Achiral‐to‐Chiral Transition in Benzil Solidification: Analogies with Racemic Conglomerates Systems Showing Deracemization

Experimental results show that benzil (1,2‐diphenyl‐1,2‐ethanedione), an achiral compound that crystallizes as a racemic conglomerate, yields by solidification polycrystalline scalemic mixtures of high enantiomeric excesses. These results are related to those previously reported in this type of compounds on deracemizations of racemic mixtures of crystal enantiomorphs obtained by wet grinding. However, the present results strongly suggest that these experiments cannot be explained without taking into account chiral recognition interactions at the level of precritical clusters. The conditions that would define a general thermodynamic scenario for such deracemizations are discussed. Chirality 25:393–399, 2013. © 2013 Wiley Periodicals, Inc.     

Metal-independent production of hydroxyl radicals by halogenated quinones and hydrogen peroxide: an ESR spin trapping study

The metal-independent production of hydroxyl radicals (*OH) from H(2)O(2) and tetrachloro-1,4-benzoquinone (TCBQ), a carcinogenic metabolite of the widely used wood-preservative pentachlorophenol, was studied by electron spin resonance methods. When incubated with the spin trapping agent 5,5-dimethyl-1-pyrroline N-oxide (DMPO), TCBQ and H(2)O(2) produced the DMPO/*OH adduct. The formation of DMPO/*OH was markedly inhibited by the *OH scavenging agents dimethyl sulfoxide (DMSO), ethanol, formate, and azide, with the concomitant formation of the characteristic DMPO spin trapping adducts with *CH(3), *CH(CH(3))OH, *COO(-), and *N(3), respectively. The formation of DMPO/*OH and DMPO/*CH(3) from TCBQ and H(2)O(2) in the absence and presence, respectively, of DMSO was inhibited by the trihydroxamate compound desferrioxamine, accompanied by the formation of the desferrioxamine-nitroxide radical. In contrast, DMPO/*OH and DMPO/*CH(3) formation from TCBQ and H(2)O(2) was not affected by the nonhydroxamate iron chelators bathophenanthroline disulfonate, ferrozine, and ferene, as well as the copper-specific chelator bathocuproine disulfonate. A comparative study with ferrous iron and H(2)O(2), the classic Fenton system, strongly supports our conclusion that *OH is produced by TCBQ and H(2)O(2) through a metal-independent mechanism. Metal-independent production of *OH from H(2)O(2) was also observed with several other halogenated quinones.     

Quantitative 31P NMR detection of oxygen-centered and carbon-centered radical species

Quantitative 31P NMR spin trapping techniques can be used as effective tools for the detection and quantification of many free radical species. Free radicals react with a nitroxide phosphorus compound, 5-diisopropoxy-phosphoryl-5-methyl-1-pyrroline-N-oxide (DIPPMPO), to form stable radical adducts, which are suitably detected and accurately quantified using (31)P NMR in the presence of phosphorus containing internal standards. Initially, the 31P NMR signals for the radical adducts of oxygen-centered (*OH, O2*-) and carbon-centered (*CH3, *CH2OH, CH2*CH2OH) radicals were assigned. Subsequently, the quantitative reliability of the developed technique was demonstrated under a variety of experimental conditions. The 31P NMR chemical shifts for the hydroxyl and superoxide reaction adducts with DIPPMPO were found to be 25.3, 16.9, and 17.1 ppm (in phosphate buffer), respectively. The 31P NMR chemical shifts for *CH3, *CH2OH, *CH(OH)CH3, and *C(O)CH3 spin adducts were 23.1, 22.6, 27.3, and 30.2 ppm, respectively. Overall, this effort forms the foundations for a targeted understanding of the nature, identity, and mechanisms of radical activity in a variety of biomolecular processes.     

Study of the characterization and crystallization of 4-hydroxy-2-pyrrolidone

A systematic study of the characterization for racemic species of 4-hydroxy-2-pyrrolidone was undertaken. The melting point phase diagram of (R)- and (S)-4-hydroxy-2-pyrrolidone was determined by differential scanning calorimetry. The ternary phase diagram of (R)- and (S)-4-hydroxy-2-pyrrolidone with isopropanol was constructed at 15, 20, 25, and 35 degrees C. The crystalline nature of 4-hydroxy-2-pyrrolidone racemate was also characterized by means of comparison of solid-state FTIR spectra and powder X-ray diffraction patterns of the racemic mixture with those of one of the enantiomers. It is shown that (+/-)-4-hydroxy-2-pyrrolidone is a racemic conglomerate. The enthalpies of fusion of (R)-4-hydroxy-2-pyrrolidone and (+/-)-4-hydroxy-2-pyrrolidone and entropy of mixing of (R)- and (S)-4-hydroxy-2-pyrrolidone were calculated using the thermodynamic data. The solubility and supersolubility diagrams of (R)- and (S)-4-hydroxy-2-pyrrolidone in isopropanol were determined over a temperature range of 4-35 degrees C. The optical resolution of (+/-)-4-hydroxy-2-pyrrolidone was successfully achieved by preferential crystallization.     

Determination of optical purity of 3,5-dimethoxybenzoyl-leucine diethylamide by chiral chromatography and 1H and 13C NMR spectroscopy

(R)-N-3,5-dinitrobenzoyl (DNB) leucine derived chiral selector was used as an HPLC chiral stationary phase for the resolution of various racemic amino acids derivatives. In this study, determination of optical purity of an amino acid derivative was performed by chiral high performance liquid chromatography and 1H and 13C NMR spectroscopy by using the DNB leucine derived chiral selector. The accuracy and precision of each optical purity value are calculated and the data are compared to each other.     

Formation of superoxide anion during ferrous ion-induced decomposition of linoleic acid hydroperoxide under aerobic conditions

We studied the mechanism of formation of oxygen radicals during ferrous ion-induced decomposition of linoleic acid hydroperoxide using the spin trapping and chemiluminescence methods. The formation of the superoxide anion (O2*-) was verified in the present study. The hydroxyl radical is also generated through Fenton type decomposition of hydrogen peroxide produced on disproportionation of O2*-. A carbon-centered radical was detected using 5-(diethoxyphosphoryl)-5-methyl-1-pyrroline N-oxide (DEPMPO) as a spin trap. Alkoxyl radical formation is essential for the conversion of linoleic acid hydroperoxide into the peroxyl radical by ferrous ion. It is likely that the alkoxyl radical [R1CH(O*)R2] is converted into the hydroxylcarbon radical [R1C*(OH)R2] in water, and that this carbon radical reacts with oxygen to give the alpha-hydroxyperoxyl radical [R1R2C(OH)OO*], which decomposes into the carbocation [R1C+(OH)R2] and O2*-.     

High‐performance liquid chromatography quantification of enantiomers of a Dihydroxylated tetrahydrofuran natural product

Both enantiomers of petromyroxol are putative pheromones in sea lamprey (Petromyzon marinus). Here, we describe the separation and quantification of the petromyroxol enantiomers using high‐performance liquid chromatography tandem mass spectrometry. The separation was tested on a wide range of chiral columns with normal phases, and effects of the chromatographic parameters such as mobile phase and temperature on the separation were optimized. The AD‐H column showed the best separation of enantiomers with n‐hexane and ethanol as the mobile phase. The enantiomers were detected by multiple reaction monitoring with a positive atmospheric‐pressure chemical ionization on triple quadrupole mass spectrometer. Validation revealed that the method was specific, accurate, and precise. The validated method was applied to measure the amount of petromyroxol enantiomers in water conditioned with sea lamprey larvae, the source of the putative pheromone. This method will be applied in quantifying the natural scalemic petromyroxol mixture, enabling further investigations of a rare non‐racemic enantiomeric pheromone mixture in a vertebrate species.     

Synthesis and antimalarial activities of rhenium bioorganometallics based on the 4-aminoquinoline structure

A bioorganometallic approach to malaria therapy led to the discovery of ferroquine (FQ, SSR97193). To assess the importance of the electronic properties of the ferrocenyl group, cyclopentadienyltricarbonylrhenium analogues related to FQ, were synthesized. The reaction of [N-(7-chloro-4-quinolinyl)-1,2-ethanodiamine] with the cyrhetrenylaldehyde complexes (η(5)-C(5)H(4)CHO)Re(CO)(3) and [η(5)-1,2-C(5)H(3)(CH(2)OH)(CHO)]Re(CO)(3) produces the corresponding imine derivatives [η(5)-1,2-C(5)H(3)(R)(CHN-CH(2)CH(2)NH-QN)]Re(CO)(3) R=H 3a; R=CH(2)OH 3b; QN=N-(7-Cl-4-quinolinyl). Reduction of 3a and 3b with sodium borohydride in methanol yields quantitatively the amine complexes [η(5)-1,2-C(5)H(3)(R)(CH(2)-NH-CH(2)CH(2)NH-QN)]Re(CO)(3) R=H 4a; R=CH(2)OH 4b. To establish the role of the cyrethrenyl moiety in the antimalarial activity of this series, purely organic parent compounds were also synthesized and tested. Evaluation of antimalarial activity measured in vitro against the CQ-resistant strains (W2) and the CQ-susceptible strain (3D7) of Plasmodium falciparum indicates that these cyrhetrene conjugates are less active compared to their ferrocene and organic analogues. These data suggest an original mode-of-action of FQ and ferrocenyl analogues in relationship with the redox pharmacophore.     

Transfer of chirality by dithiophosphate ligands and chiral discrimination in the stereoselective formation of square-planar Ni(II) complexes

In the formation reaction of Ni(2+) with the chiral racemic ligand, (R)(R)bdtp(-)/(S)(S)bdtp(-), bdtp(-) = [SSPOCH)CH(3))CH(CH(3))O](-), cyclo- O,O'-[1,2-dimethylethylene] dithiophosphato ion, the meso-complex Ni[(R)(R)(lambda)bdtp][(S)(S)(delta)-bdtp] is stereoselectively produced. The meso-complex was compared with the enantiopure crystals of (+)(589)Ni[(R)(R)(lambda)bdtp](2) or (-)(589)Ni[(S)(S)(delta)bdtp](2), as well as racemic crystals, rac-(+/-)Ni[bdtp](2), which were prepared from the solution containing the two enantiomers in a 1:1 ratio. Dissociation constants in solutions indicate different stability of the meso and enantiopure complexes depending on the solvent, whereas a more efficient crystal packing, weak H-bonding, and nonbonding interactions contribute to stabilization of the meso-species over the racemic one. Molecular structures show that the outer five-membered ligand ring adopts the half-chair conformation C(2) with either the lambda or the delta chirality and the methyl groups are in equatorial (e) positions. Enantiopure ligands of (+)(589)Ni[(R)(R)(lambda)bdtp](2) and (-)(589)Ni[(S)(S)(delta)bdtp](2) induce chirality into the symmetric SSNiSS chromophore with slightly helical distortion. Thus, their CD spectra exhibit weak negative or positive Cotton effects at 662 nm. CD spectra in L(+)- and D(-)diethyltartrate of the meso-complex and racemic crystal, rac-(+/-)Ni[bdtp](2), exhibit different weak Cotton effects of opposite sign. Complexes dissociate in methanol; rac-(+/-)Ni[bdtp](2) in methanol undergoes a crystallization-induced second-order asymmetric transformation which finally yields crystals of the meso-Ni[(R)(R)(lambda)bdtp][(S)(S)(delta)bdtp] complex.     

Chirality-dependent interactions between molecular propeller structures in solution. Chiral recognition and discrimination processes modulated by temperature and incremental changes in structural chirality

Time-resolved chiroptical luminescence (TR-CL) measurements are used to study chirality-dependent intermolecular interactions in dynamic excited-state quenching processes. The measurements are carried out on solution samples that contain a racemic mixture of chiral luminophore molecules (with enantiomeric structures denoted by LambdaL and DeltaL) and a small, optically resolved concentration of chiral quencher (CQ) molecules. The luminophores are excited with a pulse of linearly polarized laser radiation to produce an initially racemic excited-state population of LambdaL* and DeltaL* enantiomers, and TR-CL measurements are then used to monitor the differential decay kinetics of the LambdaL* and DeltaL* subpopulations. Observed differences between the LambdaL* and DeltaL* decay kinetics reflect differential rate processes and efficiencies for LambdaL*-CQ vs. DeltaL*-CQ quenching actions, and they are diagnostic of chiral discriminatory interactions between the luminophore and quencher molecules. Twelve different luminophore-quencher systems are examined, in both H(2)O and D(2)O solutions, and in each case the quenching kinetics are measured over the 273-308 K temperature range. In all of the systems examined here, quenching occurs via electronic energy-transfer processes in transient (LambdaL*-CQ) and (DeltaL*-CQ) encounter complexes, and the chiral discriminatory rate parameters reflect the relative stabilities and lifetimes of these complexes as well as their structures and internal (electronic and nuclear) dynamics. All of the luminophore and quencher molecules examined in this study have three-bladed propeller-like structures that are very similar in overall shape and size. However, they exhibit small differences in the structural details of their propeller blades, and it is found that these small differences in structure can produce both qualitative and very substantial quantitative differences in their chiral recognition and discrimination properties.     

(+)-9-Benzyloxy-α-Dihydrotetrabenazine as an Important Intermediate for the VMAT2 Imaging Agents: Absolute Configuration and Chiral Recognition

This article reports, for the first time, on the absolute configuration of (+)-9-benzyloxy-α-dihydrotetrabenazine ( 8 ), as determined from the perspective of X-ray crystallography. Compound 8 was prepared by a six-step reaction using 3-benzyloxy-4-methoxybenzaldehyde ( 1 ) as a starting material. The X-ray crystal diffraction structure of two compounds, racemic 9-benzyloxy-tetrabenazine ( 5 ) and the diastereomeric salt of compound 8 , is also described for the first time in this article. The X-ray results and the chiral HPLC helped elucidate that compound 8 has an absolute configuration as 2R,3R,11bR. The crystal structure of racemic compound 5 contains two symmetry- independent molecules in the unit cell. Interestingly, while they are structural isomers, they are enantiomers, too, i.e., in solution, because they are not mirror images of each other in the crystal lattice. In order to elucidate the intermolecular interaction mechanism of the diastereomeric salt of compound 8 , its crystal packing was investigated with regard to the weak interactions, such as salt bridge, OH…O and CH…O hydrogen bonds, and intermolecular CH…π interaction. The results showed that the carbonyl-assisted salt bridges and the OH…O hydrogen bonds formed polar columns in the crystal structure of the diastereomeric salt of compound 8 , resembling butterflies with open wings as viewed along the c-axis. These polar columns were extended to three-dimensional network by intermolecular CH…O hydrogen bonds and intermolecular CH…π interactions. Chirality, 2013. © 2013 Wiley Periodicals, Inc.     

Single diastereomers of unsymmetrical tris-spirocyclic cyclotriphosphazenes based on 1,1'-bi-2-naphthol--synthesis and structures

Diastereoselective synthesis and characterization of chiral unsymmetrical tris-spirocyclic cyclotriphosphazenes based on chiral 1,1'-bi-2-naphthol (BINOL) are reported. Specifically, the chiral compounds (-)N(3)P(3)[1,1'-O(2)(C(10)H(6))(2)](O-2,2'C(6)H(4)-C(6)H(4)O)Cl(2) [(-)-4] and (-)N(3)P(3)[1,1'-O(2)(C(10)H(6))(2)](OCH(2)CH(2)NMe)(2) [(-)-5] are prepared by starting with the chiral mono-spiro compound (-)N(3)P(3)[1,1'-O(2)(C(10)H(6))(2)]Cl(4) [(-)-3]. Synthesis of four other chiral spirocyclics, N(3)P(3)[1,1'-O(2)(C(10)H(6))(2)](OCH(2)CH(2) NMe)(O-2,2'C(6)H(4)-C(6)H(4)O)[(-)-6 and (+)-6], N(3)P(3)[1,1'-O(2)(C(10)H(6))(2)](NMe(2))(4) [(-)-7], N(3)P(3)[1,1'-O(2)(C(10)H(6))(2)](O-2,2'C(6)H(4)-C(6)H(4)O)(NMeCH(2)CH(2)OH)(2) [(-)-8 and (+)-8], and N(3)P(3)[1,1'-O(2)(C(10)H(6))(2)](O-2,2'C(6)H(4)-C(6)H(4)O)[NHCH(2)CH(2)CH(2)Si(OEt)(3)](2) (9) is also reported herein. Compounds 4-6 are obtained in the solid state diastereoselectively and their X-ray structures have been determined and discussed. The diastereoselectivity is also shown by structural characterization of two distinct isomers in the case of 6 [(-)-6 and (+)-6, respectively] by starting with precursor of 3 having (R) or (S)-BINOL residue. The (1)H NMR spectra of 7 and 8 exhibit doublets with virtual coupling for the methyl protons, consistent with the chiral nature of the binaphthoxy residue. The potential of 9, which hydrolyzes readily in CDCl(3) solution, as a useful precursor for chiral polymer applications is highlighted.     

Solubility, metastable zone width, and racemic characterization of propranolol hydrochloride

Characterization of the racemic species, which can be a racemic compound, a racemic conglomerate, or a pseudoracemate (solid solution), is a prerequisite for the design of crystallization resolution processes. It is useful to determine the solid/liquid equilibrium solubility of the enantiomer mixtures for crystallization operation. For the beta-blocker drug propranolol hydrochloride, Gibbs free energy of formation of racemic compound and entropy of mixing of the (R)- and (S)- enantiomers in the liquid state for racemic conglomerate were calculated. The structural differences between (R, S)-propranolol hydrochloride and its (S)-enantiomer were further investigated by powder X-ray diffraction patterns, infrared spectra, and solid-state NMR spectra. The solubility and metastable zone width of (R, S)- propranolol hydrochloride in a mixed solvent of methanol and acetone were determined by cooling crystallization over the temperature range 3.5-42.5 degrees C. The ternary solubility diagram of (R)-, (S)-propranolol hydrochloride was constructed using the same mixed solvent. The diagram will be useful as a guide for choosing crystallization operation conditions to produce pure enantiomers.     

Factors that influence siderophoremediated iron bioavailability: catalysis of interligand iron (III) transfer from ferrioxamine B to EDTA by hydroxamic acids

Deferriferrioxamine B (H3DFB) is a linear trihydroxamic acid siderophore with molecular formula NH2(CH2)5[N(OH)C(O)(CH2)2C(O)NH(CH2)5]2N(OH)C(O)CH3 that forms a kinetically and thermodynamically stable complex with iron(III), ferrioxamine B. Under the conditions of our study (pH = 4.30, 25 degrees C), ferrioxamine B, Fe(HDFB)+, is hexacoordinated and the terminal amine group is protonated. Addition of simple hydroxamic acids, R1C(O)N(OH)R2 (R1 = CH3, R2 = H; R1 = C6H5, R2 = H; R1 = R2 = CH3), to an aqueous solution of ferrioxamine B at pH = 4.30, 25.0 degrees C, I = 2.0, results in the formation of ternary complexes Fe(H2DFB)A+ and Fe(H3DFB)A2+, and tris complexes FeA3, where A- represents the bidendate hydroxamate anion R1C(O)N(O)R2-. The addition of a molar excess of ethylenediaminetetraacetic acid (EDTA) to an aqueous solution of ferrioxamine B at pH 4.30 results in a slow exchange of iron(III) to eventually completely form Fe(EDTA)- and H4DFB+. The addition of a hydroxamic acid, HA, catalyzes the rate of this iron exchange reaction: (formula; see text) A four parallel path mechanism is proposed for reaction (1) in which catalysis occurs via transient formation of the ternary and tris complexes Fe(H2DFB) A+, Fe(H3DFB)A2+, and FeA3. Rate and equilibrium constants for the various reaction paths to products were obtained and the influence of hydroxamic acid structure on catalytic efficiency is discussed. The importance of a low energy pathway for iron dissociation from a siderophore complex in influencing microbial iron bio-availability is discussed. The system represented by reaction (1) is proposed as a possible model for in vivo catalyzed release of iron from its siderophore complex at the cell wall or interior, where EDTA represents the intracellular storage depot or membrane-bound carrier and HA represents a low molecular weight hydroxamate-based metabolite capable of catalyzing interligand iron exchange.     

Propagation of Biochirality: Crossovers and Nonclassical Crystallization Kinetics of Aspartic Acid in Water

All experimental procedures discussed could be treated as a screening tool for probing the existence of molecular association among the chiral molecules and the solvent system. The molecular association phases of a racemic conglomerate solution (CS) and a racemic compound solution (RCS), and the templating effect of aspartic acid solid surface were observed to minimize the chance of redissolving racemic conglomerate and racemic compound aspartic acid in water and reforming an RCS in crossovers experiments. Only 1 %wt% of l‐aspartic acid was adequate enough to induce a transformation from a racemic compound aspartic acid to a racemic conglomerate aspartic acid. This would make the propagation of biochirality more feasible and sound. However, tetrapeptide, (l‐aspartic acid)₄, failed to induce enantioseparation as templates purely by crystallization. Nonclassical crystallization theory was needed to take into account the existence of a CS. Fundamental parameters of the crystallization kinetics such as the induction time, interfacial energy, Gibbs energetic barrier, nucleation rate, and critical size of stable nuclei of: (i) racemic compound aspartic acid, (ii) racemic compound aspartic acid seeded with 1 %wt% l‐aspartic acid, (iii) racemic conglomerate aspartic acid, and (iv) l‐aspartic acid were evaluated and compared with different initial supersaturation ratios. Morphological studies of crystals grown from the crystallization kinetics were also carried out.Chirality 25:768–779, 2013. © 2013 Wiley Periodicals, Inc.     

HPLC resolution of atropoisomeric compounds on a csp derived from (1R;2R)-diaminocyclohexane: Thermodynamic data from variable temperature chromatography

The preparation and a preliminary chromatographic evaluation of a novel polymeric chiral stationary phase (CSP) derived from (1R;2R)-diaminocyclohexane (DACH) are presented. A radical copolymerization process has been employed to generate a silica-based chiral sorbent, showing considerable high chemical and thermal stability and stereoselectivity toward racemic compounds capable of H-bonding (3-hydroxy-benzodiazepin-2-ones, chlorthalidone, atropoisomeric sulfur compounds, etc.); in the present paper we present the investigation on the resolution of racemic dihydroxy biarylic atropoisomers; the effects of eluent composition and of temperature on the separation ability of the CSP have been studied in order to elucidate the recognition mechanism operating in these chiral separations. © 1992 Wiley-Liss, Inc.     

New Karplus equations for 2JHH, 3JHH, 2JCH, 3JCH, 3JCOCH, 3JCSCH, and 3JCCCH in some aldohexopyranoside derivatives as determined using NMR spectroscopy and density functional theory calculations

The (1)H-(13)C coupling constants of methyl alpha- and beta-pyranosides of D-glucose and D-galactose have been measured by one-dimensional and two-dimensional (1)H-(13)C heteronuclear zero and double quantum, phase sensitive J-HMBC spectra to determine a complete set of coupling constants ((1)J(CH), (2)J(CH), (3)J(CH), (2)J(HH), and (3)J(HH)) within the exocyclic hydroxymethyl group (CH(2)OH) for each compound. In parallel with these experimental studies, structure, energy, and potential energy surfaces of the hydroxymethyl group for these compounds were determined employing quantum mechanical calculations at the B3LYP level using the 6-311++G( * *) basis set. Values of the vicinal coupling constants involving (1)H and (13)C in the C5-C6 (omega) and C6-O6 (theta) torsion angles in the aldohexopyranoside model compounds were calculated with water as the solvent using the PCM method. To test the relationship between (3)J(CXCH) (X=C, O, S) and torsion angle C1-X (phi) around the anomeric center, the conformations of 24 derivatives of glucose and galactose, which represent sequences of atoms at the anomeric center of C-glycosides (C-C bond), O-glycosides (C-O bond), thioglycosides (C-S bond), glycosylamines (C-N bond), and glycosyl halides (C-halogen (F/Cl) bond) have been calculated. Nonlinear regression analysis of the coupling constants (1)J(C1,H1), (2)J(C5,H6R), (2)J(C5,H6S), (2)J(C6,H5), (3)J(C4,H6R), (3)J(C4,H6S), (2)J(H6R,H5), and (3)J(H5,H6R) as well as (3)J(CXCH) (X=C, O, S) on the dihedral angles omega, theta, and phi have yielded new Karplus equations. Good agreement between calculated and experimentally measured coupling constants revealed that the DFT method was able to accurately predict J-couplings in aqueous solutions.     

Synthesis, enantiomeric resolution, and selective C-11 methylation of a highly selective radioligand for imaging the norepinephrine transporter with positron emission tomography

Reboxetine, 2-[alpha-(2-ethoxyphenoxy)benzyl]morpholine, is a highly selective norepinephrine transporter (NET) blocker that has been used for the treatment of depression. Its methyl analogue, 2-[alpha-(2-methoxyphenoxy)benzyl]morpholine (MRB), has been radiolabeled with C-11 for studies of the NET system with positron emission tomography (PET). The normethyl precursor, 2-[alpha-(2-hydroxyphenoxy)benzyl]morpholine (desethylreboxetine), was synthesized in 6% overall yield via a multi-step regio- and stereo-specific synthesis, starting from a mono-O-protected catechol. The resulting racemic mixture of desethylreboxetine was resolved by chiral HPLC to provide the (2S,3S) and (2R,3R) enantiomers in >98% enantiomeric excess. These enantiomers were then used as precursors for radiosynthesis to prepare enantiomerically pure individual 11C-labeled MRB enantiomers for comparative PET studies in baboons. Selective C-11 methylation at the phenolic oxygen with [11C]CH3I was achieved in the presence of excess base. After HPLC purification, racemic ((2S,3S)/(2R,3R)) or enantiomerically pure ((2S,3S) or (2R,3R)) [11C]MRB was obtained in 61-74% decay-corrected radiochemical yields from [11C]CH3I in a synthesis time of 40 min with a radiochemical purity of >96% and a specific activity of 1.7-2.3 Ci/micromol (63-85 GBq/micromol) corrected from the end of bombardment (EOB).     

5-Substituted-2,3-diphenyltetrahydrofurans: a new class of moderately selective COX-2 inhibitors

The nature of C-5 substituent and the configuration at C-5 carbon of 2,3-diphenyltetrahydrofurans, with chiral centres at C-2, C-3 and C-5, show a remarkable influence on their COX-2 inhibition and selectivity. Out of the eight compounds investigated here, 1b with COOH group and R* configuration at C-5, and 2d with CH2SCH2CH3 group and S* configuration at C-5 have been identified as lead molecules for further studies on COX-2 inhibition.