ag0 facilitated the generation of active O* from O2. Ag+ and active O* cooperatively promoted the precise cleavage of the C2−C3 bond, and more importantly O* allowed the immediate fast oxidization of the D‐glyceraldehyde intermediate to stabilize D‐glyceric acid, thereby inhibiting the side reaction that induced racemization. This strategy makes a significant breakthrough in overcoming the limitation of poor enantioselectivity in current chemocatalytic conversion of biomass.

Selective Stereoretention of Carbohydrates upon C-C Cleavage Enabling D-Glyceric Acid Production with High Optical Purity over a Ag/γ-Al2O3 Catalyst.

Chiral carboxylic acid production from renewable biomass by chemocatalysis is vitally important for reducing our carbon footprint, but remains underdeveloped. We herein establish a strategy that make use of a stereogenic center of biomass to achieve a rare example of D-glyceric acid production with the highest yield (86.8 %) reported to date as well as an excellent ee value (>99 %). Unlike traditional asymmetric catalysis, chiral catalysts/additives are not required. Ample experiments combined with quantum chemical calculations established the origins of the stereogenic center and catalyst performance. The chirality at C4 in D-xylose was proved to be retained and successfully delivered to C2 in D-glyceric acid during C-C cleavage. The remarkable cooperative-roles of Ag+ and Ag0 in the constructed Ag/γ-Al2O3 catalyst are disclosed as the crucial contributors. Ag+ was responsible for low-temperature activation of D-xylose, while Ag0 facilitated the generation of active O* from O2. Ag+ and active O* cooperatively promoted the precise cleavage of the C2-C3 bond, and more importantly O* allowed the immediate fast oxidization of the D-glyceraldehyde intermediate to stabilize D-glyceric acid, thereby inhibiting the side reaction that induced racemization. This strategy makes a significant breakthrough in overcoming the limitation of poor enantioselectivity in current chemocatalytic conversion of biomass.

Therapeutic applications of carbohydrate-based compounds: a sweet solution for medical advancement.

Carbohydrates, one of the most abundant biomolecules found in nature, have been seen traditionally as a dietary component of foods. Recent findings, however, have unveiledtheir medicinal potential in the form of carbohydrates-derived drugs. Their remarkable structural diversity, high optical purity, bioavailability, low toxicity and the presence of multiple functional groups have positioned them as a valuable scaffold and an exciting frontier in contemporary therapeutics. At present, more than 170 carbohydrates-based therapeutics have been granted approval by varying regulatory agencies such as United States Food and Drug Administration (FDA), Japan Pharmaceuticals and Medical Devices Agency (PMDA), Chinese National Medical Products Administration (NMPA), and the European Medicines Agency (EMA). This article exploresan overview of the fascinating potential and impact of carbohydrate-derived compounds as pharmacological agents and drug delivery vehicles.

An innovative temperature control strategy to improve optically pure L-lactic acid production from food waste

Fermentation of food waste to lactic acid (LA) is a strategy for resource recovery. However, the poor yield and optical activity (OA) of L-lactic acid (L-LA) are major bottlenecks for such efforts. This study focuses on enhancing L-LA yield and optical purity from the food waste without sterilization and inoculation at pilot-scale. First, the effects of temperature on LA production were explored. A higher LA yield but lower purity was obtained under mesophilic conditions, whereas the opposite results were represented at high temperature. On the basis of these findings, a novel two-stage temperature regulation strategy was developed that combined the benefits of both temperature conditions. This strategy not only ensured a L-LA yield of 0.371 g/g volatile solid, but also achieved a high optical purity of 98.0%. The underlying mechanism is that high temperature could enrich L-lactic acid bacteria (LAB) and inhibit LAB producing both L- and D-LA. Overall, this innovative strategy may be well-suited for generating optically pure L-LA from food waste fermentation.

Synthesis, chiral separation and physical properties of the cinnamic acid derivatives exhibiting short-pitch cholesteric and TGB phases

ABSTRACT Two new photosensitive chiral liquid crystalline materials derived from cinnamic acid were synthesised in (R) and (S) enantiomer forms. The materials were characterised by NMR spectroscopy, purified by preparative liquid chromatography, and the chemical purity of the final products was determined by high performance liquid chromatography (HPLC). High optical purity was reached for all enantiomers. The enantiomer elution order was confirmed by the analysis of non-racemic (R) and (S) mixed samples. The cinnamic acid derivatives are capable of undergoing photoisomerisation. Sample irradiation was performed to realise E-Z isomerisation and investigate its effect on the enantioseparation. The conditions of the enantioselective HPLC method were optimised to achieve a baseline separation for all studied materials both before and after irradiation by the UV light. The mesogenic properties of the studied enantiomers and their racemic mixtures were obtained from differential scanning calorimetry measurements, optical textures observed under the polarising light microscope and X-ray diffraction measurements. Cholesteric and TGB phases have been found for the enantiomers and, analogously, nematic and smectic phases have been confirmed for their racemates. The temperature dependence of the optical birefringence has been studied for the racemates in the temperature range of the mesophases.

Consecutive chirality transfer: efficient synthesis of chiral C,O-chelated BINOL/gold(iii) complexes for asymmetric catalysis and chiral resolution of disubstituted BINOLs.

A novel approach for efficient synthesis of chiral C,O-chelated BINOL/gold(iii) complexes by diastereomeric resolution using enantiopure BINOL as a chiral resolving agent was demonstrated. The BINOL/gold(iii) diastereomers with different solubility were separated by simple filtration, providing optically pure BINOL/gold(iii) complexes with up to >99 : 1 dr. By combining this with an efficient BINOL ligand dissociation process, a simple and column-free method for chiral resolution of racemic gold(iii) dichloride complexes on a gram scale was established, affording their enantiopure forms in good yields. Conversely, the resolved enantiopure gold(iii) dichloride complexes could serve as chiral resolving agents to resolve disubstituted BINOL derivatives, achieving both BINOLs and gold(iii) complexes in good to excellent yields (overall 77-96% and 76-95%, respectively) with a high optical purity of up to 99% ee. Through a consecutive chirality transfer process, the chiral information from an inexpensive chiral source was transferred to highly valuable gold(iii) complexes, followed by sterically bulky BINOL derivatives. This work would open a new synthetic strategy facilitating the development of structurally diverse chiral gold(iii) complexes and gold(iii)-mediated chiral resolution of BINOL derivatives. In addition, this new class of C,O-chelated BINOL/gold(iii) complexes achieved asymmetric carboalkoxylation of ortho-alkynylbenzaldehydes with an excellent enantioselectivity of up to 99% ee.

Sustainable production of optically pure platform chemical bio-based (R,R)−2,3-butanediol from sugarcane molasses in a low-cost salt medium

Bio-based 2,3-butanediol (2,3-BDO) viability production on a large scale depends on the culture medium costs, fermentation broth, and bioprocess biosafety. This study investigated sugarcane molasses, corn steep liquor, and ammonium chloride to replace commercial glucose and yeast extract for 2,3-BDO production by a safe and wild-type Paenibacillus peoriae NRRL BD-62. A savings of 75.2% were achieved using sugarcane molasses and NH4Cl-based medium, whose final cost was 4.74 US$/kg2,3-BDO. Levo-2,3-BDO was produced with high optical purity and no acetoin accumulation in batch fermentation. The selectivity was maintained above 90% in fed-batch fermentation at constant feeding. In contrast, the yield showed a 20% reduction, indicating that this feeding strategy was less efficient than batch cultures. To the best of our knowledge, this is the first time that levo-2,3-BDO with high optical purity has been produced by a newly isolated P. peoriae strain from sugarcane molasses in a low-cost salt medium, making the large-scale process sustainably promising.