Chiral mono and diamide derivatives of calix[4]arene for enantiomeric recognition of chiral amines

Novel chiral mono and diamide derivatives of calix[4]arene have been prepared from the aminolysis reaction of 5,11,17,23-tetra-tert-butyl-25,27-diethoxycarbonyl-methoxy-26,28-dihydroxycalix[4]arene 1 and 25,27-diethoxycarbonyl-methoxy-26,28-dihydroxycalix[4]arene 2 with chiral (S)-(-)-1-phenylethylamine (PEA) and (1S,2S)-(+)-2-amino-1-(4-nitrophenyl)-1,3-propanediol, respectively. Spectrophotometric titrations have been performed in CHCl(3) at 20-30 degrees C in order to obtain the binding constants (K) and the thermodynamic quantities (DeltaH and DeltaS) for the stoichiometric 1:1 inclusion complexation of various chiral amines with these new host compounds. Preliminary experiments were undertaken to confirm the complexation properties of receptors 9 and 13 with PEA by (1)H NMR in CDCl(3) at room temperature. The molecular recognition abilities and enantioselectivities for guests (R and S)-alpha-PEA and (R and S)-cyclohexylethylamine (CHEA) are discussed from a thermodynamic point of view.     

A colorimetric chiral sensor based on chiral crown ether for the recognition of the two enantiomers of primary amino alcohols and amines

A new colorimetric chiral sensor material consisting of three different functional sites such as chromophore (2,4-dinitrophenylazophenol dye), binding site (crown ether), and chiral barrier (3,3'-diphenyl-1,1'-binaphthyl group) was prepared and applied to the recognition of the two enantiomers of primary amino alcohols and amines. Among five primary amino alcohols and two primary amines tested, the two enantiomers of phenylalaninol show the highest difference in the absorption maximum wavelength (Δλ(max)=43.5 nm) and in the association constants (K(S)/K(R)=2.51) upon complexation with the colorimetric chiral sensor material and, consequently, the two enantiomers of phenylalaninol were clearly distinguished from each other by the color difference.     

Improvement of water solubility of non-competitive AMPA receptor antagonists by complexation with beta-cyclodextrin

The (R,S)-2-acetyl-1-(4'-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ((R,S)-1) was previously identified as a potent non-competitive AMPA receptor antagonist able to prevent epileptic seizures and reduce AMPA-induced current in electrophysiological experiments. Through the enantiomeric resolution of racemate by chiral HPLC we already demonstrated that the (R)-1 enantiomer was the eutomer. Considering the poor water solubility, these compounds have been complexed with beta-cyclodextrin (beta-CyD). The effect of beta-cyclodextrin on the spectral features of molecules was quantitatively investigated, in fully aqueous medium by phase-solubility study and the obtained diagrams suggested that it forms complexes with a molar ratio 1:1. The binding constant (K((R)-1)=15889M(-1), K((R,S)(-1))=1079 M(-1)) and the complexation efficiency (CE) were calculated. Then the solid complexes in 1:1 molar ratio were prepared by the co-precipitation method and the FTIR-ATR measurements were carried out in order to confirm the host-guest interactions that drive the complexation process, by monitoring the significant differences of the spectra of the complexes with respect to those of the corresponding physical mixtures in the same molar ratio. The experimental data have been compared with molecular modelling studies and we confirmed our hypothesis.     

Chiral discrimination in nonracemic mixtures of methanephosphonic acid,N,N′-bis(1-phenylethyl)diamides

Enantiomeric (S,S)- and (R,R)-bis(1-phenylethyl)diamidomethylphosphonates, the phosphorus atom being prochiral, have been synthesized, starting from the methanephosphonic acid dichloride and corresponding chiral amines. The splitting observed in the ³¹P-NMR spectra of their nonracemic mixtures may be accounted for the self-discrimination of chiral species. This effect can be very useful for enantiomeric analysis of amines based on coupling reactions with methanephosphonic acid dichloride. © 1994 Wiley-Liss, Inc.     

Circular dichroism of host-guest complexes of achiral pyridino- and phenazino-18-crown-6 ligands with the enantiomers of chiral aralkyl ammonium salts

Circular dichroism (CD) spectroscopy was used for distinguishing different types of chiral interactions in host-guest complexes of achiral pyridino- and phenazino-18-crown-6 ligands with chiral aralkyl ammonium salts. The general feature of the CD spectra of many homochiral (e.g., (R,R)-host and (R)-guest) and heterochiral (e.g., (R,R)-host and (S)-guest) alpha-(1-naphthyl)ethylamine hydrogenperchlorate salt (NEA) complexes with chiral pyridino- and phenazino-18-crown-6 hosts is exciton interaction. The most interesting example is the coupling of the transitions of the chiral guest NEA with the energetically close transitions of the achiral phenazino-18-crown-6 host 6. The CD spectrum of the complex is predominated by exciton coupling between the (1)B(b) transition of the chiral guest and the (1)B(b) transition of the achiral host. The redshifted intense spectra of the complexes of (R)- or (S)-1-phenylethylamine hydrogenperchlorate salt (PEA) with the achiral diester-pyridino-18-crown-6 host 4 are indicative of merging the pi electron systems into one joint charge transfer chromophore. The appearance of weak bands with alternating sign in the spectrum of PEA complexes of the achiral "parent" pyridino-18-crown-6 host (1) indicates the presence of two or more conformers. The CD spectra of the complexes of achiral phenazino-18-crown-6 host 6 with PEA are also determined by pi-pi interaction. In addition to charge transfer bands, CD bands are also induced in the long-wavelength spectral region of the achiral host. The weak pi-pi interaction between the achiral phenazino-18-crown-6 host and methyl phenylglycinate hydrogenperchlorate (PGMA) or methyl phenylalaninate hydrogenperchlorate (PAMA) does not result in a definite spectral effect in the (1)L(a) region of the spectrum of the chiral guest, but its existence is proven by the weak CD bands induced in the long-wavelength spectral region of the achiral host.     

The conformation of xanthene dyes in the myosin sulfhydryl one binding site Part I. Methods and model systems

Derivatives of the fluorescent probes fluorescein and rhodamine specifically and covalently modify the highly reactive thiol (SH1) of myosin subfragment 1 (S1). Both probes develop circular dichroism (CD) upon modification of SH1 at the visible absorption band of the chromophore. A model system of chiral complexing agents (aromatic chiral amines) interacting with fluorescein in solvent develops a CD signal that mimics that produced by S1. The model system suggests that a specific interaction of the probe with an aromatic chiral residue in the SH1 binding pocket induces the CD signal. Several other spectroscopic signals, including absorption and fluorescence intensity and anisotropy, characterize the fluorescein or rhodamine binding to SH1. A coupled dipole method is adapted to interpret these spectroscopic signals in terms of the probe-S1 complex conformation. The computation of the orientation of the principal hydrodynamic frame (PHF) of S1 from its crystallographic -carbon backbone structure permits the known orientation of the probe in the PHF of S1 to further constrain the conformation of the probe-S1 complex. The coupled dipole interpretation of spectroscopic data combined with constraints relating the probe dipole orientation to the PHF of S1 determines the conformation of the probe-S1 complex. The methods developed here are applied to the spectroscopic signals from fluorescein or rhodamine in the SH1 binding site of S1 to obtain an atomic resolution model of the probe-S1 conformation [Ajtai and Burghardt, Biochemistry, 34 (1995) 15943–15952].     

Monitoring proton dissociation and solution conformation of chiral ytterbium complexes with near-IR CD

The ytterbium complex [Yb((S)-THP)](3+) ((S)-THP = (1S,4S,7S,10S-tetrakis(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane) is investigated in solution through NMR, near-IR absorption, and CD spectroscopy. Quantitative analysis of the paramagnetic pseudocontact NMR shift shows Lambda helicity of the ligand cage around the metal. The NIR CD spectrum recorded at acidic pH is found to be very similar to that of [Yb((R)-DOTMA)](-) ((R)-DOTMA = (1R,4R,7R,10R)-alpha,alpha',alpha',alpha'-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), which in solution assumes a twisted square antiprism (TSA) conformation. The similarity of the NIR CD spectra is discussed, and it is the first proof of the Lambda(lambda,lambda,lambda,lambda) conformation of [Yb((S)-THP)](3+). NIR CD spectra recorded in the pH range of 2-9 allow one to easily follow proton dissociation and to calculate the pK of this equilibrium in water (pK(A) = 6.4 +/- 0.1). This value agrees well with that determined for [Lu((S)-THP)](3+) using potentiometric methods. This demonstrates once again that NIR CD spectroscopy is a powerful technique for investigating the solution structure and dynamics of these complexes.     

Stereoselective formation and hydration of 12-methylbenz[a]anthracene 5,6-epoxide enantiomers by rat liver microsomal enzymes.

The K-region trans-5,6-dihydrodiols formed in the metabolism of 12-methylbenz[a]anthracene (12-MBA) by liver microsomal preparations from untreated, phenobarbital-treated and 3-methylcholanthrene-treated male Sprague-Dawley rats were found by chiral stationary-phase h.p.l.c. (c.s.p.-h.p.l.c.) analyses to contain (5S,6S)/(5R,6R) enantiomer ratios of 93:7, 88:12 and 97:3 respectively. The absolute stereochemistry of a 12-MBA trans-5,6-dihydrodiol enantiomer was elucidated by the exciton-chirality c.d. method. The 5,6-epoxides formed in the metabolism of 12-MBA by liver microsomal preparations from untreated, phenobarbital-treated and 3-methylcholanthrene-treated male Sprague-Dawley rats in the presence of the epoxide hydrolase inhibitor 3,3,3-trichloropropylene 1,2-oxide were isolated from a mixture of metabolites by normal-phase h.p.l.c., and their (5S,6R)/(5R,6S) enantiomer ratios were found by c.s.p.-h.p.l.c. analyses to be 73:27, 78:22 and 99:1 respectively. The absolute configurations of 12-MBA 5,6-epoxide enantiomers, resolved by c.s.p.-h.p.l.c., were determined via high-resolution (500 MHz) proton-n.m.r. and c.d. spectral analyses of the two isomeric methoxylation products derived from each of the 12-MBA 5,6-epoxide enantiomers. Enantiomeric pairs of the two methoxylation products were resolved by c.s.p.-h.p.l.c. The results indicate that enantiomeric 5S,6R-epoxide and 5S,6S-dihydrodiol were the major enantiomers preferentially formed in the metabolism at the K-region 5,6-double bond of 12-MBA by all three rat liver microsomal preparations. Optically pure 12-MBA 5S,6R-epoxide was hydrated predominantly at the C(6) position (R centre) to form 12-MBA trans-5,6-dihydrodiol with a (5S,6S)/(5R,6R) enantiomer ratio of 97:3. However, optically pure 12-MBA 5R,6S-epoxide was hydrated nearly equally at both C(5) and C(6) positions to form 12-MBA trans-5,6-dihydrodiol with a (5S,6S)/(5R,6R) enantiomer ratio of 57:43.     

Novel approach to determining the absolute configurations at the C3-positions of various types of sterols based on an induced circular dichroism

Circular dichroism (CD) spectra of the 2,2'-binaphthyl ester derived from Δ(5)-sterols showed not bisignate CD but diagnostic CD bands at around 210 and 240nm. These bands might be attributable to an interaction between an olefinic chromophore and a binaphthyl one. Various types of unsaturated sterols were thus derivatized followed by complete hydrogenation, to give saturated sterols. As a result, CD spectra of the binaphthyl derivatives of the saturated sterols showed bisignate curves centered at 240nm (3S(β): positive chirality; 3R(α): negative one). This suggested a straightforward and practical method for discriminating the absolute stereogenic center at the C-3 positions of sterols based on an induced CD. This finding should contribute significantly to the analysis of metabolites of various types of sterols.     

Ultraviolet, circular dichroism, fluorescence, and circularly polarized luminescence spectra of regioregular poly-[3-((s)-2-methylbutyl)-thiophene] in solution

Ultraviolet (UV), Circular Dichroism (CD), Fluorescence, and Circularly Polarized Luminescence (CPL) spectra were recorded for mixed chloroform/methanol and chloroform/butanol solutions of regioregular poly[3-((S)-2-methylbutyl)-thiophene]. An evaluation of the chiral and nonchiral components in solution is proposed on the basis of the UV and CD spectra. The fluorescence and CPL spectra are observed in a wavelength range where some UV and CD activity still appears. For this reason, the observed CPL features are strongly influenced by CD. A general procedure for evaluating true CPL spectra is proposed, when absorption and emission coexist. Chirality 24:725-730, 2012. ? 2012 Wiley Periodicals, Inc.     

Exciton coupling effects and conformational change of perhexyloligosilanes with optically active methyl(1-naphthyl)phenylsilyl terminals

Perhexyloligosilanes (R,R)-(+)-MeNpPhSi*(Hex(2)Si)(n)Si*PhNpMe (n = 2; (R,R)-(+)-4a, n = 4; (R,R)-(+)-6a, n = 6; (R,R)-(+)-8a) with chiral methyl(1-naphthyl)phenylsilyl terminals were synthesized and characterized. The absorption wavelengths lambda(max) by (1)L(a,Ph) transition of phenyl chromophore conjugated with oligosilane units in (R,R)-(+)-4a - (R,R)-(+)-8a show bathochromic shift of about 3-4 nm compared with those of the alpha,omega-phenyl substituted perhexyloligosilanes Ph(Hex(2)Si)(m)Ph (m = 4; 4b, m = 6; 6b, m = 8; 8b) having the same silicon chain length. Longer chain length induces the separated lambda(max) of (1)L(a,Ph) from (1)B(b,Np) of naphthyl chromophore with positive exciton chiralities. In (R,R)-(+)-8a, although the extremum wavelengths lambda(ext) of exciton coupling between (1)B(b,Np) and (1)L(a,Ph) are separated by about 80 nm, the compound retains the positive exciton chirality, which provides definite information on the absolute configuration of terminal chiral silicon atoms. Bulky terminal substituents and lowering the temperature affect the conformation of the main chain, inducing extended silicon backbone structure.     

Chiral cruciferous phytoalexins: preparation, absolute configuration, and biological activity

Synthesized by an efficient one-pot spirocyclization method, two chiral cruciferous phytoalexins, 1-methoxyspirobrassinin (2) and 1-methoxyspirobrassinol methyl ether (4a), were prepared through optical resolution using the chiral HPLC method of corresponding racemates. The absolute configuration of natural (+)-2 was elucidated as R by using the direct comparison of ECD and VCD spectra with those of known (S)-(-)-spirobrassinin (1). Another chiral phytoalexin, (-)-4a, had its absolute configuration 2R,3R elucidated through the comparison of observed and calculated VCD. Interestingly, the absolute configurations of natural (S)-(-)-spirobrassinin (1) and (R)-(+)-1-methoxyspirobrassinin (2) were opposite of each other, even though their structures are almost similar, with the exception of an N-methoxy group. A significant difference in the antiproliferative activity between (2R,3R)-(-) and (2S,3S)-(+)-4a was observed.     

Versatile precursor to ruthenium-bis(phosphine) hydrogenation catalysts

The known complex trans-RuCl2(NBD)Py2 (1, NBD is norbornadiene, Py is pyridine) reacts with either (R)-BINAP ((R)-2, 2'-bis(diphenylphosphino)-1,1'-binaphthyl), (S;S)-Chiraphos ((2S;3S-(-)-2,3-bis(diphenylphosphino)butane), (S;S)-Skewphos ((2S;4S)-(-)-2,4-bis(diphenylphosphino)pentane), (R)-(S)-Josiphos ((R)-(-)-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyl-dicyclohexylpho sphine), (R;R)-Norphos ((2R;3R)-(-)-2, 3-bis(diphenylphosphino)bicyclo[2.2.1]hept-5-ene), or (R;R)-Me-DUPHOS ((-)-1,2-bis((2R;5R)-2, 5-dimethylphospholano)benzene) to generate in high yields the crystalline complexes trans-RuCl2(P-P*)Py2 (P-P* is the corresponding chiral bis(phosphine)). The complexes trans-RuCl2(P-P*)Py2 are active enantioselective hydrogenation catalysts for ketoesters and noncarboxylic olefins in the presence of small amounts of HBF4 (aq.). They are active for hydrogenation of carboxylic substrates in the presence of Et3N. Reaction of trans-RuCl2(P-P*)Py2 with (rac)-1,2-diphenylethylene-diamine (N-N*, either enantiomer) forms in good yields the corresponding compounds trans-RuCl2(P-P*)(N-N*). Representative hydrogenations with these catalysts are presented.     

Chiral recognition of metalaxyl enantiomers by human serum albumin: evidence from molecular modeling and photophysical approach

Metalaxyl is an acylamine fungicide, belonging to the most widely known member of the amide group. This task is aimed to scrutinize binding region and spatial structural change of principal vector human serum albumin (HSA) complex with (R)-/(S)-metalaxyl by exploiting molecular modeling, steady-state and time-resolved fluorescence, and circular dichroism (CD) approaches. According to molecular modeling, (R)-metalaxyl is situated within subdomains IIA and IIIA and the affinity of site I with (R)-metalaxyl is greater than site II, whereas (S)-metalaxyl is only located at subdomain IIA and the affinity of (S)-metalaxyl with site I is superior compared with that with (R)-metalaxyl. This coincides with the competitive ligand binding, guanidine hydrochloride-induced unfolding of protein, and hydrophobic 8-anilino-1-naphthalenesulfonic acid experiments; the acting forces between (R)-/(S)-metalaxyl and HSA are hydrophobic, π-π interactions, and hydrogen bonds, as derived from molecular modeling. Fluorescence emission manifested that the complex of (R)-/(S)-metalaxyl to HSA is the formation of adduct with an affinity of 10(4) M(-1), which corroborates the time-resolved fluorescence that the static type was operated. Furthermore, the changes of far-UV CD spectra evidence the polypeptide chain of HSA partially unfolded after conjugation with (R)-/(S)-metalaxyl. Through this work, we envisage that it can offer central clues on the biodistribution, absorption, and bioaccumulation of (R)-/(S)-metalaxyl.     

Combinations of chiral and prochiral singlet radical-pairs in reaction cavities of polyethylene films. Control and analysis of radical tumbling and translation.

The regio- and stereo-chemistries of combination products from chiral 1-naphthoxy/(R)-2-phenylpropanoyl and prochiral 1-naphthoxy/1-phenylethyl singlet radical-pairs (radical-pairs A and B, respectively) have been studied at different temperatures in polyethylene (PE) films with different crystallinities. The radical-pairs have been generated as intermediates along the photo-Fries reaction course of 1-naphthyl (R)-2-phenylpropanoate ((R)-1) and the photo-Claisen reaction course of 1-naphthyl (R)-1-phenylethyl ether ((R)-2). Radical-pair was produced directly upon lysis of the first excited singlet state of (R)-2 and indirectly after irradiation of (R)-1 and subsequent decarbonylation of the 2-phenylpropanoyl radical of radical-pair A. Comparison of the fates of the directly and indirectly formed radical-pairs provides detailed information about the nature of the reaction cavities within the polyethylene hosts and how the combinations of the radical-pairs are influenced by their initial locations within a cavity. The results, especially when taken with those from irradiations in n-alkanes, indicate that the cavities are "templated" by the (R)-1 and (R)-2 guest molecules and that the templated shapes are retained in some form for periods that are at least as long as the time required for decarbonylation of a 2-phenylpropanoyl radical. In addition, the enantiomeric excesses of the decarbonylated photoproducts from (R)-1(2, 2-(1-phenylethyl)-1-naphthol (2BN), and 4-(1-phenylethyl)-1-naphthol (4BN)) or 2BN and 4 BN from (R)-2 indicate different influences of temperature on translational and tumbling motions of the radicals of radical-pairs B within their polyethylene cages.     

Stereoselective metabolism of 7-methylbenz[a]anthracene: absolute configuration of five dihydrodiol metabolites and the effect of dihydrodiol conformation on circular dichroism spectra

7-Methylbenz[a]anthracene (7-MBA) was metabolized stereoselectively by rat liver microsomes to form five optically active dihydrodiols as the predominant metabolites. The dihydrodiols were purified by a combination of reversed-phase and normal-phase high performance liquid chromatography (HPLC). By comparison of their circular dichroism (CD) spectra with the corresponding benz[a]anthracene (BA) dihydrodiols of known absolute stereochemistry, the major dihydrodiol enantiomers of 7-MBA have been determined to have 1R,2R-, 3R,4R- and 10R , 11R - absolute configurations, respectively. Due to their quasi- diaxial conformations, the absolute configuration of trans-5,6- and trans-8,9-dihydrodiols, the two most abundant metabolites of 7-MBA, could not be determined by simple comparisons of their circular dichroism spectra with those of the quasidi -equatorial BA 5R, 6R - and 8R , 9R -dihydrodiols. The major enantiomers of the quasi- diaxial trans-5,6- and trans-8,9-dihydrodiol metabolites of 7-MBA were determined by comparison to the CD spectrum of 7-bromo-BA 5R, 6R -dihydrodiol and by the exciton chirality method to have R,R absolute stereochemistry. This study also revealed that the circular dichroism Cotton effects of an enantiomeric dihydrodiol of polycyclic aromatic hydrocarbons can be drastically altered if the conformation (quasi- diaxial vs. quasi di-equatorial ) of the dihydrodiol is changed.     

Application of L-proline derivatives as chiral shift reagents for enantiomeric recognition of carboxylic acids

Four proline-derived chiral receptors 5-8 were readily synthesized starting from L-proline. The enantiomeric recognition ability of chiral receptors was examined with a series of carboxylic acids by (1) H NMR spectroscopy. The molar ratio and the association constants of the chiral compounds with each of the enantiomers of guest molecules were determined by using Job plots and a nonlinear least-squares fitting method, respectively. The Job plots indicate that the hosts form 1:1 instantaneous complexes with all guests. The receptors exhibited different chiral recognition abilities toward the enantiomers of racemic guests. Among the chiral receptors used in this study, prolinamide 6 was found to be the best chiral shift reagent and is effective for the determination of the enantiomeric excess of chiral carboxylic acids.     

Conformational study by CD of chirally tethered naphthalene moieties: toward an understanding of the asymmetric intramolecular coupling reaction?

The carbonate (R,R)-1 and the diester (R,R)-2, precursors of optically active 1,1'-binaphthyl derivatives through asymmetric intramolecular coupling, were prepared and fully characterized. The absorption and CD spectra, together with the cholesteric induction measurement of (R,R)-1, indicate that it assumes a conformation in which the naphthalene rings are M-skewed. Since the intramolecular coupling of (R,R)-1 affords a P-twisted (S) binaphthyl derivative, a change of twist from M to P must occur during the reaction. Moreover, this conformation allows the coupling to occur along only one pathway, thus explaining the high stereoselectivity. The CD analysis of (R,R)-2 indicates that it assumes a rigid conformation as well, with the naphthalene rings fixed relative to each other. However, in this compound the naphthalene moieties can give rise to a coupling reaction following two different pathways, leading to oppositely configured binaphthyls with almost the same probability so that low stereoselectivity results. Copyright 2000 Wiley-Liss, Inc.     

Some applications of a chiral fluorometric reagent, (S)-TBMB carboxylic acid

Molecular design and applications of a fluorometric chiral agent, (S)-TBMB carboxylic acid, are briefly reviewed. The agent, possessing an asymmetric 1,3-benzodioxole skeleton, was designed as a novel class of chiral agent that functions also as a benzoate chromophore for exciton chirality CD methods. The utility of this agent has been demonstrated in an application to determine enantiomeric amino acids, acyl-sn-glycerols, glycosyl-sn-glycerols, and other chiral alcohols and amines.     

Vibrational circular dichroism spectroscopy study of paroxetine and femoxetine precursors

The solution structures of (3R,4S)- and (3S,4R)- 4-(4-fluorophenyl)-3-hydroxylmethyl- 1-methylpiperidine, which are intermediates in the synthesis of the two pharmaceuticals paroxetine and femoxetine, were studied by vibrational circular dichroism (VCD) spectroscopy. In addition, six derivatives with different substituents attached to the C3 atom were prepared and their VCD and absorption spectra discussed with the aid of ab initio simulations. The VCD spectra were found to be sensitive to the geometry changes. In addition, a subtle variation caused by intermolecular aggregation was apparent in the spectra. The VCD technique can be applied for structural analysis of chiral pharmaceuticals in solutions.