Diastereoselective Research Articles

Efficient Method of (S)-Nicotine Synthesis

Improved methods for the synthesis of nicotine are of great importance due to the wide range of applications of synthetic nicotine, which is free from contamination with nitrosamines. Herein, we present a four-step chemical synthesis of (S)-nicotine, involving the reduction in myosmine, enantiomeric separation of nornicotine, and subsequent methylation of the appropriate enantiomer of nornicotine obtained. The reduction in myosmine was investigated using both electrochemical and chemical approaches, achieving up to 90% yields of pure nornicotine. To achieve the enantioseparation of nornicotine, its diastereomeric salts with chiral acids, specifically, N-lauroyl-(R)-alanine, were obtained in a mixture of methyl tert-butyl ether (MTBE) and chloroform, which led to the isolation of (S)-nornicotine with 92% ee. The structures of the obtained salts were determined by the X-ray diffraction (XRD) technique, which helped to explain the origin of enantiodiscrimination during the crystallization. The described methodology allows efficient regeneration of the reagents and solvents used, leading to cost-effective production of (S)-nicotine suitable for industrial-scale applications.

Triantaspirols A-C and Paraphaeolactone Cs from Paraphaeosphaeria sp. KT4192: Sensitivity of CP3 in Distinguishing Close NMR Signals.

Hybridized spirobisnaphthalene derivatives, triantaspirols A-C (1-3) and paraphaeolactones C1 and C2 (4 and 5), were identified from the culture broth of the fungus Paraphaeosphaeria sp. KT4192. The NMR spectra of 2 and 3, as well as 4 and 5, closely resembled each other, indicating that these were pairs of diastereomers. Although this NMR spectral resemblance made it challenging to distinguish their relative configurations, detailed analysis of the electronic circular dichroism (ECD) spectra and NOE correlations allowed us to deduce them. The CP3 metric with the DFT-based NMR chemical shifts was found to distinguish configurations of diastereomers in a highly sensitive and accurate manner that DP4 could not account for because of the very close chemical shift differences in the experimental NMR spectra. The reliability of this method was assessed using 23 published examples which could not be distinguished by DP4 protocol.

Sustainable solutions for direct TLC enantioseparation with in-home thought-out, prepared/modified chiral stationary phases.

TLC is used globally, yet less attention has been paid to TLC (in enantioseparation) despite its advantages. The present paper describes/reviews successfully practiced direct approaches of 'chiral additive in achiral stationary phase' (as an application of in-home thought out, prepared, tested, and modified chiral stationary phase), 'pre-mixing of chiral reagent with the enantiomeric mixture' (an approach using both achiral phases during chromatographic separation) and 'chiral additive in mobile phase', and chiral ligand exchange for enantioseparation of DL-amino acids, their derivatives, and some active pharmaceutical ingredients. It provided efficient enantioseparation, quantitative determination, and isolation of native forms via in-situ formation of non-covalent diastereomeric pair. The mechanism of enantioseparation in these approaches has been discussed along with the isolation and establishment of the structure of diastereomers. This may help chemists gain useful insights into fields outside their specialization and the experts get brief accounts of recent key developments, providing solutions for sustainable development of less expensive methods for control of enantiomeric purity and isolation of native enantiomers.

Chiral resolution of RS-ofloxacin through a novel diastereomeric cocrystal formation with L-glutamic acid by evaporative crystallization and quantification with capillary electrophoresis

Chiral drugs often exhibit significant differences in pharmacological activity between their enantiomers, highlighting the importance of effective chiral separation to enhance therapeutic efficacy and safety. Despite advances in this field, efficient methods for enantiomer separation remain a critical demand, especially for drugs like RS-Ofloxacin (RS-OFX), a chiral fluoroquinolone antibiotic. For RS-OFX, the S-enantiomer exhibits significantly higher potency—approximately 8–128 times greater—than the racemic mixture. This highlights the need to accurately separate the enantiomers. This study presents a new cocrystallization-based method for the precise and economical chiral separation of RS-OFX using amino acids by utilizing the formation of diastereomeric cocrystals. L-Glutamic acid (L-Glu) was identified as an appropriate coformer during the screening of potential coformers; consequently, diastereomeric cocrystals of R-OFX:L-Glu and S-OFX:L-Glu were successfully obtained. Melting point data, Fourier-Transform Infrared Spectroscopy (FTIR), and Powder X-Ray Diffraction (PXRD) analyses all confirmed the existence of a new solid state, revealing significant modifications in the crystal structure indicative of cocrystal formation. Capillary electrophoresis (CE) was employed to quickly identify the most suitable solvent mixture for the separation of the diastereomeric pair. The diastereomeric cocrystals exhibited distinct solubility profiles in various solvent mixtures, allowing effective chiral separation through evaporative crystallization in methanol:chloroform (50:50, v/v) mixture, yielding 61.82% enantiomeric excess (ee) of the more active S-OFX:L-Glu. The results of this study suggest that the chiral resolution of racemic APIs through diastereomeric cocrystal formation with amino acids has the potential for scalability and adaptability in other APIs. This approach has the potential to be a valuable tool for the pharmaceutical industry in improving the efficiency of producing enantiopure pharmaceuticals.

Modulating Helix-Preference of an Axially-Twisted Molecular Scaffold Through Diastereomeric Salt Formation with Tartaric Acid Stereoisomers.

Herein, we designed a chiral, axially-twisted molecular scaffold (ATMS) using pyridine-2,6-dicarboxamide (PDC) unit as pivot, chiral trans-cyclohexanediamine (CHDA) residues as linkers, and pyrene residues as fluorescent reporters. R,R-ATMS exclusively adopted M-helicity and produced differential response in UV-vis, fluorescence, and NMR upon addition of tartaric acid (TA) stereoisomers allowing naked-eye detection and enantiomeric content determination. Circular dichroism (CD) profile of R,R-ATMS underwent unique changes during titration with TA stereoisomers - while loss of CD signal at 345 nm was observed with equimolar D-TA and meso-TA, inversion was seen with equimolar L-TA. Temperature increase weakened these interactions to partially recover the original CD signature of R,R-ATMS. 2D NMR studies also indicated the significant structural changes in R,R-ATMS in the solution state upon addition of L-TA. Single crystal X-ray diffraction (SCXRD) studies on the crystals of the R,R-ATMS⊃D-TA salt revealed the interacting partners stacked in arrays and ATMS molecules stabilized by π-π stacking between its PDC and pyrene residues. Contrastingly, tightly-packed supramolecular cages comprised of four molecules each of R,R-ATMS and L-TA were seen in R,R-ATMS⊃L-TA salt, and the ATMS molecules contorted to achieve CH-π interactions between its pyrene residues. These results may have implications in modulating the helicity of topologically-similar larger biomolecules.

A new pair of butylphthalide diastereomers from the roots of Angelica sinensis

A new pair of butylphthalide diastereomers, dangguinolide A (1) and dangguinolide B (2), together with two known butylphthalide were isolated from Angelica sinensis. Their structures were determined by extensive spectroscopic analyses, and the absolute configurations of 1 and 2 were assigned via NMR calculations and ECD calculations. Their anti-inflammatory activities have evaluated in vitro.

Enantioselective Synthesis of β-l-5-[(E)-2-Bromovinyl)-1-((2S,4S)-2-(hydroxymethyl)-1,3-(dioxolane-4-yl) Uracil)] (l-BHDU) via Chiral Pure l-Dioxolane.

β-l-5-((E)-2-Bromovinyl)-1-((2S,4S)-2-(hydroxymethyl)-1,3-(dioxolane-4-yl) uracil (l-BHDU, 17) is a potent and selective inhibitor of the varicella-zoster virus (VZV). l-BHDU (17) has demonstrated excellent anti-VZV activity and is a preclinical candidate to treat chickenpox, shingles (herpes zoster), and herpes simplex virus 1 (HSV-1) infections. Its monophosphate prodrug (POM-l-BHDU-MP, 24) demonstrated an enhanced pharmacokinetic and antiviral profile. POM-l-BHDU-MP (24), in vivo, effectively reduced the VZV viral load and was effective for the topical treatment of VZV and HSV-1 infections. Therefore, a viable synthetic procedure for developing POM-l-BHDU-MP (24) is needed. In this article, an efficient approach for the synthesis of l-BHDU (17) from a readily available starting material is described in 7 steps. An efficient and practical methodology for both chiral pure l- & d-dioxolane 11 and 13 were developed via diastereomeric chiral amine salt formation. Neutralization of the amine carboxylate salt of l-dioxolane 10 provides enantiomerically pure l-dioxane 11 (ee ≥ 99%). Optically pure 11 was utilized to construct the final nucleoside l-BHDU (17) and its monophosphate ester prodrug (POM-l-BHDU-MP, 24). Notably, the reported process eliminates expensive chiral chromatography for the synthesis of chiral pure l- & d-dioxolane, which offers avenues for the development and structure-activity relationship studies of l- & d-dioxolane-derived nucleosides.

Cyclic Azahelicene Dimers Showing Bright Circularly Polarized Luminescence and Selective Fluoride Recognition.

Although helicenes are promising molecules, the synthetic difficulty and tediousness have often been problems, and only small amounts of optically pure helicenes have been obtained by using chiral HPLC in most cases. Herein, aza[7]helicenes or closed-aza[7]helicenes with (1R)-menthyl substituents were selectively synthesized via the intramolecular Scholl reaction, and the diastereomeric pairs were separated by silica gel column chromatography. The optically pure helicenes were further transformed into the corresponding cyclic dimers, and the chiroptical properties were investigated. The rigid π-frameworks of the dimers led to the high molar extinction coefficients and fluorescence quantum yields, while the twisted helicene moieties induced clear Cotton effects and CPL in the visible region, and the high CPL brightness (BCPL) was achieved. Furthermore, the cyclic dimers were found to have the macrocyclic cavity with the two NH groups suitable for the selective binding of a fluoride anion, which induced significantly redshifted fluorescence and CPL in the red region.

Cyclic Azahelicene Dimers Showing Bright Circularly Polarized Luminescence and Selective Fluoride Recognition

AbstractAlthough helicenes are promising molecules, the synthetic difficulty and tediousness have often been problems, and only small amounts of optically pure helicenes have been obtained by using chiral HPLC in most cases. Herein, aza[7]helicenes or closed‐aza[7]helicenes with (1R)‐menthyl substituents were selectively synthesized via the intramolecular Scholl reaction, and the diastereomeric pairs were separated by silica gel column chromatography. The optically pure helicenes were further transformed into the corresponding cyclic dimers, and the chiroptical properties were investigated. The rigid π‐frameworks of the dimers led to the high molar extinction coefficients and fluorescence quantum yields, while the twisted helicene moieties induced clear Cotton effects and CPL in the visible region, and the high CPL brightness (BCPL) was achieved. Furthermore, the cyclic dimers were found to have the macrocyclic cavity with the two NH groups suitable for the selective binding of a fluoride anion, which induced significantly redshifted fluorescence and CPL in the red region.

New methods for resolution of hydroxychloroquine by forming diastereomeric salt and adding chiral mobile phase agent on RP-HPLC.

Hydroxychloroquine (HCQ), 2-([4-([7-Chloro-4-quinolyl]amino)pentyl]ethylamino)ethanol, exhibited significant biological activity, while its side effects cannot be overlooked. The RP-HPLC enantio-separation was investigated for cost-effective and convenient optical purity analysis of HCQ. The thermodynamic resolution of Rac-HCQ, driven by enthalpy and entropy, was achieved on the C18 column using Carboxymethyl-β-cyclodextrin (CM-β-CD) as the chiral mobile phase agent (CMPA). The effects of CCM-β-CD, pH, and triethylamine (TEA) V% on the enantio-separation process were explored. Under the optimum conditions at 24°C, the retention times for the two enantiomers were and , resulting in . The resolution via diastereomeric salt formation of Rac-HCQ was developed to obtain the active pharmaceutical ingredient of single enantiomer S-HCQ. Di-p-Anisoyl-L-Tartaric Acid (L-DATA) was proved effective as the resolution agent for Rac-HCQ. Surprisingly, it was found that refluxing time was a key fact affecting the resolution efficiency, which meant the kinetic dominate during the process of the resolution. Four factors-solvent volume, refluxing time, filtration temperature, and molar ratio-were optimized using the single-factor method and the response surface method. Two cubic models were established, and the reliability was subsequently verified. Under the optimal conditions, the less soluble salt of 2L-DATA:S-HCQ was obtained with a yield of 96.9% and optical purity of 63.0%. The optical purity of this less soluble salt increases to 99.0% with a yield of 74.2% after three rounds recrystallization.

Synthesis and enzymatic resolution of novel analogs of alicyclic and heterocyclic mandelic acid derivatives

Synthesis and enzymatic resolution of a new class of alicyclic and heterocyclic mandelic acid derivatives was described. The method relied on the preparation of cyanohydrins from the commercially available aldehydes followed by hydrolysis to corresponding racemic hydroxy esters that were used in the resolution with the Amano PS enzyme. An alternative approach was proposed for compounds that were not suitable for this procedure. For the selected examples, synthesis of the corresponding mandelic acid analogs using the subsequent hydrolysis of esters followed by enantiomeric enrichment via recrystallization of the diastereomeric salt was performed.

Diastereoselective Supramolecular Encapsulation and Chirality Transfer Between Cholesteryl Binaphthyl Conjugates and Polyaromatic Hydrocarbon.

Diastereoselective effect plays an important role in the synthesis of chiral complexes and macrocyclic compounds, while its function in selective coassembly and chirality transfer has yet to be unveiled. In this work, two pairs of diastereomers containing R/S- binaphthyl and homochiral cholesteryl domains are synthesized, which provide multiple sites to encapsulate polyaromatic hydrocarbon through π-π and CH-π interactions. X-ray structures and computational studies suggest the binaphthol derivatives feature CH-π folding into butterfly-like open geometry, while binaphthylenediamine derivatives adopt closed geometry supported by van der Waals between cholesteryl domains. Driven by solvophobic forces, the building units self-assemble into vesicles and nanofibers in the aqueous and methanol phases, respectively. Binaphthol derivatives selectively encapsulate pyrene by naphthalene domains in the vesicle phase, while binaphthylenediamine derivatives encapsulate pyrene by cholesteryl domains in the nanofiber phase. Density functional theory-based calculations and circular dichroism spectra evidence the closed geometry of binaphthylenediamine derivatives facilitates a clamp-type host to increase the affinity toward pyrene in spite of the strong solvation competition. This work unveils the diastereoselectivity in the chiral coassembly, deepening the understanding of the precise synthesis of functional chiroptical complexes.

Synthesis of New Chiral β-Carbonyl Selenides with Antioxidant and Anticancer Activity Evaluation-Part I.

A series of unsymmetrical phenyl β-carbonyl selenides with o-amido function substituted on the nitrogen atom with chiral alkyl groups was obtained. The compounds form a series of enantiomeric and diastereomeric pairs and present the first examples of this type of chiral Se derivatives. All obtained selenides were further evaluated as antioxidants and anticancer agents to define the influence of the particular stereochemistry of the attached functional groups on the bioactivity of the molecules. The highest H2O2 reduction potential was observed for N-(cis-2-hydroxy-1-indanyl)-2-((2-oxopropyl)selanyl)benzamide, and the best radical scavenging properties for N-(-1-hydroxy-2-butanyl)-2-((2-oxopropyl)selanyl)benzamide. Also, both enantiomers of the N-(1-hydroxy-2-butanyl) selenide expressed the highest cytotoxic potential towards human promyelocytic leukemia HL-60 cell line with similar IC50 values 14.4 ± 0.5 and 16.2 ± 1.1 µM, respectively. On the other hand, breast cancer cell line MCF-7 was most sensitive to N-((R)-(-)-1-hydroxy-2-butanyl)- 2-((2-oxopropyl)selanyl)benzamide (IC50 of 35.7 ± 0.6 µM). The structure-activity dependence of the obtained Se derivatives was discussed, and the most potent compounds were selected.

Chlorido-pentamethylcyclopentadienyl-[2-(2-pyridyl-кN)-ferrocenyl-кC]-iridium(III)

Treatment of 2-pyridyl-ferrocene wit [Cp*IrCl2]2 in the presence of NaOAc produces the title compound Cp*ClIr[(C5H3C5H4N-кN,кC)Fe(C5H5)] (2) in low yield. A crystal structure determination shows the (SpSIr/RpRIr)-2 enantiomeric pair of diastereomers.

Diastereomers of Steroidal Alkaloids with Cytotoxic Activities against Non-Small-Cell Lung Cancer from the Bulbs of Fritillaria sinica.

Eleven new steroidal alkaloids, along with nine known related compounds, were isolated from the bulbs of Fritillaria sinica. Seven pairs of diastereomers were identified, including six and four 20-deoxy cevanine-type steroidal alkaloid diastereomers with molecular weights of 413 and 415, respectively. Structures were elucidated based on spectroscopic data analysis, chemical derivatization, and single-crystal X-ray diffraction analysis. Compounds 5, 9, 11, 12, 16, and 20 exhibited significant in vitro cytotoxic activity against non-small-cell lung cancer with CC50 values from 6.8 ± 3.9 to 12 ± 5 μM.

Resolution of trans-1,2-cyclohexanedicarboxylic acid containing two carboxylic groups by forming diastereomeric salts based on feeding molar ratio control.

To investigate the thermodynamic and molecular self-assembly mechanism of trans-1,2-cyclohexane dicarboxylic acid containing two carboxylic acid groups in the chiral resolution process, (S)-phenylethylamine was used as the chiral resolving agent. Two stoichiometric salts were formed when the raw materials were fed at different molar ratios: cyclohexane dicarboxylate monophenylethylamine salt and cyclohexane dicarboxylate diphenylethylamine salt. When the molar ratio of the (S)-phenylethylamine to trans-1,2-cyclohexane dicarboxylic acid was less than 3:1, trans-(1S,2S)-cyclohexane dicarboxylic acid was obtained with 97 e.e% purity. But when the molar ratio exceeded 3:1, the product was the racemic trans-(1,2)-cyclohexane dicarboxylic acid. In addition, single crystal structures of more soluble mono-salt, less soluble mono-salt, and less soluble di-salt were obtained. The weak intermolecular interactions and the way of the molecules packing in the crystals were analyzed. The hydrogen bond was stronger in the less soluble salt than that in the more soluble salt. And a "lock-and-key" structure in the hydrophobic layers makes it more tightly packed through the van der Waals interaction, which is responsible for the stability of less soluble salts.

Enantiomer separation of 2-halomandelic acids via diastereomeric salt formation with chiral N-substituted 2-amino-2-phenylethanols.

Chiral N-substituted secondary 1,2-aminoalcohols have been developed for the enantioseparation of ortho-halomandelic acids (o-X-MAs) via diastereomeric salt formation. Two structural isomers, N-methyl-2-amino-1,2-diphenylethanol and N-benzyl-2-amino-2-phenylethanol, showed high separation abilities for o-X-MAs (X = Cl, Br, I). The chiral recognition mechanism was elucidated by crystallographic analysis of the less-soluble salts. The substituents on the nitrogen atom of the resolving agents and the inclusion of the crystallization solvent stabilized the salt and enhanced their separation ability.

Resolution of (rac)-Phenylethylamine by Lithocholic Acid: Structures and Analysis of Both the n- and p-Diastereomeric Salts

Resolution of (rac)-Phenylethylamine by Lithocholic Acid: Structures and Analysis of Both the <i>n-</i> and <i>p-</i>Diastereomeric Salts

Stereoselective Synthesis of Fluoroalkanes via FLP Mediated Monoselective C─F Activation of Geminal Difluoroalkanes.

A method of desymmetrization of geminal difluoroalkanes using frustrated Lewis pair (FLP) mediated monoselective C-F activation where a chiral sulfide is the Lewis base component is reported. The stereoselective reaction provides generally high yields of diastereomeric sulfonium salts with dr of up to 95:5. The distribution of diastereomers is found to be thermodynamically controlled via facile sulfide exchange. The use of enantiopure chiral sulfides allows for high stereospecificity in nucleophilic substitution reactions and the formation of stereoenriched products.

Synthesis of Organosilicon‐Based Thioether Ligand Class Showing Defined S‐Stereogenic Coordination in Crystalline Palladium(II) Complexes

AbstractA synthesis route to aromatic organosilicon‐based thioether ligands could be established and utilised for three congeners 2. These ligands were suitable for complexation with palladium(II) chloride forming three new complexes 3. The single crystal X‐ray diffraction and temperature‐dependent 1H and 13C‐NMR analysis of 3 are presented. The elucidated solid‐state structures suggested that one pair of diastereomers is favoured in crystalline phase and is controllable by the aromatic substituent. However, at room temperature in solution, the conformation at the sulphur atoms can fluctuate with a coalescence temperature for 1H‐NMR around 24 °C. At −31 °C, two signal sets could be observed since the inversion is slower than the 1H‐NMR timescale at lower temperatures.