Trifluoroacetylation and varying sulfur oxidation states can modulate the stereodynamic features in N-aryl peptoids. This study elucidates the restricted rotation about both the chiral Caryl-N axis and the N-C(O) amide bond, highlighting the inherently flexible nature of tertiary amide scaffolds. Tertiary amide bond isomerization, axial chirality, and multiple stereochemical forms were investigated utilizing 19F NMR, dynamic HPLC, crystallographic studies, and computational analysis. Notably, the introduction of a sulfoxide moiety as an auxiliary stereogenic element facilitates the formation of multiple and distinct stereochemical forms, as evident from 19F NMR studies and computational modeling. These structural modifications can provide a robust platform to understand stereodynamic features in N-aryl peptoids.
A new enantioselective molecularly imprinted polymer (MIP) was developed for recognizing S-ketorolac (S-KR), a model chiral acidic drug. The synthetic process started with a resorcinol-formaldehyde resin (RSF), which was cyanoethylated under phase-transfer catalytic conditions to obtain RSF-CN. Then, the nitrile groups turned into cationic/basic hydrazidine sites after reacting with hydrazine hydrate, resulting in RSF-HD. Next, S-KR was interacted with RSF-HD in a DMF/water solution at pH 7, before adding glutaraldehyde for post-crosslinker. After that, the S-KR template was removed to get the final S-KR-imprinted polymer (S-KR-P). Tests, such as elemental analysis and solid-state 13C NMR, verified each step. Adsorption tests showed a strong pH dependence, working best between pH 6 and 7. For isotherm studies, the maximum capacity for S-KR on S-KR-P was 525 mg/g, whereas R-KR had 252 mg/g. The non-imprinted polymers (NIPs) worked similarly for both, around 180 mg/g. The Langmuir model fits better than the Freundlich model, pointing to adsorption on defined binding sites. With a selectivity coefficient of about 12, it shows effective stereoselective recognition, making S-KR-P a great option for separating chiral ketorolac.
Chiral covalent organic frameworks (CCOFs) integrate high crystallinity, permanent porosity, and programmable chiral microenvironments, making them attractive platforms for chiroptical materials and circularly polarized light-responsive devices. This review summarizes recent progress in CCOFs, covering the introduction of chirality through post-synthetic modification, de novo synthesis, chiral induction, and catalytic asymmetric synthesis, as well as the amplification of chirality from molecular units to pore architectures, helical morphologies, thin films, and devices. We further discuss representative CCOF systems for circularly polarized luminescence and circularly polarized light detection, focusing on the relationships among framework structure, host-guest confinement, chirality-induced spin selectivity-mediated transport, and dissymmetry factors. Helical morphology amplifies chirality across scales through ordered chromophore organization and anisotropic charge and spin transport. Together, these advances establish a multiscale design framework for translating molecular chirality into measurable optical and device responses. Finally, we identify key challenges in balancing luminescence efficiency with chiroptical asymmetry, stabilizing helical architectures, fabricating oriented films, and establishing quantitative structure-property relationships.
Emerging contaminants are an increasing global concern, with antibiotics representing a notable case due to their continuous release and possible contribution to antimicrobial resistance. Fluoroquinolones (FQs) combine high stability, low biodegradability, and biological activity at trace levels, which result in persistence, ecotoxicity, and bioaccumulation in aquatic systems. Nadifloxacin (NAD) is a chiral FQ prescribed as a racemate for dermatological infections, but (S)-NAD is more potent than the racemate and 64 to 256 times more active than (R)-NAD against both Staphylococcus aureus and Propionibacterium acnes, as well as other gram-positive and gram-negative pathogens. Though the stereochemistry plays a decisive role in both pharmacological activity and environmental fate, the enantioselective ecotoxicological evaluation of NAD is of high importance. Thus, this work described the enantioseparation of NAD by chiral liquid chromatography (cLC) on a Lux amylose-1 column (4.6 mm I.D. × 250 mm L, particle size 5 μm) under normal-phase conditions. Optimized analytical conditions provided good chromatographic parameters (Rs = 5.92, α = 2.77, retention 6-10 min) and were successfully scaled up to semipreparative enantioseparation on a CHIRALPAK AD-H DAICEL column (10 mm I.D. × 250 mm L, particle size 5 μm), allowing the separation of both enantiomers in > 98% enantiomeric purity. The absolute configuration and the elution order of the enantiomers were determined by the agreement between the experimental and calculated data of electronic circular dichroism. The acute ecotoxicity of the NAD racemate and its enantiomers was evaluated using Daphnia magna as an aquatic model organism.
Extending morphological complexity and thus achieving emergent functions remain a central challenge in materials science. Here, we report a chirality-engineering strategy to tune morphological complexity and optical activity (OA) in Ag-thiolate coordination polymers (ATCPs). By introducing either the opposite enantiomer D-cys or the achiral 3-mercaptopropionic acid (MPA) into L-cys-induced ATCP synthesis, we found two coinduction systems exhibiting distinct molecular mixing behaviors quantified via the entropy of mixing (EoM) of thiol precursors. The resulting morphologies, including triangular nanosheets, flower-like architectures, nanoscrolls, and nanotube-like assemblies, were quantitatively analyzed using a graph-theoretical complexity index (CI). In the L-/D-cys system, increasing EoM led to chirality cancelation, a decreased CI and an attenuated g-factor, demonstrating that maximum EoM does not necessarily generate higher complexity or stronger OA. In contrast, in the L-cys/MPA system, packing mismatch transformed maximum EoM into an enhanced CI alongside OA inversion and enhancement (a maximal 8.3-fold enhancement). These results reveal that the molecular role of the second thiol component, rather than EoM alone, determines whether molecular mixing suppresses or amplifies complexity and OAs. This work provides ligand-modification strategy for programming complex functional coordination-polymer assemblies.
S-Naproxen (NPX) exhibits an unusual inversion of its ECD spectrum upon solvent change, a phenomenon that this work analyzes both experimentally and theoretically. By evaluating NPX in water, ethanol, and acetonitrile, it was observed that pH variation shifts the chemical equilibrium between protonated and deprotonated forms, making this transition the direct cause of the ECD signal inversion. Molecular dynamics and TD-DFT (CAM-B3LYP/aug-cc-pVDZ) calculations corroborated the experimental data, demonstrating that structural changes alter the predominant electronic transitions from π → π* in NPX to n → π* in the NPX- anion, as evidenced by transition density differences and natural transition orbitals (NTOs). These findings demonstrate that explicit solvent treatment and statistical analysis are requisite to accurately reproduce the data, validating that the negative signal in water and the positive signal in acetonitrile is governed by the predominant species dictated by the chemical equilibrium.
A stereodivergent synthetic strategy enabling access to enantiopure C5-α-substituted linezolid analogues has been developed from D-mannitol as an inexpensive chiral pool precursor. The approach provides controlled access to both syn- and anti-configured derivatives bearing ethyl or phenyl substituents at the α-position of the C5 acetamidomethyl side chain, thereby introducing a second stereogenic center with high diastereocontrol. Key steps include highly selective nucleophilic additions of organometallic reagents to chiral N-benzyl imines derived from protected D-glyceraldehyde and base-promoted condensation of enantiopure N-Boc-aminoepoxides with aryl carbamates to construct the 2-oxazolidinone core. Comparative analysis of both configurational series revealed marked differences in cyclization efficiency, particularly for α-phenyl-substituted intermediates in the anti series, highlighting the steric sensitivity of oxazolidinone formation. In vitro assays against Gram-positive and Mycobacterium spp. species showed complete loss of antibacterial activity for all α-substituted derivatives, irrespective of configuration. These results establish a clear structural limitation at C5 and demonstrate that steric expansion at the α-position overrides stereochemical effects. This study underscores the value of stereodivergent synthesis for rigorously disentangling configurational and substituent contributions in chiral bioactive scaffolds.
Methamphetamine, an amphetamine-type stimulant, is a potent and psychoactive compound distinguished by the presence of a single stereogenic center in its structure. Consequently, it exists as two enantiomers: (S)-(+)-methamphetamine [(S)-(+)-MA (1)] and (R)-(-)-methamphetamine [(R)-(-)-MA (2)]. The chirality of these molecules confers distinct biological and pharmacological properties, with notable differences between the two forms. These enantioselective variations extend beyond their mechanisms of action, encompassing differences in the central nervous system interactions, metabolism, excretion, and other physiological processes. Understanding these disparities is crucial for elucidating the pharmacological and potential therapeutic profiles of each enantiomer. Achieving such insight requires examination of the enantioselective synthetic routes through which the desired chirality can be either inherited or constructed. This review integrates chemical and biological perspectives to provide a comprehensive overview of both methamphetamine enantiomers, thereby bridging the gap between laboratory synthesis and biological behavior in these two chemically fascinating yet dangerous molecules.
Amino acids are the basic building blocks of proteins that are required to control various vital biological processes, including immune response, hormone regulation, metabolic control, and gene expression. Although L-amino acids are the primary components of protein synthesis, their mirror-image counterparts, D-amino acids, exhibit distinct pharmacological and biological characteristics. As a result, reliable identification and measurement of these enantiomers have become critical criteria in biology, chemistry, and medicine. Because changes in D-amino acid levels are closely related to the onset and progression of a variety of human disorders, the therapeutic utility of these amino acids as diagnostic biomarkers is gaining traction. This article investigates the vital role of chiral amino acids in clinical disorders, with a particular emphasis on their implications for neurological conditions. It also evaluates the several techniques and analytical systems used to identify enantiomeric amino acids in complex biological matrices, focusing on current technological breakthroughs that have increased the sensitivity and precision of these evaluations.
Novel tetraazacalix derivatives were synthesized and evaluated for their catalytic performance in direct asymmetric aldol reactions carried out in organic solvents. Chiral functionalities were introduced onto the tetraazacalix[2]arene[2]triazine and tetraazacalix[4]arene[2]triazine framework via reactions with (S)-(+)-2-Phenylglycinol. The resulting tetraazacalix derivatives exhibited high catalytic efficiency in the aldol reactions between ketone and various aldehydes. The experimental results demonstrated that the structural moiety of the catalyst plays a decisive role in controlling the stereochemical configuration of the aldol products. Under the optimized conditions, the aldol adducts were obtained in excellent yields of up to 92% and enantioselectivities reaching 95%.
Determination of the absolute configuration of chiral molecules is essential across multiple scientific disciplines, as handedness determines the chiroptical, biological, and pharmaceutical properties. For crystalline materials, single crystal x-ray diffraction is the standard technique for assigning the absolute configuration. However, its application typically requires a large number of reflections and analysis of Friedel pair intensities using the Flack parameter or related approaches, such as those of Hooft or Parsons. Here, we introduce a conceptually distinct approach for determining the absolute configuration of a known crystal structure, based on the x-ray energy dependent intensity of a single Bragg reflection that is sensitive to the absolute configuration. By monitoring the variation in the intensity of a Bragg peak across an absorption edge, this method provides an unambiguous probe of chirality. The proposed approach is demonstrated for the 211 reflection of a 2-(3-bromophenyl)-N,N-diisopropyl-2-oxoacetamide single crystal, showing that the absolute configuration can be reliably determined from a single reflection. To confirm the assignment of chirality and assess potential limitations, the x-ray energy dependence of additional diffraction peaks was also investigated. This method is particularly advantageous for systems with a limited number of accessible reflections, where conventional statistical methods based on Flack parameter analysis are not reliable.
ABSTRACT Chirality is an interesting property in molecules with a plethora of potential applications. In this line, due to their origin, most chiral natural compounds can be considered enantiopure, and many of these molecules include interesting functional groups that can be of interest in both coordination and organometallic chemistry to obtain chiral coordinated and/or organometallic compounds. And most importantly, these molecules may thus confer chiral properties into their metal complexes. Therefore, in this work, we show the use of kaurenoic ( 1 ) and beyerenoic ( 2 ) acids as efficient ligands to obtain the corresponding organometallic Ru(II) complexes by using [( η 6 ‐ p ‐cymene)Ru( μ ‐Cl)Cl] 2 as starting material by a simple procedure reacting the corresponding sodium salts of 1 and 2 ( 1a and 2a ) with [( η 6 ‐ p ‐cymene)Ru( μ ‐Cl)Cl] 2 in an 2:1 M ratio to yield the corresponding ( S a)‐[Ru( η 6 ‐ p ‐cymene)( κ 2 ‐beyerenate)Cl] ( 3 ) and ( S a)‐[Ru( η 6 ‐ p ‐cymene)( κ 2 ‐kaurenate)Cl] ( 4 ) derivatives. Both complexes were fully characterized by common spectroscopic techniques and their structures unequivocally determined by single crystal X‐ray diffraction analysis. In addition, the chirality of both organometallic compounds was analyzed by electronic circular dichroism techniques as well as by in silico methods. Antimicrobial assays were boarded demonstrating slight antifungal activity. The results not only confirm the conferring of chirality by the ligands to their organometallic derivatives but also open a window for their future potential applications as, for example, potential chiral catalysts or as metallodrugs in the battle against diseases of global concern as well optimistically inspiring the potential use of other natural products as ligands with a wide number of applications.
Enantiomerically pure β- and γ-lactams are vital chiral building blocks widely used in the synthesis of antiviral and anticancer drugs. However, producing them on a large scale through chemical synthesis and enantiomeric separation is both expensive and harmful to the environment. Using integrative bioinformatics, we identified a new signature amidase, Rb-Ami, from the haloalkaliphilic bacterium Rhodococcus baikonurensis. The Rb-ami gene was cloned and successful expressed in Escherichia coli BL21. Soluble and active recombinant enzyme was obtained, and in vitro studies show that this enzyme can efficiently catalyze the enantioselective hydrolysis of different lactam substrates. Specifically, Rb-Ami can effectively resolve racemic mixtures of 3-hydroxy-4-phenylazetidin-2-one (β-lactam) and 2-azabicyclo[2.2.1]hept-5-en-3-one (γ-lactam), delivering enantiomeric excesses greater than 99.0% and yields above 49.0%. To our knowledge, this is the first reported amidase exhibiting both γ-lactamase and β-lactamase activities, and the first β-lactamase used for the kinetic resolution of racemic 3-hydroxy-4-phenylazetidin-2-one. This enzymatic method provides a highly efficient and eco-friendly approach for producing the paclitaxel side chain and precursors of carbocyclic nucleoside antivirals.
Racemization of l-alanine-derived imides is enhanced with high-water content and elevated temperature in dimethylformamide (DMF). Water hydrolyses DMF to give dimethylamine (DMA) and formic acid (FA), resulting in an increase in the basicity of the reaction medium, which in turn facilitates abstraction of the α-proton from the stereogenic center and thereby initiates racemization. A comparative analysis of five- and six-membered l-alanine-derived imides reveals that the six-membered system racemizes more slowly than the five-membered analogue and exhibits only trace side reactions. In contrast, the five-membered ring undergoes a series of side reactions alongside rapid racemization. The enhanced stability of the six-membered species is attributed to a lower degree of ring strain, which imposes a higher barrier to racemization.
The computed nonresonant optical activity of pairs of cyclo[18]carbon rings, linked and unlinked with the same symmetry, D2d, are compared. For optically active, non-enantiomorphous systems, we emphasize that the observables computed here can only be measured for oriented molecules in suitably dissymmetric configurations. Mechanically bonded linked rings have one independent gyration tensor eigenvalue, ±16 bohr4. Breaking the mechanical bond and thereby unlinking the rings, while maintaining noncovalent contact, triples the gyration, resulting in an eigenvalue of ±54 bohr4. Of the excited states with B2 and E symmetry that contribute to the optical activity, the B2 states dominate the overall response of the link and unlink. The responses of selected low-energy states, that mimic the responses of a more comprehensive sum over many states, narrate in part the paradox that two optically inactive monomers in close proximity are more chiroptically scattering than the linked pair. The behavior described here underscores the importance of noncovalent interactions in optical activity.
Pomalidomide is a 2nd-generation chiral immunomodulatory (IMiDs) drugs and have antiangiogenic activity. Despite being teratogenic, it has been shown to be effective in treating multiple myeloma. Enantioselectivity, chemical structure, and biological activity have been investigated using molecular docking. In silico docking simulations to confirm the enantioselective binding of pomalidomide to immunomodulator targets, namely, CRBN, TNF- α11, Pg G/H synthase 2, and Cadeherin-5 Protein. The protein was preprocessed using hydrogen addition, disulphide treatment, and bond order assignment. The Ligand Preparation Module was used to optimize all of the chosen ligands, and OPLS3e Forcefield was used to optimize the geometry. Site map analysis module was used to determine the top-ranked receptor binding sites for the enzymes. Molecules were docked by using Schrodinger 2020_3 software. Docking study confirms the enantioselective binding of pomalidomide to immunomodulator targets (CRBN, TNF-α_11, Pg G/H synthase 2, and Cadeherin-5 Protein). Out of all four targets S- (-) enantiomer of pomalidomide had significant binding with CRBN and TNF-α 11, while R-(+)enantiomer of pomalidomide had significant binding with Pg G/H synthase 2, and Cadeherin-5 Protein. The result suggests that, chemical interactions of S-enantiomer of pomalidomide have better binding with residues at the active site of CRBN and TNF-α 11. This concludes that S-enantiomer of pomalidomide could be a better choice for multiple myeloma therapy.
Currently, greening analytical methods have become of great interest to ensure operators' and environment health. Chiral analysis can commonly employ hazardous chemicals and large quantities of waste. In this context, this study presents a green chiral high-performance liquid chromatography (HPLC) method for the determination of lumefantrine (LUME) enantiomers. Chromatographic enantioseparation was achieved on a Chiralpak AD column with a mobile phase composed of ethanol at a flow rate of 1 mL/min. The effects of column temperature on the retention of the enantiomers were investigated, and the analysis temperature was set at 35°C. The method greenness profile was assessed using the Analytical GREEnness (AGREE) and Analytical Green Star Area (AGSA) metrics by which the method proved to be eco-friendly. The method was validated, showing adequate selectivity, linearity, precision, accuracy, and robustness over the range of 80-120 μg/mL per enantiomer. Electronic circular dichroism (ECD) analysis proposed that the first eluted peak was the R-enantiomer and the second eluted peak was the S-enantiomer. Molecular docking studies suggested that LUME may interact mainly through van der Waals and π-interactions on the Chiralpak AD. A green method was successfully developed for the chiral separation of LUME. The proposed work contributes to more environmentally friendly chiral approaches in pharmaceutical analysis.
We report enantioselective crystallization of tetraphenylethylene (TPE) directed by chiral silica nanohelices (SNHs), yielding crystalline assemblies with distinct morphologies and chiroptical signatures that are modulated by both template handedness and evaporation kinetics. When TPE solutions are deposited onto SNH-functionalized substrates and allowed to crystallize through slow solvent evaporation at 4°C, small orthorhombic crystals (2-5 μm) form with strong induced electronic circular dichroism (ECD) and circularly polarized luminescence (CPL) whose sign is correlated to the underlying SNH handedness. In contrast, rapid evaporation at room temperature leads to dendritic crystalline assemblies with strong ECD but weaker CPL with reduced correlation to the template handedness. Fluorescence microscopy confirms that emission originates exclusively from crystalline domains, consistent with restriction of intramolecular rotation upon crystal packing. The results show that right-handed (P-) and left-handed (M-)SNH preferentially promote the formation of distinct TPE enantiomeric crystals, providing a robust platform for template-directed chirality-controlled crystallization.
Suzetrigine (SUZ), an analgesic for acute pain, requires strict enantiomeric purity control. This study develops a robust chiral HPLC method for SUZ and its R-enantiomer using analytical quality by design (AQbD). Separation was achieved on a Chiralpak IC-3 column with an isocratic n-hexane-ethanol (90:10, v/v) mobile phase. The optimized method provided baseline resolution (Rs = 3.0) in 15 min. Validation via the accuracy profile approach confirmed reliable quantification, with limits of 290 μg mL-1 (SUZ) and 0.32 μg mL-1 (R-enantiomer). The AQbD strategy defined a method operable design region (MODR) ensuring robust routine performance. Furthermore, multimetric sustainability assessments demonstrated a favorable environmental profile, yielding blue applicability grade index (BAGI) and mosaic-WAC scores of 77.5 and 73.2, respectively. This approach enables reliable, eco-friendly enantiomeric purity assessment of SUZ in bulk and pharmaceutical formulations.
As a significant representative of monoterpenoid indole alkaloids (MIAs) and 1,1-disubstituted tetrahydro-β-carboline (THβC) alkaloids, Arborisidine, since its discovery in 2016 by Kam and coworkers, has emerged as a focal molecule in the field of total synthesis due to its unique pentacyclic cage-like skeleton and the quaternary carbon center at C(16). Multiple research groups have conducted in-depth investigations into its total synthesis and successfully developed novel synthetic strategies. These studies have not only advanced the total synthesis and structural modification of this class of MIA natural products but also provided scientific approaches for structure-activity relationship (SAR) studies. Furthermore, with the rapid advancement of synthetic biology, investigations into the biosynthetic pathways of these alkaloids have not only offered innovative synthetic strategies for chemical synthesis but also delivered precise tools for structure-directed modification, thereby significantly accelerating structure-based drug design (SBDD). Based on this background, this review summarizes the recent advances in the total synthesis and biosynthetic studies of arborisidine, aiming to provide scientific insights for the synthesis of other family members through comparative analysis of diverse synthetic strategies, as well as to offer methodological support for drug design based on this structural framework.
