New norlignan enantiomers from the fruit of Crataegus pinnatifida with neuroprotective activities

(±)-Crataegusnorin A (1a/1b) and B (2a/2b), two pairs of rare 8,9′-epoxy-type norlignan enantiomers featuring a γ-butyrolactone ring, were isolated from the fruit of Crataegus pinnatifida. Their structures were determined via extensive spectroscopic analyses. Gauge-independent atomic orbital (GIAO) NMR chemical shift calculations, combined with the advanced statistical method DP4+ were employed to establish the relative configurations of four compounds. Next, chiral separation was accomplished by chiral chromatographic column and the absolute configurations of the four compounds were unambiguously assigned by comparison between their experimental electronic circular dichroism curves with the quantum-mechanically calculated curves based on time-dependent density functional theory (TDDFT). All the isolates were evaluated for their neuroprotective activities against H₂O₂-induced cell injury in human neuroblastoma SH-SY5Y cells. The results showed that two pairs of enantiomers 1a/1b and 2a/2b displayed diff ;erent effect on neuroprotective activity. Among them, compound 2a displayed the most potent neuroprotective effect. Further flow cytometry analysis indicated that 2a could protect SH-SY5Y cells from oxidative damage through inhibiting cell apoptosis.     

Synthesis and configuration of the cyclin-dependent kinase inhibitor roscovitine and its enantiomer

The cyclin-dependent kinase inhibitor (R)-2-(6-benzylamino-9-isopropyl-9H-purin-2-ylamino)butan-1-ol (roscovitine, 1a), as well as its (S)-enantiomer 1b, were synthesised. The chemical structure and absolute configuration of both enantiomers was confirmed by X-ray crystallography. Furthermore, high enantiomeric excess (>98%) was demonstrated by chiral chromatography of 1a and 1b, as well as NMR analysis of the diastereomeric Mosher's ester derivatives 2a and 2b.     

Synthesis and odor properties of Phantolide analogues

Phantolide analogues 1a–1d were newly synthesized to evaluate their odor profiles. The enantiomers of 1a and 1b were also synthesized. Both (S) enantiomers of 1a and 1b had musk odor although weakly, and but neither of the (R) enantiomers 1a and 1b had musk odor. During the investigations, we encountered the undesirable racemization in Friedel-Crafts reaction of the intermediate (S)-5.     

Lipase-mediated kinetic resolution of cis-1,2-indandiol and the Ritter reaction of its mono-acetate

Lipase-mediated kinetic resolution of cis-1,2-indandiol 5 in the presence of lipase PS was examined. Enantiomerically enriched (1S,2R)-2-acetoxy-1-indanol 6a was obtained when cis-1,2-indandiol 5 was treated with one equivalent of vinyl acetate. Treatment of 5 with two equivalents of vinyl acetate furnished a mixture of (1R,2S)-2-acetoxy-1-indanol 6a and (1R,2S)-1-acetoxy-2-indanol 6b. A route to both enantiomers of 1 was also developed by using the enantiomerically enriched mono-acetate thus obtained.     

Synthesis of 4-aryl-substituted β-lactam enantiomers by enzyme-catalyzed kinetic resolution

Enantiopure 4-phenyl- and 4-(p-tolyl)-2-azetidinones 3a, 3b, 4a and 4b (with e.e.s of ≥96%) were prepared through lipase-catalyzed asymmetric butyrylation of the primary OH group of N-hydroxymethylated β-lactams (±)-5 and (±)-6 at the (R)-stereogenic centre or by lipase-catalyzed asymmetric debutyrylation of O-butyryloxymethyl-2-azetidinones (±)-7 and (±)-8 at the (R)-stereogenic centre. The ring-opening of lactams 5a, 5b, 6b and 8a with HCl/EtOH afforded the corresponding β-amino ester enantiomers 9a, 9b, 10a and 10b with e.e.s of ≥92%.     

Synthesis of optically active β-hydroxy-β-polyfluoromethyl GABAs

A general synthetic route to polyfluoromethyl containing analogues of GABA—β-hydroxy-β-tri- and difluoromethyl GABAs 9a and 9b was developed, using the corresponding β-alkoxyvinyl polyfluoromethyl ketones—enones 1a and 1b as starting materials. Both enantiomers of the potential biologically active compound 9a were obtained by chiral resolution with (R)- or (S)-phenylethylamine.     

1′,3′,3′-Trimethyl-6-nitrospiro[2H-1-benzopyran-2,2′-indoline]: its thermal enantiomerization and the equilibration with its merocyanine

The enantiomers of the title compound, the important photochromic material (RS)-1b, have been enriched semipreparatively by liquid chromatography. As a consequence, we were able to determine the barrier of the thermal interconversion (R)-1b(S)-1b via time-dependent polarimetry, amounting to ΔG^≠=85.9 kJ/mol at 22.0°C in d⁶-DMSO (Table 2). The thermal equilibration of the corresponding merocyanine 2b was monitored in d⁶-DMSO by time-dependent ¹H NMR, resulting in ΔG₁^≠=102.8 and ΔG₂^≠=92.0 kJ/mol at 22°C (Table 1). This means that, starting from (RS)-1b, the opened isomer 2b is attained by a slow reaction (ΔG₁^≠=102.8 kJ/mol, Fig. 4). Therefore, the merocyanine 2b cannot be identified with the intermediate required for the fast process of C(sp³)–O bond cleavage (ΔG^≠=85.9 kJ/mol) upon the above enantiomerization of (RS)-1b. Apparently, these two thermal isomerizations (Fig. 4) are independent of each other. The structure of the unknown intermediate of the interconversion (R)-1b(S)-1b must therefore differ from the known one of merocyanine 2b.

Table 1. Equilibration between spiro compounds (RS)-1 and merocyanines 2 at 22°C, measured by time-dependent UV absorptions[3] for (RS)-1a2a and by time-dependent ¹H NMR intensities for the other compounds

Full-size table (8K)

Asymmetric catalysis. Part 153: Metal-catalysed enantioselective α-ketol rearrangement

Promoted by catalytic amounts of Ni complexes tertiary α-hydroxyketones 1a, 3a–5a undergo rearrangement, forming chiral isomers 1b, 3b–5b. The best enantioselection was obtained with the model system 1-benzoylcyclopentanol 4a/2-hydroxy-2-phenylcyclohexanone 4b. In a ligand screening 2-[4-(S)-tert-butyloxazolin-2-yl]pyridine gave the highest enantiomeric excess of 46% (S)-4b. The analogous isomerisation reactions of α-hydroxyimines 6a, 7a forming chiral α-aminoketones 6b, 7b were established.     

Synthesis of the two enantiomers of the sex pheromone of Diabrotica Undecimpunct at a Howardi and of chiral precursors of other pheromones starting from enantiomerically pure methyl hydrogen (R)-3-methylglutarate

Readily available methyl hydrogen (R)-3-methylglutarate(2) is a useful chiral building block for the synthesis of several biologically active compounds. Enantiomerically pure (R)-2 has been employed to synthesize stereospecifically each of the two enantiomers, 1a and 1b, of 10-methyl-2-tridecanone, the sex pheromone of the southern corn rootworm, Diabrotica undecimpunctata howardi Barber. Compound (R)-2 has been also used to prepare 99% optically pure (R)-3-methyl-1-pentanol (6) and enantiomerically pure (R)-5-methyl-i-tricosyne (7). These compounds are useful building blocks suitable for the further elaboration to other chiral insect pheromones.     

Traceless chirality transfer from a norbornene β-amino acid to pyrimido[2,1-a]isoindole enantiomers

The synthesis of two enantiomeric pairs of pyrimidoisoindoles 9a, 9b and 10a, 10b is reported. During a domino ring-closure reaction, followed by cycloreversion, the chirality of diendo-(?)-(1R,2S,3R,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide [(?)-1] was successfully transfered to heterocycles (+)-9a, (+)-10a, (?)-9b, (?)-10b and (?)-10c.     

Hyperterpenoids A and B: Two pairs of unprecedented 6/6/4/6/6 polycyclic cyclobutane meroterpenoids with potent neuroprotective and anti-inflammatory activities from Hypericum beanii

Hyperterpenoid A (1) and B (2), two pairs of enantiomers, with an unprecedented 6/6/4/6/6 polycyclic skeleton, along with one known compoud hypermonone A (3) were isolated from Hypericum beanii. The racemate (±)-1 and (±)-2 were successfully separated into the two optically pure enantiomers (ee ≥ 99%) using a preparative HPLC system. Their absolute configurations were elucidated by extensive spectroscopic analyses and single-crystal X-ray diffraction method. The related plausible biogenetic pathways were presented. Compound 1-3 showed significant neuroprotective activity and potential anti-inflammatory activity. The result that (+)-2 and (-)-2 presented different anti-inflammatory properties, may lead us to new discovery of structure activity relationship between racemates, enantiomers, and diastereomers, as well as further research regarding the binding of drugs to target proteins.     

Advanced procedure for the enzymatic ring opening of unsaturated alicyclic β-lactams

Enantiopure β-amino acids 1a–4a and β-lactams 1b–4b were prepared simultaneously through the lipolase-catalysed enantioselective ring opening of unsaturated racemic β-lactams (±)-1-(±)-4. High enantioselectivities (E>200) were observed when the reactions were performed with 1 equiv of water in iPr₂O at 70 °C. The resolved (1R,2S)-amino acids (yield⩾45%) and (1S,5R)-, (1S,6R)- and (1S,8R)-lactams (yield⩾47%) could be easily separated. The ring opening of lactam enantiomers 1b–4b with 18% HCl afforded the corresponding β-amino acid hydrochlorides 1c·HCl–4c·HCl (ee >95%).     

Biocatalytic asymmetric and enantioconvergent hydrolysis of trisubstituted oxiranes

Asymmetric biohydrolysis of trialkyl oxiranes (±)-1a–3a using the epoxide hydrolase activity of whole bacterial cells proceeded in an enantioconvergent fashion and thus led to the corresponding (R)-configurated vicinal diols 1b–3b in up to 97% enantiomeric excess (e.e.) as the sole product. The mechanism of this enantioconvergence was investigated by ¹⁸O-labelling experiments and it was found that both enantiomers were hydrolysed with opposite regioselectivity.     

Optical resolution of tetra isopropyl-substituted spiro bis(isoxazoline)i-Pr-SPRIX

The optical resolution of racemic tetra isopropyl-substituted spiro bis(isoxazoline) ligand (i-Pr-SPRIX) is achieved by fractional recrystallization of palladium complexes 2a and 2b prepared from (±)-SPRIX 1 and di-μ-chlorobis{(R)-2-[1-(dimethylamino)ethyl]phenyl-C,N}dipalladium(II) (R,R)-3 followed by the decomplexation from palladium by the treatment with 1,2-bis(diphenylphosphino)ethane. The X-ray crystal structure of the complex 2a reveals that (−)-i-Pr-SPRIX has (P,R,R)-configuration.     

Stereochemical substituent effects: investigation of the cyano, amide and carboxylate group

Three pairs of diastereomeric piperidines, cis- and trans-2-methylpiperidine-3-carboxylate (6a and 6b), cis- and trans-2-methylpiperidine-3-carboxylamide (9a and 9b) and cis- and trans-2-methyl-3-cyanopiperidine (11a and 11b), were synthesised for the purpose of investigating the effect of the axial versus equatorial carboxylate, carboxamide and cyano group on piperidine base strength. The pK_a values of the six compounds were determined to be 11.0 (6a), 10.4 (6b), 9.5 (9a), 9.3 (9b), 7.8 (11a) and 8.0 (11b). This shows that the strong electron-withdrawing effect of the cyano group and the effect of the amide group are relatively independent of spacial orientation. The carboxylate, on the other hand is considerably less electron-withdrawing when axial.     

Stereoselective production of (S)-1-aralkyl- and 1-arylethanols by freshly harvested and lyophilized yeast cells

Substituted (S)-1-phenyl- 2a–h and (S)-1-benzyl-propan-2-ols 4a and b, and (S)-1-phenylethanol 6 were produced from prochiral ketones 1a–h, 3a,b and 5 by reductions with freshly harvested Zygosaccharomyces rouxii and Debaryomyces hansenii cells. The bioreductions were also performed by lyophilized cells. Comparison of the secondary alcohols from the bioreductions 2b–e,g,h and 4a and authentic (S)-alcohols (S)-2b–e,g,h and (S)-4a synthesized from enantiopure (S)-methyloxirane 7 proved the absolute configuration of the products.     

Synthesis and characterization of new cyclotriphosphazene compounds

In the present study, spiro (1a), dispiro (1b, 2, 3), per-substituted spermine-bridged (6–9) and dispiroansa spermine (10) derivatives of cyclotriphosphazene have been synthesized. The structures of the novel compounds (1b, 6–10) have been characterized by elemental analysis, FTIR, mass spectrometry, ¹H and ³¹P NMR spectroscopy. The molecular structures of 1b, 2, 8, and 10 were determined by single crystal X-ray crystallography. In order to investigate the anti-tumour properties of the newly synthesized cyclotriphosphazene derivatives, in vitro cytotoxic activity test (MTT assay) has been performed using HT-29 (human colon adenocarcinoma) and Hep2 (human epidermoid larynx carcinoma) cell lines. The result of the MTT assay showed that while compound 1a has cytotoxic effect on both Hep2 and HT-29 cell lines, compound 3 has only cytotoxic effect towards the Hep 2 cells.     

Novel thiosemicarbazone derivatives containing benzimidazole moiety: Green synthesis and anti-malarial activity

A series of (E)-2-[5-chloro-1-(1H-benzo[d]imidazol-2-yl)ethylidene] N-(substituted) hydrazine carbothioamide (7a–7t) and (E)-2-[1-(1H-benzo[d]imidazol-2-yl)ethylidene] N-(substituted) hydrazine carbothioamide (8a–8t) were prepared via the synthesis of 1-(substituted-1H-benzimidazol-2-yl) ethanol (3a–3b) which was synthesized by the condensation of substituted o-phenylenediamine (2a–2b) with dl-lactic acid (1) followed by oxidation with sodium hypochlorite in mild acidic condition to form the corresponding ketones 4a–4b. Final compounds were formed by condensation of 4a–4b with different thiosemicarbazides 6a–6t. A total of 40 compounds were synthesized and characterized by FT-IR, ¹H NMR, ¹³C NMR, Mass spectral technique and elemental analysis, in addition they were evaluated for anti-malarial properties. Among the compounds tested 7o, 7p, 7q, 7r, 7s, 8e and 8h exhibited good antimalarial activity in vitro.     

Synthesis and crystal structure analysis of 2-(4-fluorobenzyl)-6-phenylimidazo[2,1-b][1,3,4]thiadiazole and its chlorophenyl derivative

Preparations of 2-(4-fluorobenzyl)-6-phenylimidazo[2,1-b][1,3,4]thiadiazole (3a) and its chlorophenyl derivative (3b) are described. Preliminary analysis was done spectroscopically by means of ¹H NMR, ¹³C NMR spectra, mass spectra and elemental analyses. Further the structures were confirmed by X-ray crystal structure analyses. The compound (3a) has crystallized in a triclinic P-1 space group with three independent molecules in the asymmetric unit, while the compound (3b) belongs to P2₁/c space group with one molecule in the asymmetric unit. The molecule (3b) differs from molecule (3a) by the presence of chlorine substituent. Additionally, the imidazo-thiadiazole entity is as usual planar. Intramolecular C–H⋯N hydrogen bonding between the imidazole and the phenyl ring of the molecule can be observed in (3a) & (3b). The molecules of (3a) are linked into two dimensional supramolecular hexagonal hydrogen bonded network sustained by C–H⋯F interaction, while those of (3b) are linked by bifurcated C–H⋯N interactions. Further, the molecular packing of both the compounds is stabilized by π–π stacking interactions between the benzene and imidazo-thiadiazole ring systems.     

The investigation of stereogenic properties of cyclotriphosphazene derivatives with two different chiral centres

Hexachlorocyclotriphosphazene N₃P₃Cl₆ and gem-disubstituted cyclotriphosphazene derivatives N₃P₃Cl₄X₂ (X = Ph, PhS, PhNH) were reacted with N-methyl-1,3-propanediamine and 3-amino-1-propanol to give compounds (9a-12a, 9b-12b) which exist as cis and trans geometric isomers and are two different racemic isomers, respectively to describe the stereogenic properties of a series of chiral cyclotriphosphazene compounds with two different centres of chirality. The geometric isomers were separated by column chromatography on silica gel and analysed by elemental analysis, mass spectrometry, and ³¹P and ¹H NMR spectroscopies, and also the geometric forms (cis or trans) of 9b, 10a, 11a, 11b and 12a have been determined by the X-ray crystallography. The enantiomers of all racemic compounds have been analysed by the changes in ³¹P NMR spectra on addition of a Chiral Solvating Agent (CSA), (R)-(+)-2,2,2-trifluoro-1-(9′-anthryl)ethanol. On the other hand, the racemic forms of chiral cyclotriphosphazene derivatives have been confirmed by contribution of chiral HPLC methods which have been developed for this study.