Stereoselective total synthesis of the E-isomer of putative lucentamycin A

A synthesis of the E-isomer of the proposed structure of the novel tripeptide, lucentamycin A, was performed in an attempt to define the correct stereochemistry of this natural product. The synthetic route developed employs a stereoselective Rh-catalyzed reductive cyclization process to generate the key pyrrolidine residue in the target and a stereospecific inversion of the Z-olefin geometry to form desired E-isomer. Subsequent amide coupling reactions afforded the desired E-isomer of putative lucentamycin A. A comparison of the NMR data of synthetic E-1a with that of the naturally occurring lucentamycin A demonstrated that they are not identical substances and the E-1a was found to display no anti-proliferative activity on the colon cancer cell line HCT-116 in contrast to natural lucentamycin A.     

Chiral resolution,absolute configuration determination,and stereo-activity relationship study of IDO1 inhibitor NLG919

NLG919 (1) with two chiral carbon atoms on its chemical structure is a potent indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor. We developed an effective way to prepare all stereoisomers of 1, the key step being the chiral resolution of racemic intermediate 2. The optimal resolution solvent system was identified as dichloromethane and n-pentane or petroleum ether. Using (?)-di-p-toluoyl-d-tartaric acid as resolution reagent, optical pure (R)-2 (e.e.?>?99%, yield?=?70%) was obtained. The mechanism of chiral resolution was clarified through single-crystal X-ray diffraction of the diastereomeric salt. The absolute configurations of four stereoisomers of 1 were established through electronic circular dichroism spectra, quantum chemical calculation and transition metal method. Their IDO1 inhibitory activity was assessed by pharmacological experiments in vitro and in mouse, demonstrating that S configuration of C5 played an important role on the inhibition of IDO1, while the stereochemistry on C2′ exerted little effect on the IDO1 inhibitory activity in mouse.     

Recognition of enantiomers with chiral molecular tweezers derived from (+)- or (−)-usnic acid

The synthesis of four stereoisomers of a chiral molecular tweezer using trans-1,2-diaminocyclohexane as spacer and two molecules of usnic acid as pincers is reported. The behavior of these chiral tweezers as chiral complexing agents was evaluated in NMR with various chiral esters containing an electron-poor aromatic ring to allow non-covalent aromatic–aromatic interactions.     

Absolute configuration of the four stereoisomers of valnoctamide (2-ethyl-3-methyl valeramide), a potentially new stereospecific antiepileptic and CNS drug

Valnoctamide (2-ethyl-3-methyl valeramide, Nirvanil^®, VCD), a mild tranquilizer endowed with anticonvulsant properties, exhibits diastereoselective and enantioselective pharmacokinetics in healthy subjects and epileptic patients. The purpose of this paper is to assign the absolute configuration of the four VCD stereoisomers and to describe the stereoselective synthesis used to prepare two-key VCD stereoisomers. We have synthesized two out of the four stereoisomers, with high diastereomeric excess, by two different synthetic methods. In both methods the (S) configuration at C-3 of VCD was fixed by synthesizing (S)-3-methyl valeric acid from l-isoleucine. In the first method the diastereomeric mixture (2RS,3S)-VCD was prepared. This mixture gave one of the diastereomers via repeated crystallizations, and its absolute configuration (2R,3S)-VCD, was established by X-ray crystallography using a single crystal. The absolute configuration of all four VCD stereoisomers, separated by chiral gas chromatography, was established on the basis of diastereomeric and enantiomeric correlations. In order to assess stereoselective pharmacodynamic properties of VCD, the single stereoisomers have to be synthesized. Stereoselective synthesis of (2R,3S)-VCD and (2S,3S)-VCD was accomplished by using chiral oxazolidinone auxiliaries. These diastereomers were obtained in 99.6% diastereomeric excess.     

Separation and quantitation of the four stereoisomers of itraconazole in pharmaceutical formulations by electrokinetic chromatography

The four stereoisomers of itraconazole were resolved for the first time by EKC using a CD as chiral selector. A study on the enantiomeric separation ability of different neutral CDs was carried out. Heptakis-2,3,6-tri-O-methyl-beta-CD was shown to provide the highest values for the enantiomeric resolution. The influence of some experimental conditions, such as pH, chiral selector concentration, and temperature, on the enantiomeric separation was also studied. The use of a 100 mM phosphate buffer (pH 2.5), 30 mM in heptakis-2,3,6-tri-O-methyl-beta-CD together with an applied voltage of 30 kV and a temperature of 20 degrees C enabled the separation of the enantiomers of itraconazole with high resolutions (Rs > 3.0). Finally, the method was validated and successfully applied to the quantitation of itraconazole in three pharmaceutical formulations.     

Enantiomer Separation of the Four Stereoisomers of 1-(4-Hydroxy-3-Methoxy)-Phenyl-2-[4-(1,2,3-Trihydroxy-Propyl)-2-Methoxy]-Phenoxy-1,3-Propandiol from Hydnocarpus annamensis by Capillary Zone Electrophoresis with HP-β-CD as Chiral Selector

A capillary zone electrophoresis method with HP-β-CD as chiral selector was established for the chiral separation of four stereoisomers of 1-(4-hydroxy-3-methoxy)-phenyl-2-[4-(1,2,3-trihydroxy-propyl)-2-methoxy]-phenoxy-1,3-propandiol for the first time, which were isolated from Hydnocarpus annamensis. The effects of chiral selector type and concentration, buffer composition, pH and concentration, and cartridge temperature on the enantioseparation were investigated. A baseline separation of the four stereoisomers was achieved in less than 18 min under the optimized conditions: 40 mmol L⁻¹ Borax–NaOH buffer (pH 10.02) in the presence of 100 mmol L⁻¹ HP-β-CD at 15°C and 30 kV. The experimental results showed that the method by capillary zone electrophoresis for the separation of four stereoisomers is powerful, sensitive and fast, requires less amounts of reagents, and can be employed as a reliable alternative to other methods.     

Chiral HPLC Method for the Novel Triazole Antitubercular Compound MSDRT 12

Cyclohex-3-enyl(5-phenyl-4H-1,2,4-triazol-3-yl)methanol (MSDRT 12) is a novel triazole-based antitubercular compound with two chiral centres. Evaluation of the enantio-specific antitubercular activity has established that the stereoisomer 3 of MSDRT12 (Isomer 3) was the most potent isomer with a minimum inhibitory concentration of 0.78 μg/mL. The other stereoisomers show negligible or no activity. A sensitive, simple, specific, precise and accurate chiral chromatographic method for the direct analysis of the four stereoisomers of MSDRT 12 and the active Isomer 3 has been developed and validated. The method has also been validated for analysing the stereoisomeric impurities Isomer 1, Isomer 2 and Isomer 4 in the active Isomer 3. The separation of the four stereoisomers of MSDRT 12 was achieved using an immobilized polysaccharide-based column, Chiralpak ID with amylose tris(3-chlorophenylcarbamate) as the chiral selector. The separation was performed using a mixture of n-hexane, isopropyl alcohol, ethanol and diethylamine (60:35:5:0.1 v/v/v/v) at a flow rate of 1 mL/min. The method offers excellent separation of the four stereoisomers with resolution more than 1.5 and tailing factor <1.5. The standard curves were linear over the concentration range 5–500 μg/mL and 0.40–505 μg/mL for MSDRT 12 and Isomer 3, respectively. Excellent linearity in the range 0.4–5 μg/mL was obtained for Isomer 1, Isomer 2 and Isomer 4 and these stereoisomeric impurities could be accurately and precisely quantified at a level of 0.1 % of the active isomer.     

A practical chromatography-free synthesis of a 5,6-dihydroimidazolo[1,5-f]pteridine derivative as a polo-like kinase-1 inhibitor

A practical chromatography-free synthesis of a potent polo-like kinase-1 inhibitor possessing a unique 5,6-dihydroimidazolo[1,5-f]pteridine structure has been developed. We showed that key cyanoimidazole ring formation could be conducted at benign temperature and obtained a chiral 5,6-dihydroimidazolo[1,5-f]pteridine derivative in good yield without epimerization. An aniline derivative containing a trans 1,4-cyclohexyl diamine structure was prepared by a synthesis that makes use of defined stereocenters of commercially available trans-cyclohexane-1,4-diamine via selective piperazine ring formation from a primary diamine. A coupling reaction of the 3-chloro-5,6-dihydroimidazolo[1,5-f]pteridine derivative and the aniline derivative in the endgame was closely investigated, and good yields were achieved both by palladium-catalyzed amination and acid-promoted coupling under benign reaction conditions. As a result of these investigations, the polo-like kinase-1 inhibitor was successfully obtained in a practical way without concern for generation/separation of stereoisomers.     

Enantioselective synthesis and stereochemical revision of communiols A-C

Enantioselective synthesis of the proposed structure of communiol C, an antibacterial tetrahydrofuran derivative produced by Podospora communis, and its stereoisomers revealed that the genuine stereochemistry of communiol C should be 3R, 5R, and 6S. Two other structurally related metabolites of the same microbial origin, communiols A and B, were also synthesized based on the revised stereochemistry.     

trans‐Dichloridobis(4,8‐dimethyl‐2‐phenyl‐2‐phosphabicyclo[3.3.1]nonane‐κP)platinum(II)

The crystal structure of the title compound, trans‐[PtCl₂(C₁₆H₂₃P)₂], has been determined at 100 K. The Pt atom is located on a twofold axis and adopts a distorted square‐planar coordination geometry. The structure is only the second example of a coordination complex containing a derivative of the 4,8‐dimethyl‐2‐phosphabicyclo[3.3.1]nonane (Lim) phosphine ligand family. The ligand contains four chiral C atoms, with the stereochemistry at three of these fixed during synthesis, therefore resulting in two possible ligand stereoisomers. The compound crystallizes in the chiral space group P4₃2₁2 but is racemic, comprising an equimolar mixture of both stereoisomers disordered on a single ligand site. The effective cone angles for both isomers are the same at 146°.     

Stereoselective Chiral Molecular Carbon Imides Featuring 12-Fold [5]helicenes Around Four Cores**

Despite the great progress in research on molecular carbons containing multiple helicenes around one core, realizing the stereoselectivity of carbons containing multiple helicenes around more cores is still a great challenge. Herein, molecular carbon C₂₀₄ featuring 12-fold [5]helicenes around four cores was successfully constructed by using nine perylene diimide (PDI) units, and exhibits good solubility and stability. Despite 256 possible stereoisomers caused by the 12-fold [5]helicenes, we only obtained one pair of enantiomers with D₃ symmetry. There are four possible pairs of enantiomers with D₃ symmetry, namely 7A, 7B, 7C and 7D. Theoretical and experimental results verify that the obtained structure belongs to 7C, which has the lowest energy. The enantiomers can also be separated by chiral HPLC. These results suggest that choosing PDIs as building blocks can not only improve the solubility and stability but also realize the stereoselectivity and chirality of molecular carbons.     

Estimation of the pH-independent binding constants of alanylphenylalanine and leucylphenylalanine stereoisomers with beta-cyclodextrin in the presence of urea

The separation of stereoisomers, particularly enantiomers, is important when their physiological activity differs. We have resolved the four stereoisomers each of alanylphenylalanine (Ala-Phe) and of leucylphenylalanine (Leu-Phe) by capillary electrophoresis using beta-cyclodextrin as a buffer additive and urea to enhance its solubility. A study of the influence of pH and beta-cyclodextrin concentration on the separations showed that weak inclusion complexes were formed between the dipeptides and chiral selector. It was found that pH could alter the migration order of enantiomers L-Ala-L-Phe and D-Ala-D-Phe, as well as L-Leu-L-Phe and D-Leu-D-Phe; however, there was no change in order for the other pairs of optical isomers. Electrophoretic mobility data were used to estimate the acid dissociation constants of the dipeptide isomers at pH < 7 with no chiral selector present. By varying the concentration of beta-cyclodextrin, the chiral selector, the binding constants of Ala-Phe and Leu-Phe optical isomers in their fully protonated and zwitterionic forms were estimated. For the four Ala-Phe stereoisomers, K = 42-66 M(-1) and 4-41 M(-1) for the cationic and zwitterionic forms, respectively. For the four Leu-Phe stereoisomers, K = 43-94 M(-1) and 1-28 M(-1) for the cationic and zwitterionic forms, respectively.     

Energetics of Competing Chiral Supramolecular Polymers

Chirality can have unexpected consequences including on properties other than spectroscopic. We show herein that a racemic mixture of bis-urea stereoisomers forms thermodynamically stable supramolecular polymers that result in a more viscous solution than for the pure stereoisomer. The origin of this macroscopic property was probed by characterizing the structure and stability of the assemblies. Both racemic and non-racemic bis-urea stereoisomers form two competing helical supramolecular polymers in solution: a double and a single helical structure at low and high temperature, respectively. The transition temperature between these assemblies, as probed by spectroscopic and calorimetric analyses, is strongly influenced by the composition (by up to 70 °C). A simple model that accounts for the thermodynamics of this system, indicates that the stereochemical defects (chiral mismatches and helix reversals) affect much more the stability of single helices. Therefore, the heterochiral double helical structure predominates over the single helical structure (whilst the opposite holds for the homochiral structures), which explains the aforementioned higher viscosity of the racemic bis-urea solution. This rationale constitutes a new basis to tune the macroscopic properties of the increasing number of supramolecular polymers reported to exhibit competing chiral nanostructures.     

Conformationally constrained amino acids: enantiodivergent synthesis of all four stereoisomers of 2-(tetrahydrofuran-2-yl)glycine

The first enantiodivergent synthesis of all four possible 2-(tetrahydrofuran-2-yl)glycine stereoisomers is described. The key step of the route is the highly stereocontrolled allylboration of the (S)- or (R)-Garner's aldehydes to give four chiral homoallylalcohols. Starting from them, the title compounds are obtained in five steps.     

Synthesis and Mechanism of a Main‐Chain Chiral Polymer Based on Asymmetric Cyclopolymerization

A systematic study of the asymmetric cyclocopolymerization of bis(4‐vinylbenzoate)s, derived from chiral diols, with styrene has been made from the viewpoint of synthesizing the main‐chain chiral polymer. On the basis of using over 30 chiral diols as templates, we summarize the relationship between the structure of the chiral template and the chiroptical properties of the template‐free polymer. For simple chiral diols, the chirality induction efficiency increased in the order 1,2‐diol < 1,4‐diol < 1,3‐diol. Chiral diols with two chiral centers exhibited higher chirality induction efficiency than those having one chiral center only. The chirality induction efficiency for cyclic 1,2‐diols increased with the ring size in the order 5‐ < 6‐ < 7‐ < 8‐membered rings, and that for acyclic 1,2‐diols increased with the bulkiness of the substituent at the chiral center. In addition, a chirality induction mechanism has been proposed on the basis of model radical cyclization experiments and computational studies. Chirality induction could be caused by the inhibition of the formation of one racemo unit among the four stereoisomers due to the strong dependence of the stereoselectivity in intermolecular additions on the absolute configuration of the cyclized radical. The mechanism was examined using the Lewis‐acid and monomer‐concentration effects.     

Analytical and semipreparative chiral separation of cis‐itraconazole on cellulose stationary phases by high‐performance liquid chromatography

cis‐Itraconazole is a chiral antifungal drug administered as a racemate. The knowledge of properties of individual cis‐itraconazole stereoisomers is vital information for medicine and biosciences as different stereoisomers of cis‐itraconazole may possess different affinity to certain biological pathways in the human body. For this purpose, either chiral synthesis of enantiomers or chiral separation of racemate can be used. This paper presents a two‐step high‐performance liquid chromatography approach for the semipreparative isolation of four stereoisomers (two enantiomeric pairs) of itraconazole using polysaccharide stationary phases and volatile organic mobile phases without additives in isocratic mode. The approach used involves the separation of the racemate into three fractions (i.e. two pure stereoisomers and one mixed fraction containing the remaining two stereoisomers) in the first run and consequent separation of the collected mixed fraction in the second one. For this purpose, combination of cellulose tris‐(4‐methylbenzoate) and cellulose tris‐(3,5‐dimehylphenylcarbamate) columns with complementary selectivity for cis‐itraconazole provided full separation of all four stereoisomers (with purity of each isomer > 97%). The stereoisomers were collected, their optical rotation determined and their identity confirmed based on the results of a previously published study. Pure separated stereoisomers are subjected to further biological studies.     

High‐performance liquid chromatographic separations of stereoisomers of chiral basic agrochemicals with polysaccharide‐based chiral columns and polar organic mobile phases

The separation of the stereoisomers of 23 chiral basic agrochemicals was studied on six different polysaccharide‐based chiral columns in high‐performance liquid chromatography with various polar organic mobile phases. Along with the successful separation of analyte stereoisomers, emphasis was placed on the effect of the chiral selector and mobile phase composition on the elution order of stereoisomers. The interesting phenomenon of reversal of enantiomer/stereoisomer elution order function of the polysaccharide backbone (cellulose or amylose), type of derivative (carbamate or benzoate), nature, and position of the substituent(s) in the phenylcarbamate moiety (methyl or chloro) and the nature of the mobile phase was observed. For several of the analytes containing two chiral centers all four stereoisomers were resolved with at least one chiral selector/mobile phase combination.     

Assignment of absolute configurations of permethrin and its synthon 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid by electronic circular dichroism,optical rotation,and X-ray crystallography

The availability of single stereoisomers of biologically/toxicologically relevant chiral compounds such as the pyrethroid-type insecticide permethrin (PM) and the reliable determination of their absolute configurations are of central importance for the detailed investigation and correct assignment of stereoselective effects. In this context, single stereoisomers of 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid (DCCA), a precursor, metabolite, and environmental degradation product of PM, were isolated from a mixture of all four stereoisomers in enantiomeric excesses of >99% via a two-step chromatographic process combining a diastereoselective reversed-phase separation in the first step with a direct enantiomer separation in the second step. Esterification of DCCA stereoisomers with 3-phenoxybenzyl alcohol yielded PM. Electronic circular dichroism (ECD) spectra of DCCA and PM stereoisomers were measured in non-polar (cyclohexane containing 5% v/v 1,2-dichloroethane) and non-protic polar (acetonitrile) solvents. Cotton effects suitable to distinguish the four stereoisomers of each DCCA and PM were obtained. Absolute configurations of DCCA were determined by confrontation of calculated (time-dependent density-functional theory using B3LYP hybrid functional) and experimental ECD and optical rotation (OR) data. Fully convergent results between ECD and X-ray diffractometry (analysis of DCCA isomers co-crystallized with O-9-(2,6-diisopropylphenylcarbamoyl)quinine), which was employed as a reference method, were obtained. The importance of considering dimer formation of DCCA in solution for the computational delineation of absolute configurations was demonstrated by (1R,3R)-cis-DCCA for which the ΔG Boltzmann averaged calculated monomeric form delivered the opposite sign of OR compared to the dimeric form and the value determined experimentally in dichloromethane. For (1S,3R)-trans-DCCA both monomer and dimer delivered the identical sign of OR and this was in agreement with the experimental measurement. In contrast to OR, the calculated ECD spectra of these two DCCA stereoisomers were less sensitive toward intermolecular association.     

The first total synthesis and structural determination of antibiotics K1115 B1s (alnumycins)

K1115 B₁, isolated from the broth of Streptomyces species, was found to be a mixture of stereoisomers. Authors synthesized all stereoisomers of K1115 B₁ by convergent synthesis coupling a rhamnose derivative, an isobenzofuranone, and a chiral tetraol. Comparison of ¹H NMR spectra and optical rotations made it clear that the absolute structures of K1115 B_1α (the major isomer) and K1115 B_1β (the minor isomer) were (1R, 17S)- and (1R, 17R)-configurations, respectively. The optical rotations of the stereoisomers revealed that alnumycin, reported as the identical structure with K1115 B₁, might be another mixture of stereoisomers.     

Pheromone synthesis. Part 245: Synthesis and chromatographic analysis of the four stereoisomers of 4,8-dimethyldecanal, the male aggregation pheromone of the red flour beetle, Tribolium castaneum

All four stereoisomers of 4,8-dimethyldecanal (1) were synthesized from the enantiomers of 2-methyl-1-butanol and citronellal. Enantioselective GC analysis enabled separation of (4R,8R)-1 and (4R,8S)-1 from a mixture of (4S,8R)-1 and (4S,8S)-1, when octakis-(2,3-di-O-methoxymethyl-6-O-tert-butyldimethylsilyl)-γ-cyclodextrin was employed as a chiral stationary phase. Complete separation of the four stereoisomers of 1 on reversed-phase HPLC at −54 °C was achieved after oxidation of 1 to the corresponding carboxylic acid 12 followed by its derivatization with (1R,2R)-2-(2,3-anthracenedicarboximido)cyclohexanol, and the natural 1 was found to be a mixture of all the four stereoisomers.