Preparative enantioseparation of loxoprofen precursor by recycling countercurrent chromatography with hydroxypropyl‐β‐cyclodextrin as a chiral selector

Recycling countercurrent chromatography was successfully applied to the resolution of 2‐(4‐bromomethylphenyl)propionic acid, a key synthetic intermediate for synthesis of nonsteroidal anti‐inflammatory drug loxoprofen, using hydroxypropyl‐β‐cyclodextrin as chiral selector. The two‐phase solvent system composed of n‐hexane/n‐butyl acetate/0.1 mol/L citrate buffer solution with pH 2.4 (8:2:10, v/v/v) was selected. Influence factors for the enantioseparation were optimized, including type of substituted β‐cyclodextrin, concentration of hydroxypropyl‐β‐cyclodextrin, separation temperature, and pH of aqueous phase. Under optimized separation conditions, 50 mg of 2‐(4‐bromomethylphenyl)propionic acid was enantioseparated using preparative recycling countercurrent chromatography. Technical details for recycling elution mode were discussed. The purities of both the S and R enantiomers were over 99.0% as determined by high‐performance liquid chromatography. The enantiomeric excess of the S and R enantiomers reached 98.0%. The recovery of the enantiomers from eluted fractions was 40.8–65.6%, yielding 16.4 mg of the S enantiomer and 10.2 mg of the R enantiomer. At the same time, we attempted to enantioseparate the anti‐inflammatory drug loxoprofen by countercurrent chromatography and high‐performance liquid chromatography using a chiral mobile phase additive. However, no successful enantioseparation was achieved so far.     

Synergetic mechanism and enantioseparation of aromatic β‐amino acids by biphasic chiral high‐speed counter‐current chromatography

A biphasic chiral recognition system based on chiral ligand exchange with Cu(II)‐N‐n‐dodecyl‐L‐proline and hydroxypropyl‐β‐cyclodextrin as an additive was developed to enantioseparate aromatic β‐amino acids by high‐speed counter‐current chromatography. The biphasic chiral recognition system was established with an n‐butanol/water (1:1, v/v) solvent system by adding N‐n‐dodecyl‐L‐proline and Cu(II) ions to the organic phase and hydroxypropyl‐β‐cyclodextrin to the aqueous phase. Several separation parameters, such as temperature, pH value, and chiral selector concentration, were systematically investigated by enantioselective liquid–liquid extraction. Under the optimal separation conditions, 54.5 mg of (R,S)‐β‐phenylalanine and 74.3 mg of (R,S)‐β‐3,4‐dimethoxyphenylalanine were baseline enantioseparated. More importantly, the synergistic enantiorecognition mechanism, based on the Cu(II)‐N‐n‐dodecyl‐L‐proline and hydroxypropyl‐β‐cyclodextrin, was discussed for the first time.     

Separation of epimeric aromatic acid (−)‐menthol esters by countercurrent chromatography using hydroxypropyl‐β‐cyclodextrin as an additive

The separation of ten epimeric aromatic acid (−)‐menthol esters by countercurrent chromatography with hydroxypropyl‐β‐cyclodextrin as the mobile phase additive was investigated, and methods for the analysis of all the epimeric esters by reversed‐phase high‐performance liquid chromatography were established. A biphasic solvent system composed of n‐hexane/20–70% methanol containing 50 mmol/L of hydroxypropyl‐β‐cyclodextrin (1:1, v/v) was selected, which provided high separation factors for five of the epimeric esters, and successful separations by countercurrent chromatography were achieved. The complete separation of five pairs of epimeric ester was obtained with the purity being over 98% for each peak fractions, as determined by high‐performance liquid chromatography. The recovery of each analyte from the eluted fractions reached around 80–88%.     

Asymmetric Synthesis of the cis‐ and trans‐3,4‐Dihydro‐2,4,8‐trihydroxynaphthalen‐1(2H)‐ones

A short and efficient protocol for the asymmetric synthesis of cis‐ and trans‐3,4‐dihydro‐2,4,8‐trihydroxynaphthalen‐1(2H)‐one ( 1 and 2 , resp.) is described, with a phthalide annulation as the key step. Introduction of a OH substituent at position 2 was performed by Sharpless dihydroxylation of a silyl enol ether or by means of an N‐sulfonyloxaziridine. The absolute configuration of each isomer was determined via Mosher‐ester derivatives. By comparison with previously recorded CD spectra of our natural sample, we established that the natural trans‐ and cis‐isomers from Ceratocystis fimbriata sp. platani were the (?)‐(2S,4S)‐isomer (?)‐ 2 and the (+)‐(2S,4R)‐isomer (+)‐ 1 , respectively.     

Enantiomeric separation of oxybutynin by recycling high‐speed counter‐current chromatography with hydroxypropyl‐β‐cyclodextrin as chiral selector

Recycling high‐speed counter‐current chromatography was successfully applied to the preparative separation of oxybutynin enantiomers. The two‐phase solvent system consisted of n‐hexane, methyl tert‐butyl ether, and 0.1 mol/L phosphate buffer solution (pH = 5.0) with the volume ratio of 6:4:10. Hydroxypropyl‐β‐cyclodextrin was employed as the chiral selector. The influence of factors on the chiral separation process, including the concentration of chiral selector, the equilibrium temperature, the pH value of the aqueous phase were investigated. Under optimum separation conditions, 15 mg of oxybutynin racemate was separated with the purities of both the enantiomers over 96.5% determined by high‐performance liquid chromatography. Recovery for the target compounds reached 80–82% yielding 6.00 mg of (R)‐oxybutynin and 6.15 mg of (S)‐oxybutynin. Technical details for recycling elution mode were discussed.     

Comparative study on the liquid chromatographic enantioseparation of cyclic β‐amino acids and the related cyclic β‐aminohydroxamic acids on Cinchona alkaloid‐based zwitterionic chiral stationary phases

The enantiomeric pairs of cis and trans stereoisomers of cyclic β‐aminohydroxamic acids and their related cis and trans cyclic β‐amino acids containing two chiral centers were directly separated on four structurally related chiral stationary phases derived from quinine and quinidine modified with (R,R)‐ and (S,S)‐aminocyclohexanesulfonic acids. Applying these zwitterionic ion‐exchangers as chiral selectors, the effects of the composition of the bulk solvent, the acid and base additives, the structures of the analytes, and temperature on the enantioresolution were investigated. To study the effects of temperature and obtain thermodynamic parameters, experiments were carried out at constant mobile phase compositions in the temperature range 5–50°C. The differences in the changes in standard enthalpy Δ(ΔH°), entropy Δ(ΔS°), and free energy Δ(ΔG°) were calculated from the linear van't Hoff plots derived from the ln α versus 1/T curves in the studied temperature range. Results thus obtained indicated enthalpy‐driven separations in all cases. The sequence of elution of the enantiomers was determined and found to be reversed when ZWIX(–)™ was changed to ZWIX(+)™ or ZWIX(–A) to ZWIX(+A).     

(1R,3R,4S)‐1‐Benzyl‐3‐(tert‐butyldimethylsilyloxy)‐4‐(hydroxymethyl)pyrrolidine–borane: novel B—H...H—O hydrogen bonding

The absolute configuration of the title cis‐(1R,3R,4S)‐pyrrolidine–borane complex, C₁₈H₃₄BNO₂Si, was confirmed. Together with the related trans isomers (3S,4S) and (3R,4R), it was obtained unexpectedly from the BH₃·SMe₂ reduction of the corresponding chiral (3R,4R)‐lactam precursor. The phenyl ring is disordered over two conformations in the ratio 0.65:0.35. The crystallographic packing is dominated by the rarely found donor–acceptor hydroxy–borane O—H...H—B hydrogen bonds.     

Analogues of α‐Campholenal (= (1R)‐2,2,3‐Trimethylcyclopent‐3‐ene‐1‐acetaldehyde) as Building Blocks for (+)‐β‐Necrodol (= (1S,3S)‐2,2,3‐Trimethyl‐4‐methylenecyclopentanemethanol) and Sandalwood‐like Alcohols

To complete our panorama in structure–activity relationships (SARs) of sandalwood‐like alcohols derived from analogues of α‐campholenal (= (1R)‐2,2,3‐trimethylcyclopent‐3‐ene‐1‐acetaldehyde), we isomerized the epoxy‐isopropyl‐apopinene (?)‐ 2d to the corresponding unreported α‐campholenal analogue (+)‐ 4d (Scheme 1). Derived from the known 3‐demethyl‐α‐campholenal (+)‐ 4a , we prepared the saturated analogue (+)‐ 5a by hydrogenation, while the heterocyclic aldehyde (+)‐ 5b was obtained via a Bayer‐Villiger reaction from the known methyl ketone (+)‐ 6 . Oxidative hydroboration of the known α‐campholenal acetal (?)‐ 8b allowed, after subsequent oxidation of alcohol (+)‐ 9b to ketone (+)‐ 10 , and appropriate alkyl Grignard reaction, access to the 3,4‐disubstituted analogues (+)‐ 4f,g following dehydration and deprotection. (Scheme 2). Epoxidation of either (+)‐ 4b or its methyl ketone (+)‐ 4h , afforded stereoselectively the trans‐epoxy derivatives 11a,b , while the minor cis‐stereoisomer (+)‐ 12a was isolated by chromatography (trans/cis of the epoxy moiety relative to the C₂ or C₃ side chain). Alternatively, the corresponding trans‐epoxy alcohol or acetate 13a,b was obtained either by reduction/esterification from trans‐epoxy aldehyde (+)‐ 11a or by stereoselective epoxidation of the α‐campholenol (+)‐ 15a or of its acetate (?)‐ 15b , respectively. Their cis‐analogues were prepared starting from (+)‐ 12a . Either (+)‐ 4h or (?)‐ 11b , was submitted to a Bayer‐Villiger oxidation to afford acetate (?)‐ 16a . Since isomerizations of (?)‐ 16 lead preferentially to β‐campholene isomers, we followed a known procedure for the isomerization of (?)‐epoxyverbenone (?)‐ 2e to the norcampholenal analogue (+)‐ 19a . Reduction and subsequent protection afforded the silyl ether (?)‐ 19c , which was stereoselectively hydroborated under oxidative condition to afford the secondary alcohol (+)‐ 20c . Further oxidation and epimerization furnished the trans‐ketone (?)‐ 17a , a known intermediate of either (+)‐β‐necrodol (= (+)‐(1S,3S)‐2,2,3‐trimethyl‐4‐methylenecyclopentanemethanol; 17c ) or (+)‐(Z)‐lancifolol (= (1S,3R,4Z)‐2,2,3‐trimethyl‐4‐(4‐methylpent‐3‐enylidene)cyclopentanemethanol). Finally, hydrogenation of (+)‐ 4b gave the saturated cis‐aldehyde (+)‐ 21 , readily reduced to its corresponding alcohol (+)‐ 22a . Similarly, hydrogenation of β‐campholenol (= 2,3,3‐trimethylcyclopent‐1‐ene‐1‐ethanol) gave access via the cis‐alcohol rac‐ 23a , to the cis‐aldehyde rac‐ 24 .     

SmI2‐induced cyclizations and their applications in natural product synthesis

Since the isolation of brevetoxin‐B, a red tide toxin, many bioactive marine natural products featuring synthetically challenging trans‐fused polycyclic ether ring systems have been reported. We have developed SmI₂‐induced cyclization of β‐alkoxyacrylate with aldehyde, affording 2,6‐syn‐2,3‐trans‐tetrahydropyran (THP) or 2,7‐syn‐2,3‐trans‐oxepane with complete stereoselection, as a key reaction of efficient iterative and bi‐directional strategies for the construction of these polycyclic ethers. This reaction is also applicable to the synthesis of 3‐, 5‐, and 6‐methyl‐THPs and 3,5‐dimethyl‐THP. The synthesis of 2‐methyl‐ and 2,6‐dimethyl‐THPs was accomplished by means of a unique methyl insertion. Recently, the SmI₂‐induced cyclization was extended to similar reactions using β‐alkoxyvinyl sulfone and sulfoxide. Reaction of (E)‐ and (Z)‐β‐alkoxyvinyl sulfone‐aldehyde afforded 2,6‐syn‐2,3‐trans‐ and 2,6‐syn‐2,3‐cis‐ THPs, respectively. Reaction of (E)‐β‐alkoxyvinyl (R)‐ and (S)‐sulfoxides gave 2,6‐anti‐2,3‐cis‐ and 2,6‐syn‐2,3‐trans‐THPs, respectively. Reaction of (Z)‐β‐alkoxyvinyl (R)‐sulfoxides gave 2,6‐syn‐2,3‐cis‐THP and an olefinic product, while that of (Z)‐β‐alkoxyvinyl (S)‐sulfoxide afforded a mixture of many products. These SmI₂‐induced cyclizations have been applied to the total syntheses of various natural products, including brevetoxin‐B, mucocin, pyranicin, and pyragonicin. Synthetic studies on gambierol and maitotoxin are also introduced. © 2010 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 10: 159–172; 2010: Published online in Wiley InterScience ( www.interscience.wiley.com ) DOI 10.1002/tcr.200900027     

Photoregulated Sol‐Gel Transition of Novel Azobenzene‐Functionalized Hydroxypropyl Methylcellulose and Its α‐Cyclodextrin Complexes

Summary: Novel azobenzene‐functionalized hydroxypropyl methylcellulose (AZO‐HPMC) polymers and their α‐cyclodextrin (α‐CD) complexes have been prepared. These polymers show interesting sol‐gel transition behavior in aqueous solutions. In the absence of α‐CD, the gelation temperature increases after UV irradiation, while in the presence of α‐CD, the gelation temperature decreases after UV irradiation. The difference in the gelation temperatures between the trans and cis samples of AZO‐HPMC opens a wide operating window for reversible regulation of the sol‐gel transition behavior by photoirradiation.

The UV‐induced cis/trans isomerism of azobenzene‐functionalized hydroxypropyl methylcellulose and its α‐cyclodextrin complexes.     

The Implications of (2S,4S)‐Hydroxyproline 4‐O‐Glycosylation for Prolyl Amide Isomerization

The conformations of peptides and proteins are often influenced by glycans O‐linked to serine (Ser) or threonine (Thr). (2S,4R)‐4‐Hydroxyproline (Hyp), together with L ‐proline (Pro), are interesting targets for O‐glycosylation because they have a unique influence on peptide and protein conformation. In previous work we found that glycosylation of Hyp does not affect the N‐terminal amide trans/cis ratios (K_trans/cis) or the rates of amide isomerization in model amides. The stereoisomer of Hyp—(2S,4S)‐4‐hydroxyproline (hyp)—is rarely found in nature, and has a different influence both on the conformation of the pyrrolidine ring and on K_trans/cis. Glycans attached to hyp would be expected to be projected from the opposite face of the prolyl side chain relative to Hyp; the impact this would have on K_trans/cis was unknown. Measurements of ³J coupling constants indicate that the glycan has little impact on the C^γ‐endo conformation produced by hyp. As a result, it was found that the D ‐galactose residue extending from a C^γ‐endo pucker affects both K_trans/cis and the rate of isomerization, which is not found to occur when it is projected from a C^γ‐exo pucker; this reflects the different environments delineated by the proline side chain. The enthalpic contributions to the stabilization of the trans amide isomer may be due to disruption of intramolecular interactions present in hyp; the change in enthalpy is balanced by a decrease in entropy incurred upon glycosylation. Because the different stereoisomers—Hyp and hyp—project the O‐linked carbohydrates in opposite spatial orientations, these glycosylated amino acids may be useful for understanding of how the projection of a glycan from the peptide or protein backbone exerts its influence.     

Enantioseparation of chiral aromatic acids by multiple dual mode counter‐current chromatography using hydroxypropyl‐β‐cyclodextrin as chiral selector

This work concentrates on extending the utilization of multiple dual mode (MDM) counter‐current chromatography in chiral separations. Two aromatic acids, 2‐(6‐methoxy‐2‐naphthyl)propionic acid (NAP) and 2‐phenylpropionic acid (2‐PPA), were enantioseparated by MDM counter‐current chromatography using hydroxypropyl‐β‐cyclodextrin (HP‐β‐CD) as chiral selector. The two‐phase solvent systems consisting of n‐hexane/ethyl acetate 0.1 mol/L phosphate buffer pH 2.67 containing 0.1 mol/L HP‐β‐CD (7.5:2.5:10 for NAP and 7:3:10 for 2‐PPA, v/v/v) were used. Conventional MDM and modified MDM were compared according to peak resolution under current separation mechanism. The influence of elution time after the first‐phase inversion and number of cycles for MDM were investigated. Peak resolution of NAP and 2‐PPA increased from 0.62 to 1.05 and 0.72 to 0.84, respectively, using optimized MDM conditions. Being an alternative elution method for counter‐current chromatography, MDM elution greatly improved peak resolution in chiral separations.     

Preparation of chiral oxazolinyl‐functionalized β‐cyclodextrin‐bonded stationary phases and their enantioseparation performance in high‐performance liquid chromatography

A simple procedure for the synthesis of three new oxazolinyl‐substituted β‐cyclodextrins (6‐deoxy‐6‐R‐(–)‐4‐phenyl‐4,5‐dihydrooxazolinyl‐β‐cyclodextrin, 6‐deoxy‐6‐S‐(–)‐4‐phenyl‐4,5‐dihydrooxazolinyl‐β‐cyclodextrin, and 6‐deoxy‐6‐S‐(–)‐(4‐pyridin‐1‐ium‐4‐methyl‐benzenesulphonate)‐4,5‐dihy‐drooxazolinyl‐β‐cyclodextrin) and their covalent bonding to silica are reported. The ability of these chiral stationary phase columns for separating compounds is also presented and discussed. Twenty‐eight compounds were examined in the polar‐organic mobile phase mode, and 11 β‐nitroethanols were tested in the reversed‐phase mode. Excellent enantioseparations were achieved for most of the analytes, even for several challenging compounds. The rigid and flexible structures of mono‐substituted chiral groups and the fragments around the rim of the β‐cyclodextrin cavity played an important role in the separation process. Factors such as π–π stacking, dipole–dipole interactions, ion‐pairing, and steric hindrance effects were found to affect the chromatographic performance. Moreover, the buffer composition, and percentages of organic modifiers in the mobile phase, were investigated and compared. The mechanisms involved in the separation were postulated based on the chromatographic data.     

A Conformational Study of Cyclohexane‐1,3,5‐tricarbonitrile Derivatives

Cyclohexane‐1,3,5‐tricarbonitrile reached equilibrium having 1,3‐cis‐1,5‐cis and 1,3‐cis‐1,5‐trans isomers in a ratio of 3:7. The cis, cis‐isomer preferred the conformation with three equatorial cyano groups, where as the cis, trans‐isomer displayed two cyano groups on equatorial positions and another cyano group on axial position. Condensation of cis, cis‐cyclohexane‐1,3,5‐tricarbonitrile with L‐(S)‐valinol by the catalysis of ZnCl₂ in refluxing 1,2‐dichlorobenzene afforded two isomeric cyclohexane‐1,3,5‐trioxazolines in favor of the 1,3‐cis‐1,5‐trans isomer. Metalation of cis, cis‐cyclohexane‐1,3,5‐tricarbonitrile, followed by alkylations with dimethyl sulfate, benzyl bromide or allyl bromide, gave the cor responding trialkylation products with predominance of 1,3‐cis‐1,5‐trans isomers. The cis, trans‐isomer showed two cyano groups on axial positions and another cyano group on equatorial position, where as the cis, cis‐isomer exhibited three axial cyano groups. Treatment of trimethyl cis, cis‐cyclohexane‐1,3,5‐tricarboxylate with lithium diisopropylamide and dimethyl sulfate afforded mainly the trimethyl ester of Kemp's triacid, which showed three axial carboxylate groups. Two competitive factors, i.e. the steric effect of in coming electrophiles and the dipole‐dipole inter actions of the cyano or carboxylate groups, might inter play to give different stereoselectivities in these reaction systems.     

1‐Aminoindan‐2‐ol,a Suitable Ligand for the Synthesis of Chiral,Intramolecularly Stabilized Compounds of Aluminum,Gallium, and Indium

The reactions of enantiomerically pure (1R, 2S)‐(+)‐cis‐1‐aminoindan‐2‐ol, (1S, 2R)‐(‐)‐cis‐1‐aminoindan‐2‐ol, and racemic trans‐1‐aminoindan‐2‐ol with trimethylaluminum, ‐gallium, and ‐indium produce the intramolecularly stabilized, enantiomerically pure dimethylmetal‐1‐amino‐2‐indanolates (1R, 2S)‐(+)‐cis‐Me₂AlO‐2‐C*HC₇H₆‐1‐C*HNH₂ ( 1 ), (1S, 2R)‐(‐)‐cis‐Me₂AlO‐2C*HC₇H₆‐1‐C*HNH₂ ( 2 ), (1R, 2S)‐(+)‐cis‐Me₂GaO‐2‐C*HC₇H₆‐1‐C*HNH₂ ( 3 ), (1R, 2S)‐(+)‐cis‐Me₂InO‐2‐C*HC₇H₆‐1‐C*HNH₂ ( 4 ), (1S, 2R)‐(‐)‐cis‐Me₂InO‐2‐C*HC₇H₆‐1‐C*HNH₂ ( 5 ), and racemic (+/‐)‐trans‐Me₂InO‐2‐C*HC₇H₆‐1‐C*HNH₂ ( 6 ). The compounds were characterized by ¹H NMR, ¹³C NMR, ²⁷Al NMR and mass spectra as well as 1 and 3 to 6 by determination of their crystal and molecular structures. The dynamic dissociation/association behavior of the coordinative metal‐nitrogen bond was studied by low temperature ¹H NMR spectroscopy.     

The diastereoisomers methyl 5‐(S)‐[2‐(R)/(S)‐methoxycarbonyl)‐2,3,4,5‐tetrahydropyrrol‐1‐ylcarbonyl]‐1‐(4‐methylphenyl)‐4,5‐dihydropyrazole‐3‐carboxylate

The title diastereoisomers, methyl 5‐(S)‐[2‐(S)‐methoxy­carbonyl)‐2,3,4,5‐tetra­hydro­pyrrol‐1‐yl­carbonyl]‐1‐(4‐methyl­phenyl)‐4,5‐di­hydro­pyrazole‐3‐carboxyl­ate and methyl 5‐(S)‐[2‐(R)‐methoxycarbonyl)‐2,3,4,5‐tetrahydropyrrol‐1‐ylcarbonyl]‐1‐(4‐methyl­phenyl)‐4,5‐di­hydro­pyrazole‐3‐carboxylate, both C₁₉H₂₃N₃O₅, have been studied in two crystalline forms. The first form, methyl 5‐(S)‐[2‐(S)‐methoxy­carbonyl)‐2,3,4,5‐tetrahydropyrrol‐1‐ylcarbonyl]‐1‐(4‐methylphenyl)‐4,5‐di­hydro­pyrazole‐3‐carboxyl­ate–methyl 5‐(S)‐[2‐(R)‐methoxy­carbonyl)‐2,3,4,5‐tetra­hydro­pyrrol‐1‐yl­carbonyl]‐1‐(4‐methylphenyl)‐4,5‐dihydropyrazole‐3‐carboxylate (1/1), 2(S),5(S)‐C₁₉H₂₃N₃O₅·2(R),5(S)‐C₁₉H₂₃N₃O₅, contains both S,S and S,R isomers, while the second, methyl 5‐(S)‐[2‐(S)‐methoxycarbonyl)‐2,3,4,5‐tetrahydro­pyrrol‐1‐ylcarbonyl]‐1‐(4‐methyl­phenyl)‐4,5‐di­hydro­pyrazole‐3‐carboxyl­ate, 2(S),5(S)‐C₁₉H₂₃N₃O₅, is the pure S,S isomer. The S,S isomers in the two structures show very similar geometries, the maximum difference being about 15° on one torsion angle. The differences between the S,S and S,R isomers, apart from those due to the inversion of one chiral centre, are more remarkable, and are partially due to a possible rotational disorder of the 2‐­(methoxycarbonyl)tetrahydropyrrole group.     

Highly Diastereoselective,Biogenetically Patterned Synthesis of (+)‐(1S,6R)‐Volvatellin (=(+)‐(4R,5S)‐5‐Hydroxy‐4‐(5‐methyl‐1‐methylenehex‐4‐en‐2‐ynyl)cyclohex‐1‐ene‐1‐carbaldehyde)

The synthesis of volvatellin ( 4a ), previously isolated from a herbivorous marine mollusk, was achieved with high diastereoselectivity from putative dietary oxytoxin‐1 ( 2 ). A biogenetically patterned carbonyl‐ene route was chosen, proceeding from 2 predominantly via the trans cyclization product 3 without the use of enzymes. This challenges the involvement of enzymes in the formation of 4a in nature. The optical purity and absolute configuration (1S,4S,6R), assigned to 3 from high‐field ¹H‐NMR examination of its Mosher (MTPA) esters 6 , was retained on its chemical conversion to (+)‐(1S,6R)‐configured 4a and is consistent with the (4S) configuration previously established for caulerpenyne ( 1 ).     

Estimating the lipophilicity of a number of 2‐amino‐1‐cyclohexanol derivatives exhibiting anticonvulsant activity

The lipophilicity of a number of N‐acyl derivatives of trans‐ or cis‐: racemic, (1R,2R)‐ or (1S,2S)‐aminocyclohexanol (1–13) exhibiting anticonvulsant activity was investigated. Their lipophilicity (R_{m 0}) was determined using reversed‐phase thin‐layer chromatography (RP‐TLC) with mixtures of methanol and water as mobile phases. The partition coefficients of compounds 1–13 (log P) were also calculated using two computer programs (Pallas and Chem DU) and compared with R_{m 0}. Copyright © 2009 John Wiley & Sons, Ltd.     

Water‐Promoted Kinetic Separation of trans‐ and cis‐Limonene Oxides

The efficient hydrolytic kinetic separation of trans/cis‐(R)‐(+)‐limonene oxides was realized in a 1:1 mixed solvent of water and 1,4‐dioxane without additional catalyst. Optically pure trans‐(R)‐(+)‐limonene oxide was recovered in high yield (77%).     

Molecular Switching: A Fully Reversible,Optically Active Photochemical Switch Based on a Tetraethynylethene‐1,1′‐Binaphthalene Hybrid System

The synthesis, characterization, and physical properties of a novel, fully reversible, light‐driven molecular switch, (R,R)‐ 1 /(R,R)‐ 2 , based on a tetraethynylethene‐1,1′‐binaphthalene hybrid system are presented. trans‐Configured (R,R)‐ 1 was synthesized in 57% yield by Stille cross‐coupling between stannylated tetraethynylethene 3 and 3‐iodo‐1,1′‐binaphthalene derivative (R)‐ 4 (cf. Scheme 2). The cis‐isomer (R,R)‐ 2 was prepared from (R,R)‐ 1 by photoisomerization. X‐Ray crystal‐structure analyses were obtained for both cis‐ and trans‐forms of the photoswitch (Figs. 1 and 2). In the crystalline state, molecules of the cis‐isomer (R,R)‐ 2 exhibit intramolecular edge‐to‐face (C−H⋅⋅⋅π) interactions between naphthalene rings of the two 1,1‐binaphthalene moieties (Fig. 3). The switching properties were investigated by electronic absorption spectroscopy (Table and Fig. 4): irradiation at λ=398 nm converts trans‐isomer (R,R)‐ 1 into cis‐isomer (R,R)‐ 2 , whereas switching occurs in the opposite direction upon irradiation at λ=323 nm. No thermal interconversion between the two isomers was observed in CH₂Cl₂ at room temperature over a period of 2 – 3 months, and the system possesses good resistance against photofatigue (Fig. 5). Investigations of the circular dichroism of (R,R)‐ 1 and (R,R)‐ 2 in CH₂Cl₂ solution showed that the chiral binaphthalene moieties induce a weak Cotton effect in the achiral tetraethynylethene core (Fig. 6). System (R,R)‐ 1 /(R,R)‐ 2 represents one of the rare switches allowing two‐way photochemical interconversions, not perturbed by thermal‐isomerization pathways.