Practical synthesis of wybutosine, the hypermodified nucleoside of yeast phenylalanine transfer ribonucleic acid

An improved synthesis of 3-beta-D-ribofuranosylwybutine (2) has been achieved by the Wittig reaction between 4,6-dimethyl-9-oxo-3-[2,3,5-tris-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]-4,9-dihydro-3H-imidazo[1,2-a]-purine-7-carbaldehyde (8) and the phosphorane derived from (R)-2-[(methoxycarbonyl)amino]-3-(triphenylphosphonio)propanoate (9), followed successively by methylation, hydrogenation, and deprotection. On the other hand, the minor nucleoside wybutosine of yeast tRNA(Phe) was isolated on a scale of 80 microg by partial digestion of unfractionated tRNA (1 g) with nuclease P1, followed successively by reversed-phase column chromatography, complete digestion with nuclease P1/alkaline phosphatase, and reversed-phase HPLC. Comparison of this nucleoside with 2 has unambiguously established that the structure of wybutosine is (alphaS)-alpha-[(methoxycarbonyl)-amino]-4,6-dimethyl-9-oxo-3-beta-D-ribofuranosyl-4,9-dihydro-3H-imidazo[1,2-a]purine-7-butanoic acid methyl ester (2).     

Mononuclear, dinuclear, and pentanuclear [[N,S(thiolate)]iron(II)] complexes: nuclearity control, incorporation of hydroxide bridging ligands, and magnetic behavior

The mixed N3S(thiolate) ligand 1-[bis[2-(pyridin-2-yl)ethyl]amino]-2-methylpropane-2-thiol (Py2SH) was used in the synthesis of four iron(II) complexes: [(Py2S)FeCl] (1), [(Py2S)FeBr] (2), [(Py2S)4Fe5II(mu-OH)2](BF4)4 (3), and [(Py2S)2Fe2II(mu-OH)]BF4 (4). The X-ray structures of 1 and 2 revealed monomeric iron(II)-alkylthiolate complexes with distorted trigonal-bipyramidal geometries. The paramagnetic 1H NMR spectra of 1 and 2 display resonances from delta = -25 ppm to +100 ppm, consistent with a high-spin iron(II) ion (S = 2). Spectral assignments were made on the basis of chemical shift information and T1 measurements and show the monomeric structures are intact in solution. To provide entry into hydroxide-containing complexes, a novel synthetic method was developed involving strict aprotic conditions and limiting amounts of H2O. Reaction of Py2SH with NaH and Fe(BF4)2.6 H2O under aprotic conditions led to the isolation of the pentanuclear, mu-OH complex 3, which has a novel dimer-of-dimers type structure connected by a central iron atom. Conductivity data on 3 show this structure is retained in CH2Cl2. Rational modification of the ligand-to-metal ratio allows control over the nuclearity of the product, yielding the dinuclear complex 4. The X-ray structure of 4 reveals an unprecedented face-sharing, biooctahedral complex with an [S2O] bridging arrangement. The magnetic properties of 3 and 4 in the range 1.9-300 K were successfully modeled. Dinuclear 4 is antiferromagnetically coupled [J = -18.8(2) cm(-1)]. Pentanuclear 3 exhibits ferrimagnetic behavior, with a high-spin ground state of S(T) = 6, and was best modeled with three different exchange parameters [J = -15.3(2), J' = -24.7(3), and J' = -5.36(7) cm(-1)]. DFT calculations provided good support for the interpretation of the magnetic properties.     

Study of the mechanism of enantioseparation part VI: thermodynamic study of HPLC separation of some enantiomers of phenylcarbamic acid derivatives on a (S,S) Whelk-O 1 column

The enantiomers of thirteen 2-, 3-, and 4-alkoxyphenylcarbamic acid 2-methoxy-1-[(4-methylpiperazino)methyl]ethyl ester were separated on a (S,S) Whelk-O 1 CSP column isothermally in the range of 0-50 degrees C at 10 degrees C increments, using methanol/ water (90/10, v/v) containing 17.5 mmol L(-1) acetic acid and 14.36 mmol L(-1) triethylamine as a mobile phase. The dependence of the natural logarithms of retention and selectivity factors (In k, In alpha, respectively) on the inverse of temperature, 1/T, was used to determine thermodynamic data of enantiomers of alkoxysubstituted phenylcarbamic acid 2-methoxy-1-[(4-methylpiperazino) methyl]ethyl esters. Enthalpyentropy compensation plots showed that all of the compounds in this study separate via the same enthalpy-driven chiral recognition mechanism.     

Synthesis, structure, and reactivity of palladacycles that contain a chiral rhenium fragment in the backbone: New cyclometalation and catalyst design strategies

The bromocyclopentadienyl complex [(eta5-C5H4Br)Re(CO)3] is converted to racemic [(eta5-C5H4Br)Re(NO)(PPh3)(CH2PPh2)] (1 b) similarly to a published sequence for cyclopentadienyl analogues. Treatment of enantiopure (S)-[(eta5-C5H5)Re(NO)(PPh3)(CH3)] with nBuLi and I2 gives (S)-[(eta5-C5H4I)Re(NO)(PPh3)(CH3)] ((S)-6 c; 84 %), which is converted (Ph3C+ PF6 -, PPh2H, tBuOK) to (S)-[(eta5-C5H4I)Re(NO)(PPh3)(CH2PPh2)] ((S)-1 c). Reactions of 1 b and (S)-1 c with Pd[P(tBu)3]2 yield [{(eta5-C5H4)Re(NO)(PPh3)(mu-CH2PPh2)Pd(mu-X)}2] (10; X = b, Br, rac/meso, 88 %; c, I, S,S, 22 %). Addition of PPh3 to 10 b gives [(eta5-C5H4)Re(NO)(PPh3)(mu-CH2PPh2)Pd(PPh3)(Br)] (11 b; 92 %). Reaction of (S)-[(eta5-C5H5)Re(NO)(PPh3)(CH2PPh2)] ((S)-2) and Pd(OAc)(2) (1.5 equiv; toluene, RT) affords the novel Pd3(OAc)4-based palladacycle (S,S)-[(eta5-C5H4)Re(NO)(PPh3)(mu-CH2PPh2)Pd(mu-OAc)2Pd(mu-OAc)2Pd(mu-PPh2CH2)(Ph3P)(ON)Re(eta5-C5H4)] ((S,S)-13; 71-90 %). Addition of LiCl and LiBr yields (S,S)-10 a,b (73 %), and Na(acac-F6) gives (S)-[(eta5-C5H4)Re(NO)(PPh3)(mu-CH2PPh2)Pd(acac-F6)] ((S)-16, 72 %). Reaction of (S,S)-10 b and pyridine affords (S)-[(eta5-C5H4)Re(NO)(PPh3)(mu-CH2PPh2)Pd(NC5H5)(Br)] ((S)-17 b, 72 %); other Lewis bases yield similar adducts. Reaction of (S)-2 and Pd(OAc)2 (0.5 equiv; benzene, 80 degrees C) gives the spiropalladacycle trans-(S,S)-[{(eta5-C5H4)Re(NO)(PPh3)(mu-CH2PPh2)}2Pd] (39 %). The crystal structures of (S)-6 c, 11 b, (S,S)- and (R,R)-132 C7H8, (S,S)-10 b, and (S)-17 b aid the preceding assignments. Both 10 b (racemic or S,S) and (S)-16 are excellent catalyst precursors for Suzuki and Heck couplings.     

Precursors to clusters with the topology of the P(N) cluster of nitrogenase: edge-bridged double cubane clusters [(Tp)2Mo2Fe6S8L4]z: synthesis, structures, and electron transfer series

Members of the cluster set [(Tp)2Mo2Fe6S8L4]z contain the core unit M2Fe6(mu3-S)6(mu4-S)2 in which two MoFe3S4 cubanes are coupled by two Fe-(mu4-S) interactions to form a centrosymmetric edge-bridged double cubane cluster. Some of these clusters are synthetic precursors to [(Tp)2Mo2Fe6S9L2]3-, which possess the same core topology as the P(N) cluster of nitrogenase. In this work, the existence of a three-member electron-transfer series of single cubanes [(Tp)MoFe3S4L3](z) (z = 3-, 2-, 1-) and a four-member series of double cubanes [(Tp)2Mo2Fe6S8L4]z (z = 4-, 3-, 2-, 1-) with L = F-, Cl-, N3, PhS- is demonstrated by electrochemical methods, cluster synthesis, and X-ray structure determinations. The potential of the [4-/3-] couple is extremely low (<-1.5 V vs SCE in acetonitrile) such that the 4- state cannot be maintained in solution under normal anaerobic conditions. The chloride double cubane redox series was examined in detail. The members [(Tp)2Mo2Fe6S8Cl4]4-,3-,2- were isolated and structurally characterized. The redox series includes the reversible steps [4-/3-] and [3-/2-]. Under oxidizing conditions, [(Tp)2Mo2Fe6S8Cl4]2- cleaves with the formation of single cubane [(Tp)MoFe3S4Cl3]1-. The quasireversible [2-/1-] couple is observed at more positive potentials than those of the single cubane redox step. Structure comparison of nine double cubanes suggests that significant dimensional changes pursuant to redox reactions are mainly confined to the Fe2(mu4-S)2 bridge rhomb. The synthesis and structure of [(Tp)2Mo2Fe6S9F2.H2O]3-, a new topological analogue of the P(N) cluster of nitrogenase, is described. (Tp = hydrotris(pyrazolyl)borate(1-)).     

Effective, high-yielding, and stereospecific total synthesis of D-erythro-(2R,3S)-sphingosine from D-ribo-(2S,3S,4R)-phytosphingosine

The synthesis of naturally occurring D-erythro-(2R,3S,4E)-sphingosine from commercially available D-ribo-(2S,3S,4R)-phytosphingosine is described. The key step in the reaction sequence comprises TMSI/DBN promoted regio- and stereoselective oxirane opening of intermediate 2-phenyl-4-(S)-[(1S,2S)-1,2-epoxyhexadecyl]-1,3-oxazoline followed by the in situ trans-elimination of 2-phenyl-4-(S)-[(1S,2R)-1,2-dideoxy-2-iodo-1-trimethylsilyloxyhexadecyl]-1,3-oxazoline.     

Determination of total and free concentrations of the enantiomers of methadone and its metabolite (2-ethylidene-1,5-dimethyl-3,3-diphenyl-pyrrolidine) in human plasma by enantioselective liquid chromatography with mass spectrometric detection

A sensitive enantioselective liquid chromatographic assay with mass spectrometric detection (LC-MS) has been validated for the determination of total and free plasma concentrations of (R)- and (S)-methadone (Met) and (R)- and (S)-2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP, the primary metabolite of Met), using their respective deuterium-labeled compounds as internal standards [(R,S)-d3-Met and (R,S)-d3-EDDP]. For total drug determinations, 1 ml human plasma was extracted, using a cation-exchange solid-phase extraction cartridge; the eluate was evaporated, reconstituted in the mobile phase, and injected into the LC-MS system. The free fractions of Met and EDDP were determined, using 500 microl of plasma, which were placed in an ultrafiltration device and centrifuged at 2000 x g until 250 microl of filtrate was collected. The filtrate was extracted as described above and analyzed. Enantioselective separations were achieved using an alpha1-acid glycoprotein chiral stationary phase, a mobile phase composed of acetonitrile-ammonium acetate buffer [10 mM, pH 7.0] (18:82, v/v), a flow rate of 0.9 ml/min at 25 degrees C. Under these conditions, enantioselective separations were observed for Met (alpha = 1.30) and EDDP (alpha = 1.17) within 15 min. Met, EDDP, [2H3]-Met and [2H3]-EDDP were detected using selected ion monitoring at m/z 310.30, 278.20, 313.30, and 281.20, respectively. Linear relationships between peak height ratio and drug-enantiomer concentrations were obtained for Met in the range 1.0-300.0 ng/ml, and for EDDP from 0.1 to 25.0 ng/ml with correlation coefficients greater than 0.999, where the lower limit of quantification (LLOQ) was 1 ng/ml for Met and 0.1 ng/ml for EDDP. The relative standard deviation (R.S.D.) expressed as R.S.D. for the intra- and inter-day precision of the method were < 5.3% and the R.S.D. for accuracy was < 5.0%. The method was used to analyze plasma samples obtained from patients enrolled in a Met-maintenance program.     

Development of direct stereoselective and non-stereoselective assays in biological fluids for the enantiomers of a thieno[2,3-b]thiopyran-2-sulfonamide, a topically effective carbonic anhydrase inhibitor

A stereoselective assay for the optical isomers [(S) and (R)] of 5,6-dihydro-4-[(2-methylpropyl)amino]-4H-thieno[2,3-b]thiopyran-2- sulfonamide-7,7-dioxide in human whole blood has been developed. The assay is based on direct enantiomer separation on a chiral stationary phase column of bovine serum albumin attached to silica. The effect of pH, ionic strength, column length and organic modifier on chiral separation has been studied. The assay methodology, based on high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection (252 nm), has been fully validated in the concentration range 25-250 ng/ml of each enantiomer. Since no interconversion of the isomers was observed in vivo for the clinical studies involving the single (S)-enantiomer, a more sensitive (2.5 ng/ml), non-stereoselective assay has been developed. This method, also based on HPLC with UV detection, was fully validated in whole blood, plasma and urine in the concentration range 2.5-100 ng/ml. The details of these assays, together with some representative data from a pilot human study, are also presented.     

Studies on the constituents of Broussonetia species VIII. Four new pyrrolidine alkaloids, broussonetines R, S, T, and V and a new pyrroline alkaloid, broussonetine U, from Broussonetia kazinoki Sieb

Four new pyrrolidine alkaloids, broussonetines R, S, T, and V and a new pyrroline alkaloid, broussonetine U were isolated from the branches of Broussonetia kazinoki SIEB. (Moraceae) in low yield. Broussonetines R, S and T were formulated as (2R,3R,4R,5R)-2-hydroxymethyl-3,4-dihydroxy-5-[(1R)-1-hydroxy-3-[6-(4-hydroxybutyl)-cyclohexy-2-on-1(6)-enyllpropyl] pyrrolidine (1), (2R,3R,4R,5R)-2-hydroxymethyl-3,4-dihydroxy-5-[(1R,10S)-1,10,13-trihydroxytridecyl] pyrrolidine (2), (2R,3R,4R,5R)-2-hydroxymethyl-3,4-dihydroxy-5-[(1R,5S)-1,5, 13-trihydroxy-10-oxo-tridecyl] pyrrolidine (3). And broussonetines U and V were proposed to be (2S,3S,4S)-2-hydroxymethyl-3, 4-dihydroxy-5-(9-oxo-13-hydroxytridecyl)-5-pyrroline (4), (2R,3S,4R,5R)-2-hydroxymethyl-3,4-dihydroxy-5-[(E)-9-oxo-13-hydroxy-3-tridecenyl] pyrrolidine (5), respectively, by spectroscopic and chemical methods.     

Synthesis of an optically active, bicyclic 2-pyridone dipeptide mimetic

The eleven-step preparation of the bicyclic 2-pyridone dipeptide mimetic 1 [(3S)-6-(benzyloxycarbonylamino)-5-oxo-1,2,3,5-tetrahydroindolizine-3-carboxylic acid] in optically active form (60% ee) is described. Key steps in the synthesis of 1 include the osmium-catalyzed asymmetric dihydroxylation of olefin 13 [(6-but-3-enyl-2-methoxypyridin-3-yl)carbamic acid benzyl ester] and the intramolecular cyclization of protected diol 19 [(3'R)-[6-[4'-(tert-butyldimethylsilanyloxy)-3'-hydroxybutyl]-2-methoxypyridin-3-yl]carbamic acid benzyl ester] to afford the pyridinium salt 20 [(3S)-[3-(tert-butyldimethylsilanyloxymethyl)-5-methoxy-2,3-dihydro-1H-indolizin-6-yl]carbamic acid benzyl ester trifuoromethanesulfonic acid salt]. Several alternate methods to prepare olefin 13 are also discussed.     

Asymmetric transfer hydrogenation of alpha-aminoalkyl alpha'-chloromethyl ketones with chiral Rh complexes

Asymmetric transfer hydrogenation of N-substituted (3S)-3-amino-1-chloro-4-phenyl-2-butanones in the presence of CpRhCl[(R,R)-Tsdpen] (S/C = 1000) with a mixture of formic acid/triethylamine gave N-substituted (2R,3S)-3-amino-1-chloro-2-hydroxy-4-phenylbutanes with up to 93% de in a quantitative yield, and reduction with the enantiomeric catalyst CpRhCl[(S,S)-Tsdpen] gave (2S,3S)-diastereomeric alcohol with up to 96% de.     

Stabilization of reduced molybdenum-iron-sulfur single- and double-cubane clusters by cyanide ligation

Recent work has shown that cyanide ligation increases the redox potentials of Fe(4)S(4) clusters, enabling the isolation of [Fe(4)S(4)(CN)4]4-, the first synthetic Fe(4)S(4) cluster obtained in the all-ferrous oxidation state (Scott, T. A.; Berlinguette, C. P.; Holm, R. H.; Zhou, H.-C. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 9741). The generality of reduced cluster stabilization has been examined with MoFe(3)S(4) clusters. Reaction of single-cubane [(Tp)MoFe(3)S(4)(PEt(3))3]1+ and edge-bridged double-cubane [(Tp)2Mo(2)Fe(6)S(8)(PEt(3))4] with cyanide in acetonitrile affords [(Tp)MoFe(3)S(4)(CN)3]2- (2) and [(Tp)2Mo(2)Fe(6)S(8)(CN)4]4- (5), respectively. Reduction of 2 with KC(14)H(10) yields [(Tp)MoFe(3)S(4)(CN)3]3- (3). Clusters were isolated in approximately 70-90% yields as Et(4)N+ or Bu(4)N+ salts; clusters 3 and 5 contain all-ferrous cores, and 3 is the first [MoFe(3)S(4)]1+ cluster isolated in substance. The structures of 2 and 3 are very similar; the volume of the reduced cluster core is slightly larger (2.5%), a usual effect upon reduction of cubane-type Fe(4)S(4) and MFe(3)S(4) clusters. Redox potentials and 57Fe isomer shifts of [(Tp)MoFe(3)S(4)L3]2-,3- and [(Tp)2Mo(2)Fe(6)S(8)L(4)]4-,3- clusters with L = CN-, PhS-, halide, and PEt3 are compared. Clusters with pi-donor ligands (L = halide, PhS) exhibit larger isomer shifts and lower (more negative) redox potentials, while pi-acceptor ligands (L = CN, PEt3) induce smaller isomer shifts and higher (less-negative) redox potentials. When the potentials of 3/2 and [(Tp)MoFe(3)S(4)(SPh)3]3-/2- are compared, cyanide stabilizes 3 by 270 mV versus the reduced thiolate cluster, commensurate with the 310 mV stabilization of [Fe(4)S(4)(CN)4]4- versus [Fe(4)S(4)(SPh)4]4- where four ligands differ. These results demonstrate the efficacy of cyanide stabilization of lower cluster oxidation states. (Tp = hydrotris(pyrazolyl)borate(1-)).     

Conformationally tailored N-[(2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)carbonyl]proline templates as molecular tools for the design of peptidomimetics. Design and synthesis of fibrinogen receptor antagonists

The proline peptide bond was shown by 2D proton NMR studies to exist exclusively in the trans conformation in benzyl (2S)-1-[[(2S)-2-methyl-6-nitro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]carbonyl]-2-pyrrolidinecarboxylate [(S,S)-11], benzyl (2S)-1-[[(2S)-2-methyl-7-nitro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]carbonyl]-2-pyrrolidinecarboxylate [(S,S)-9], and in the corresponding 6-amino and 7-amino carboxylic acids (S,S)-3 and (S,S)-4. On the other hand, the diastereomers (R,S)-11 and (R,S)-9 containing an (R)[2-methyl-6/7-nitro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]carbonyl moiety, and the diastereoisomers (R,S)-3 and (R,S)-4 incorporating an (R)[6/7-amino-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]carbonyl moiety were found to exist as equilibria of trans(63-83%) and cis(17-37%) isomers. These conformationally defined templates were applied in the construction of RGD mimetics possessing antagonistic activity at the platelet fibrinogen receptor.     

An Asymmetric Synthesis of L-694,458, a Human Leukocyte Elastase Inhibitor, via Novel Enzyme Resolution of beta-Lactam Esters

A convergent synthesis of [S-(R,S)]-2-[4-[(4-methylpiperazin-1-yl)carbonyl]phenoxy]-3,3-diethyl-N-[1-[3,4-(methylenedioxy)phenyl]butyl]-4-oxo-1-azetidinecarboxamide (L-694,458, 1), a potent human leukocyte elastase inhibitor, was achieved via chiral synthesis of key intermediates: (S)-3,3-diethyl-4-[4'-[(N-methylpiperazin-1-yl)carbonylphenoxy]-2-azetidinone (2) and (R)-alpha-propylpiperonyl isocyanate (3). Synthesis of beta-lactam 2 was achieved by a novel enantioselective lipase hydrolysis of ester 5 to produce (S)-3,3-diethyl-4-(4'-carboxyphenoxy)-2-azetidinone (6) (60% yield, three cycles, 93% ee) with isolation, epimerization, and recycling of the undesired (R)-ester 5. Isocyanate 3 was prepared by chiral addition of Zn(n-Pr)(2) to piperonal (98% yield, 99.2% ee), azide displacement and reduction to (R)-alpha-propylpiperonylamine (11) (58% yield, 85% ee), crystallization as the D-pyroglutamic acid salt (92% yield, 98.2% ee), and isocyanate formation (98% yield) with phosgene.     

Synthesis of chiral hydroxyl phospholanes from D-mannitol and their use in asymmetric catalytic reactions

Chiral hydroxyl monophosphane 3 [(2S,3S,4S,5S)-3,4-dihydroxy-2, 5-dimethyl-1-phenylphospholane] and bisphospholanes 5a [1,2-bis[(2S, 3S,4S,5S)-3,4-dihydroxy-2,5-dimethylphospholanyl]benzene] and 5b [1, 2-bis[(2S,3S,4S,5S)-2,5-diethyl-3,4-dihydroxyphospholanyl]benzene] were synthesized from readily available D-mannitol in high yields. Strategies for protection and deprotection of OH-groups in the presence of phosphines have been explored. Rate acceleration in the Baylis-Hillman reaction was observed when a hydroxyl phosphine was used as the catalyst. Rhodium complexes with chiral bisphospholanes are highly enantioselective catalysts for the asymmetric hydrogenation of various kinds of functionalized olefins such as dehydroamino acid derivatives, itaconic acid derivatives, and enamides. An interesting feature of the hydroxyl phospholane system is that hydrogenation of some substrates can be carried out in water with >99% ee and 100% conversion (e.g., itaconic acid).     

Diastereoselective hydroxylation of 6-substituted piperidin-2-ones. An efficient synthesis of (2S,5R)-5-hydroxylysine and related alpha-amino acids

The synthesis of (2S,5R)-5-hydroxy-6-oxo-1,2-piperidinedicarboxylates (5) and related (3S,6R)-3-hydroxy-6-alkyl-2-oxo-1-piperidinecarboxylates has been developed. The approach is based on the asymmetric hydroxylation of enolates generated from the corresponding N-protected-6-substituted piperidin-2-ones. The utility of 5a as a precursor in the synthesis of (2S,5R)-5-hydroxylysine (1), an amino acid unique to collagen and collagen-like proteins, has also been demonstrated. (2S)-6-oxo-1,2-piperidinedicarboxylates (6) required for hydroxylation studies were prepared in 38-74% yield, starting from conveniently protected aspartic acid as inexpensive chiral adduct. Hydroxylation of 6 to 5 proceeds in high yield and excellent diastereoselectivity by treatment of their Li-enolate with (+)-camphorsulfonyloxaziridine at -78 degrees C. Ring opening of di-tert-butyl (2S,5R)-6-oxo-1,2-piperidinedicarboxylate ((5R)-5a) under reductive conditions afforded the corresponding 1,2-diol (17) in 91%, which was further transformed to (2S,5R)-5-hydroxylysine in four steps (84%). 17 is also a versatile intermediate in the preparation of tert-butyl (2S,5R)-2-[(tert-butoxycarbonyl)amino]-5-hydroxy-6-iodohexanoate (3) and tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-4-[(2R)-oxiranyl]butanoate (4), two amino acid derivatives used in the total synthesis of the bone collagen cross-link (+)-pyridinoline (2a).     

Identification of the radical anions of C2N4S2 and P2N4S2 rings by in situ EPR spectroelectrochemistry and DFT calculations

The previously unknown radical anions of unsaturated E2N4S2 ring systems (E=RC, R2NC, R2P) can be generated voltammetrically by the one-electron reduction of the neutral species and, despite half-lives on the order of a few seconds, have been unambiguously characterized by electron paramagnetic resonance (EPR) spectroelectrochemistry using a highly sensitive in situ electrolysis cell. Cyclic voltammetric studies using a glassy-carbon working electrode in CH3CN and CH2Cl2 with [nBu4N][PF6] as the supporting electrolyte gave reversible formal potentials for the [E2N4S2]0/- process in the range of -1.25 to -1.77 V and irreversible peak potentials for oxidation in the range of 0.66 to 1.60 V (vs the Fc+/0 couple; Fc=ferrocene). Reduction of the neutral compound undergoes an electrochemically reversible one-electron transfer, followed by the decay of the anion to an unknown species via a first-order (chemical) reaction pathway. The values of the first-order rate constant, kf, for the decay of all the radical anions in CH2Cl2 have been estimated from the decay of the EPR signals for (X-C6H4CN2S)2*-, where X=4-OCH3 (kf=0.04 s(-1)), 4-CH3 (kf=0.02 s(-1)), 4-H (kf=0.08 s(-1)), 4-Cl (kf=0.05 s(-1)), 4-CF3 (kf=0.05 s(-1)), or 3-CF3 (kf=0.07 s(-1)), and for [(CH3)3CCN2S]2*- (kf=0.02 s(-1)), [(CH3)2NCN2S]2*- (kf=0.05 s(-1)), and [(C6H5)2PN2S]2*- (kf=0.7 s(-1)). Values of kf for X=4-H and for [(CH3)2NCN2S]2*- were also determined from the cyclic voltammetric responses (in CH2Cl2) and were both found to be 0.05 s(-1). Possible pathways for the first-order anion decomposition that are consistent with the experimental observations are discussed. Density functional theory calculations at the UB3LYP/6-31G(d) level of theory predict the structures of the radical anions as either planar (D2h) or folded (C2v) species; the calculated hyperfine coupling constants are in excellent agreement with experimental results. Linear correlations were observed between the voltammetrically determined potentials and both the orbital energies and Hammett coefficients for the neutral aryl-substituted rings.     

1,2-bis(pyridine-2-carboxamido)benzenate(2-), (bpb)2-: a noninnocent ligand. Syntheses, structures, and mechanisms of formation of [(n-Bu)4N][FeIV2(mu-N)(bpb)2(X)2] (X = CN-, N3-) and the electronic structures of [MIII(bpbox1)(CN)2] (M = Co, Fe)

The well-known tetradentate ligand 1,2-bis(pyridine-2-carboxamido)benzenate(2-), (bpb)2-, and its 4,5-dichloro analogue, (bpc)2-, are shown to be "noninnocent" ligands in the sense that in coordination compounds they can exist in their radical one- and diamagnetic two-electron-oxidized forms (bpbox1)- and (bpbox2)0 (and (bpcox1)- and (bpcox2)0), respectively. Photolysis of high-spin [(n-Bu)4N][FeIII(bpb)(N3)2] and its (bpc)2- analogue in acetone solution at room temperature generates the diamagnetic dinuclear complex [(n-Bu)4N][FeIV2(mu-N)(bpb)2(N3)2] and its (bpc)2- analogue; the corresponding cyano complex [(n-Bu)4N][FeIV2(mu-N)(bpb)2(CN)2] has been prepared via N3- substitution by CN-. Photolysis in frozen acetonitrile solution produces a low-spin ferric species (S = 1/2) which presumably is [FeIII(bpbox2)(N)(N3)]-, as has been established by EPR and M?ssbauer spectroscopy. The mononuclear complexes [(n-Bu)4N][FeIII(bpb)(CN2)] (low spin), [Et4N][CoIII(bpb)(CN)2] and Na[CoIII(bpc)-(CN)2].3CH3OH can be electrochemically or chemically one-electron-oxidized to give [FeIII(bpbox1)(CN)2]0 (S = 0), [CoIII(bpbox1)(CN)2]0 (S = 1/2), and [CoIII(bpcox1)(CN)2]0 (S = 1/2). All complexes have been characterized by UV-vis, EPR, and M?ssbauer spectroscopy, and their electro- and magnetochemistries have been studied. The crystal structures of [(n-Bu)4N][FeIII(bpb)(N3)2].1/2C6H6CH3, Na[FeIII(bpb)(CN)2], Na[CoIII(bpc)(CN)2].3CH3OH, [(n-Bu)4N][FeIV2(mu-N)(bpb)2(CN)2], and [(n-Bu)4N][FeIV2(mu-N)(bpb)(N3)2] have been determined by single-crystal X-ray diffraction.     

Homodinuclear iron thiolate nitrosyl compounds [(ON)Fe(S,S-C6H4)2 Fe(NO)2]- and [(ON)Fe(SO2,S-C6H4)(S,S-C6H4)Fe(NO)2]- with {Fe(NO)}7-{Fe(NO)2}9 electronic coupling: new members of a class of dinitrosyl iron complexes

Reaction of Fe(CO)2(NO)2 and [(ON)Fe(S,S-C6H3R)2]- (R = H (1), CH3 (1-Me))/[(ON)Fe(SO2,S-C6H4)(S,S-C6H4)]- (4) in THF afforded the diiron thiolate/sulfinate nitrosyl complexes [(ON)Fe(S,S-C6H3R)2 Fe(NO)2]- (R = H (2), CH3 (2-Me)) and [(ON)Fe(S,SO2-C6H4)(S,S-C6H4)Fe(NO)2]- (3), respectively. The average N-O bond lengths ([Fe(NO)2] unit) of 1.167(3) and 1.162(4) A in complexes 2 and 3 are consistent with the average N-O bond length of 1.165 A observed in the other structurally characterized dinitrosyl iron complexes with an {Fe(NO)2}9 core. The lower nu(15NO) value (1682 cm(-1) (KBr)) of the [(15NO)FeS4] fragment of [(15NO)Fe(S,S-C6H3CH3)2 Fe(NO)2]- (2-Me-15N), compared to that of [(15NO)Fe(S,S-C6H3CH3)2]- (1-Me-15N) (1727 cm(-1) (KBr)), implicates the electron transfer from {Fe(NO)2}10 Fe(CO)2(NO)2 to complex 1-Me/1 may occur in the process of formation of complex 2-Me/2. Then, the electronic structures of the [(NO)FeS4] and [S2Fe(NO)2] cores of complexes 2, 2-Me, and 3 were best assigned according to the Feltham-Enemark notation as the {Fe(NO)}7-{Fe(NO)2}9 coupling (antiferromagnetic interaction with a J value of -182 cm(-1) for complex 2) to account for the absence of paramagnetism (SQUID) and the EPR signal. On the basis of Fe-N(O) and N-O bond distances, the dinitrosyliron {L2Fe(NO)2} derivatives having an Fe-N(O) distance of approximately 1.670 A and a N-O distance of approximately 1.165 A are best assigned as {Fe(NO)2}9 electronic structures, whereas the Fe-N(O) distance of approximately 1.650 A and N-O distance of approximately 1.190 A probably imply an {Fe(NO)2}10 electronic structure.     

Ketopinic acid and diisoproylideneketogulonic acid as chiral ion-pair selectors in capillary electrophoresis. Enantiomeric impurity analysis of S-timolol and 1R,2S-ephedrine

1S,4R-(+)-ketopinic acid [(+)-KPA] has been introduced as a chiral selector for the separation of pharmacologically active amines by non-aqueous capillary electrophoresis (NACE). (+)-KPA gave enantioresolution for most of the compounds previously separated by 2R,3S,4R,5S-(-)-2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid [(-)-DIKGA], but with a reversed migration order. A complete enantioresolution (Rs=4.2) was obtained for timolol, a compound that could not be resolved using (-)-DIKGA as the selector. Thus, (+)-KPA was evaluated for the enantiomeric purity determination of S-timolol. A method based on pre-concentration by transient isotachophoresis (tITP) provided a limit of detection (LOD) of 0.2% R-timolol in S-timolol samples. Because of the lack of enantioresolution of ephedrine when (+)-KPA was used as the selector, a method with (-)-DIKGA has been developed and validated for determination of the enantiomeric purity of the 1R,2S enantiomer. The method gave good precision and accuracy with an LOD (S/N=3) of 0.033% for the enantiomeric impurity 1S,2R-ephedrine.