A versatile ternary ion pair complex of 2′-amino-1,1′-binaphthalen-2-ol for sensing enantiomers and assignment of absolute configuration

2′-Amino-1,1′-binaphthalen-2-ol (NOBIN) serves as a versatile chiral solvating agent (CSA) in the presence of trifluoromethanesulfonic acid (TFMS). The formation of a ternary complex has been established by NMR, UV–Vis, fluorescence and IR studies. The mechanism of interactions among the three components in the ternary complex has been proposed and the ternary complex structures of different diastereomers have been established by DFT based theoretical calculations. The present protocol has its ubiquity not only in the analysis of the enantiomeric composition of molecules possessing diverse functionalities, but also in determining the stereospecific assignment of hydroxy acids.     

Benzyl isobornyl amines: a simple and practical class of NMR discriminating agents for effective chiral recognition of acids

The design and synthesis of a few simple N-benzyl derivatives of isobornyl amine is presented. The derivatives have been assessed as chiral solvating agents for effective discrimination of the signals of some acids in NMR analysis. The single crystal X-ray analysis of the salts of (R)-mandelic acid with two of the title derivatives help to understand the supramolecular interactions and assign the induced chemical shifts in ¹H NMR analysis. The title derivative is found to be suitable for quantitative determination of the enantiomeric excess of unknown enantiomeric purity as well as being efficient in resolving racemic mandelic acid.     

Resolution,absolute configuration and antifilarial activity of coumarinyl amino alcohols

The resolution of racemic coumarinyl amino alcohols 5–10 was achieved by using the inexpensive and readily accessible chiral resolving agent N-carbethoxy-l-proline (S)-11. Direct esterification of rac-5–10 with (S)-11 furnished diastereomeric esters, which were easily separated by column chromatography. The obtained diastereomers yielded the desired enantiopure coumarinyl amino alcohols (S)-(+)-5–10 and (R)-(?)-5–10 in good yields with high enantiomeric excess on saponification. The absolute configurations were determined by X-ray crystal analysis and/or by comparison of the specific rotations. Furthermore, in in vitro antifilarial motility inhibition assays, enantiopure coumarins (S)-(+)-9, (R)-(?)-9 and (S)-(+)-10, (R)-(?)-10 were found to be less efficient in affecting the viability of macrofilariae of Brugia malayi than their racemic forms 9 and 10, respectively, indicating the synergistic effect of the enantiomers in evoking antifilarial action.     

Synthesis,crystal structure,and absolute configuration of the enantiomers of chiral drug xibenolol hydrochloride

Based on the features of its crystallization, racemic 3-(2,3-dimethylphenoxy)propane-1,2-diol 2, the synthetic precursor of the chiral drug xibenolol 1, was resolved into pure enantiomers by the direct method of entrainment. The enantiomers of diol 2 through a Mitsunobu reaction were converted into the nonracemic 1,2-epoxy-3-(2,3-dimethylphenoxy)propanes (S)- and (R)-3, and then into the xibenolol enantiomers. Single crystals of (+)- and (?)-1·HCl were studied by X-ray diffraction. On the basis of the Flack parameter, the absolute (R)- and (S)-configurations were assigned to these compounds and to the other intermediate chiral substances.     

Ferrocene derivatives of liquid chiral molecules allow assignment of absolute configuration by X-ray crystallography

The present study investigates a synthetically simple ferrocene derivatization of natural products and active pharmaceutical ingredients. Seven new crystal structures are analyzed together with 16 structures of ferrocene derivatives reported previously. In all cases, the unambiguous determination of the absolute structure was established from anomalous dispersion using the methods of Flack and Parsons. A comparison with other derivatization approaches shows the advantage of the described ferrocene derivatization for establishing the absolute configuration of novel compounds.     

Sulfated cyclodextrins as water-soluble chiral NMR solvating agents for cationic compounds

The utility of a series of sulfated cyclodextrins as water-soluble chiral NMR solvating agents for cationic substrates is described. Sulfated α-, β- and γ-cyclodextrin with degrees of substitution of 12, 13 and 14, respectively, a sulfated β-cyclodextrin with a degree of substitution of 9 and a sulfobutyl ether β-cyclodextrin with a degree of substitution of 6.3 are examined. Results with 33 water-soluble cationic organic salts are reported. Chiral differentiation with the sulfated cyclodextrins is compared to prior results obtained with anionic carboxymethylated and phosphated cyclodextrins. The highly sulfated cyclodextrins are often more effective at causing enantiomeric differentiation in ¹H NMR spectra than the sulfobutyl ether, carboxymethylated and phosphated cyclodextrins, and are recommended as the first choice of a chiral solvating agent for the analysis of chiral cationic organic salts in aqueous solution.     

A concise enantioselective synthesis of 1,4-dideoxy-1,4-imino-d-arabinitol using Co(III)(salen)-catalyzed hydrolytic kinetic resolution of a two-stereocentered anti-azido epoxide

A concise enantioselective synthesis of 1,4-dideoxy-1,4-imino-d-arabinitol, (+)-DAB-1, has been described in good overall yield (18.1%) and with high enantiomeric purity (up to 98% ee) starting from a simple raw material, cis-2-butene-1,4-diol. The Co-catalyzed hydrolytic kinetic resolution of a two-stereocentered racemic azido epoxide followed by asymmetric dihydroxylation of the alkene and ‘one pot’ reductive cyclisation of the azido diol are key reactions in the synthetic sequence.     

A diversity oriented synthesis of d-erythro-sphingosine and siblings

An efficient building block-based synthetic protocol has been developed for the synthesis of 3-ketosphingoids with various chain lengths using cross metathesis of a Garner’s aldehyde-derived α,β-unsaturated ketone as the key step. Stereoselective reduction of the biomimetic precursors thus obtained provided d-erythro-sphingosine and truncated anaogues in good overall yields.     

Chiral benzimidazoles and their applications in stereodiscrimination processes

Chiral aspects of benzimidazoles have been over-shadowed for a long time due to the large number of reports on benzimidazoles in the medical field in numerous categories of therapeutic agents. The vigorous research activity in chiral applications of benzimidazole derivatives started after bifunctional benzimidazoles made their appearance especially in the last 2–3 decades. Thus, chiral benzimidazoles form a comparatively young branch of chiral chemistry. The presence of pyridine and pyrrole type of nitrogens along with the fused benzene ring confer on this class of molecules, special properties including useful nucleophilicity, hydrogen bonding ability and a rigid backbone, all of which play decisive roles in proven chiral applications. The present review aims to cover the synthetic routes to access chiral benzimidazoles and their applications in a plethora of chiral fields including enantioselective organocatalysis, metal-based catalysis, asymmetric transformations involving benzimidazole-N-heterocyclic carbenes, kinetic resolution, benzimidazole-based macrocyclic hosts in chiral supramolecular chemistry and other miscellaneous chiral applications.     

Immobilization of Lecitase® ultra on recyclable polymer support: application in resolution of trans-methyl (4-methoxyphenyl)glycidate in organic solvents

Lecitase® Ultra was immobilized on epoxy-activated polymer (DILBEAD-VWR) functionalized with polyethyleneimine via adsorption and crosslinking with glutaraldehyde. The resolution of methyl trans-(±)-3-(4-methoxyphenyl) glycidate was carried out in xylene (e.e. >99%, conversion 50%). The enzyme is not inhibited by the 4-methoxy phenyl acetaldehyde produced during hydrolysis and the immobilized enzyme with 7% moisture content works efficiently in an organic phase. While the immobilized enzyme can be recycled several times, the polymer support can also be recycled after removing the immobilized enzyme by washing with 1?M HCl.     

Asymmetric epoxidation of enones using cumyl hydroperoxide and in situ generated zinc complexes of chiral pyrrolidinyl alcohols

The homogeneous asymmetric epoxidation of a range of enones was carried out using cumyl hydroperoxide, diethylzinc, and chiral pyrrolidinyl alcohol-containing ligands to afford the corresponding epoxy ketones with enantioselectivities of ≤97% ee. Examination of the enantioselectivities obtained in the asymmetric epoxidation of enones using a range of chiral ligands indicated that synergy between the sterically bulky bicyclo[2.2.2]octane skeleton and the substituents attached to the carbinol moiety played an important role in determining the reaction enantioselectivity. The position and nature of the substituent on the aromatic ring of the enone also had a pronounced effect on the observed enantioselectivity.     

Stereoselective Michael-alkylation and Michael-oxidation reactions of chiral 1,3-dioxolanones

A highly diastereoselective Michael-alkylation/oxidation methodology has been developed for the synthesis of optically active α-hydroxy-1,5-diester subunits. Inverse stereochemistry at the C_2′ position could be achieved by using a Michael acceptor equipped with a suitable group followed by a highly stereoselective protonation. This methodology has been applied to the enantioselective synthesis of the upper fragment of (+)-retusine.     

Absolute configuration assignment of caffeic acid ester derivatives from Tithonia diversifolia by vibrational circular dichroism: the pitfalls of deuteration

Recently, it was observed that infrared (IR) and vibrational circular dichroism (VCD) calculations including deuterated hydroxyl groups in phenolic and saccharide moieties improved significantly the agreement with experimental data obtained in methanol-d₄. In the present study, the relative and absolute configurations of three methanol-soluble caffeic acid ester derivatives 1–3, isolated from Tithonia diversifolia, were established by a combined use of experimental and calculated ¹³C NMR chemical shifts, as well as electronic circular dichroism (ECD) and VCD spectroscopies. Interestingly, the attempt to reproduce the deuteration pattern arising from possible isotopic exchange in methanol-d₄ solution led to nearly mirror image calculated VCD spectra for 1 when compared to the non-deuterated molecule with the same absolute configuration. This latter fact can potentially lead to absolute configuration misassignments. A closer inspection of the vibrational chiroptical properties of 1 revealed that the deuteration status of the tertiary hydroxyl group at C-2 is critical for the correct reproduction of experimental VCD data in protic solvents. Therefore, in the case of stereochemical analysis of polar chiral natural product molecules, a combination of VCD and ECD is recommended.     

Absolute configuration of diterpenoids from Jatropha dioica by vibrational circular dichroism

The absolute configuration of jatropholone A 1 and B 2, including the possibility to observe the vibrational circular dichroism (VCD) capacity to differentiate between two epimeric compounds in the presence of an inherently dissymmetric chromophore, which normally dominates VCD and electronic circular dichroism (ECD) spectra, followed after comparison of their experimental and DFT calculated VCD spectra, allowed us to conclude that although non-local (M/P) chirality generated by atropisomerism dominates over local chirality generated by an (R/S) change, the stereogenic center can confidently be assigned by VCD after DFT calculations. In addition, the absolute configurations of jatrophatrione 3 and citlalitrione 4, a compound proposed as a taxonomic marker for the genus Jatropha, were assigned by contrasting their respective calculated and experimental IR and VCD spectra. The evaluation of Flack and Hooft parameters obtained from the single-crystal X-ray diffraction data of jatropholone B acetate 6, and of 4 independently confirmed the absolute configurations of these molecules.     

Tartaric acid-derived chiral phosphite-type P,N-ligands: behavioural features in Pd-catalyzed asymmetric transformations

A practical synthesis of new phosphoramidite, phosphite and diamidophosphite P,N-ligands derived from (R,R)-tartaric acid was carried out. A study of these chiral inducers showed them to provide up to 93% ee in the Pd-catalyzed asymmetric allylations of (E)-1,3-diphenylallyl acetate, up to 84% ee in the Pd-catalyzed asymmetric alkylation of cinnamyl acetate with ethyl 2-oxocyclohexane-1-carboxylate and up to 63% ee in the Pd-catalyzed desymmetrization of N,N′-ditosyl-meso-cyclopent-4-ene-1,3-diol biscarbamate. The effects of the structural modules, such as the nature of the phosphorus-containing ring or exocyclic substituent as well as of the nature of palladium source on the catalytic activity and enantioselectivity were investigated.     

Resin-bound chiral derivatizing agents for assignment of configuration by NMR spectroscopy

A general methodology for assigning the configuration of chiral mono- and polyfunctional compounds by NMR is presented. The approach is based on the use of polystyrene-bound chiral derivatizing agents (CDA-resins) specifically designed to achieve the high-yield formation of the covalent linkages (amide or ester bonds) between the substrate and the chiral auxiliary within the NMR tube, without the need for other manipulations, on a microscale level and in a short time. The deuterated NMR solvents (CDCl3, CD3CN, CS2/CD2Cl2) are also the reaction solvents and separations, purifications or workups of any kind are not necessary prior to recording the spectra. The CDA-resins prepared included MPA, 9-AMA, BPG, MTPA, and 2-NTBA as auxiliary agents incorporated either as single enantiomers or as mixed combinations of the (R)- and the (S)-enantiomers at unequal and known ratios. The high versatility of these systems was successfully demonstrated in a variety of ways based on double and single derivatization, low temperature experiments, or the formation of metal complexes. The approach allowed the absolute configurations of chiral primary amines, primary and secondary alcohols, cyanohydrins, thiols, diols, triols, and amino alcohols to be determined. Extensive high-resolution magic angle spinning (HR-MAS) NMR experiments allowed the characterization of the new CDA-resins and enabled the study of their stability and regioselectivity.     

Some experimental aspects of absolute configuration determination using single crystal X-ray diffraction

Students of single crystal X-ray diffraction are often give advice as to how best to collect their data when attempting absolute configuration determination. These ‘rules’ often have more grounding in gut-feeling than evidence. Thus, in an effort to provide advice and evidence that today’s crystallographers can pass onto to tomorrow’s young scientists, we present a systematic study of 1-deoxy-l-arabinitol, a straight chain sugar which crystalises well in the space group $\text{I}{4}_1$.     

Four new norlignan glycoside isomers from the twigs of Cephalotaxus oliveri Mast.

Four novel isomers of norlignan glycoside were isolated from Cephalotaxus oliveri Mast.. Their structures were elucidated as 3S-4″-O-β-d-glucopyranosylnyasol 1, 3S-4′-O-β-d-glucopyranosylnyasol 2, 3S-4″-O-β-d-glucopyranosylhinokiresinol 3, 3S-4′-O-β-d-glucopyranosylhinokiresinol 4 by extensive spectroscopic methods including 1D and 2D NMR experiments (¹H, ¹³C, DEPT, ¹H–¹H COSY, HSQC, HMBC, ROESY) along with HR-ESIMS and comparison to literature data. Their absolute configurations were elucidated through CD spectra coupled with the quantum chemical CD calculations.     

Design,synthesis and biological evaluation of 5-(2-(4-(substituted benzo[d]isoxazol-3-yl)piperazin-1-yl)acetyl)indolin-2-one and 5-(2-(4-substitutedpiperazin-1-yl)acetyl)indolin-2-one analogues as novel anti-tubercular agents

A series of thirty-six novel 5-(2-(4-(benzo[d]isoxazol-3-yl)piperazin-1-yl)acetyl)indolin-2-one and 5-(2-(4-substitutedpiperazin-1-yl)acetyl)indolin-2-one analogues were synthesized, characterized and screened for their in vitro anti-tubercular activity against Mycobacterium tuberculosis H37Rv strain. These compounds exhibited minimum inhibitory concentration between 1.56 and 50 μg/mL. Among these derivatives, compounds 10c, 10d, 10j, 10o and 10v (MIC 6.25 μg/mL) displayed moderate activity, while compounds 10e, 10l, 10q, 10w,10x, 12d, 12e and 12i (MIC 3.12 μg/mL) showed good anti-tubercular activity and compounds 10f, 10k, 10p, 10r, 12f, 12j and 12k (MIC 1.56 μg/mL) exhibited excellent anti-tubercular activity. In addition, MTT assay was accomplished on the active analogues of the series against mouse macrophage (RAW 264.7) cells to evaluate the cytotoxic effect of the newly synthesized compounds and selectivity index of the compounds was determined.     

Synthesis of the enantiomers of (3Z,9Z)-cis-6,7-epoxy-3,9-octadecadiene,one of the major components of the sex pheromone of Ectropis oblique Prout

Both enantiomers of (3Z,9Z)-cis-6,7-epoxy-3,9-octadecadiene, one of which is the major component of the sex pheromone of Ectropis oblique Prout, were synthesized in 23% overall yield for the (?)-(6S,7R)-enantiomer and 18% yield for the (+)-(6R,7S)-isomer. This protocol uses a sequential regioselective ring-opening strategy and provides a convenient and reliable access to other structurally related insect sex pheromones. Preliminary biological studies revealed that (?)-(6S,7R)-2a was roughly as active as the natural pheromone, while racemic (±)-2 was less bioactive and (+)-2b was much less bioactive.