Enantioselective partial reduction of 2,5-disubstituted pyrroles via a chiral protonation approach

[reaction: see text] The partial reduction of 2,5-pyrrole diester 1 followed by enantioselective protonation in situ to furnish synthetically useful building blocks is described. An enantiomeric excess of up to 74% was achieved using (-)-ephedrine and related analogues as chiral proton sources. The pyrroline product obtained could be recrystallized to give enantiomerically pure material.     

Electrochemical reduction of uracil in dimethyl sulfoxide: Autoprotonation of the anion radical

The electrochemical reduction of uracil in dimethyl sulfoxide was investigated, using d.c.and a.c. polarography, cyclic voltammetry, and controlled potential electrolysis. Uracil is reduced in a one-electron step (E_1/2=?2.3 V); the apparent number of electrons transferred (n) decreases from one at infinite dilution to one-half at concentrations above 1mM. The concentration dependent n-value is due to proton transfer by the parent compound to the radical anion formed on reduction. Such a proton transfer, which has been observed for 2-hydroxypyrimidine, deactivates part of the uracil, which would otherwise be available for reduction, by formation of the more difficultly reducible conjugate base. The uracil anion forms insoluble mercury salts, producing two oxidation waves (E_1/2 of ?0.1 and ?0.3 V); the latter wave is due to formation of a passivating film on the electrode. Digital simulations indicate that the protonation rate exceeds 10⁵M^?1 s^?1 and that, at low uracil concentration, some of the free radical formed on protonation is further reduced. At concentrations exceeding 1 mM, all of the free radical dimerizes. The effect of added acids and base on the electrochemical behavior is described.     

Structural variations of potassium aryloxides

A series of potassium aryloxides (KOAr) were isolated from the reaction of a potassium amide (KN(SiMe(3))(2)) and the desired substituted phenoxide (oMP, 2-methyl; oPP, 2-iso-propyl; oBP, 2-tert-butyl; DMP, 2,6-di-methyl; DIP, 2,6-di-iso-propyl; DBP, 2,6-di-tert-butyl) in tetrahydrofuran (THF) or pyridine (py) as the following: [([K(mu(4)-oMP)(THF)][K(mu(3)-oMP)])(5)]( infinity ) (1), [[K(6)(eta(6),mu(3)-oMP)(4)(eta(6),mu(4)-oMP)(2)(py)(4)].[K(6)(eta(6),mu(3)-oMP)(6)(eta(6)-py)(4)]]( infinity ) (2), [K(mu(3)-oPP)](4)(THF)(3) (3), [K(4)(eta(6),mu(3)-oPP)(2)(mu(3)-oPP)(2)(py)(3)]( infinity ) (4), [K(mu(3)-oBP)(THF)](6) (5), [K(6)(eta(6),mu(3)-oBP)(2)(mu(3)-oBP)(4)(py)(4)]( infinity ) (6), [K(3)(eta(6),mu(3)-DMP)(2)(mu-DMP)(THF)]( infinity ) (7), [[K(eta(6),mu-DMP)(py)](2)]( infinity ) (8), [K(eta(6),mu-DIP)]( infinity ) (9), [K(eta(6),mu-DBP)]( infinity ) (10). Further exploration of the aryl interactions led to the investigation of the diphenylethoxide (DPE) derivative which was isolated as [K(mu(3)-DPE)(THF)](4) (11) or [K(mu(3)-DPE)(py)](4).py(2) (12) depending on the solvent used. In general, the less sterically demanding ligands (oMP, oPP, oBP, and DMP) were solvated polymeric species; however, increasing the steric bulk (DIP and DBP) led to unsolvated polymers and not discrete molecules. For most of this novel family of compounds, the K atoms were pi-bound to the aryl rings of the neighboring phenoxide derivatives to fill their coordination sites. The synthesss and characterization of these compounds are described in detail.     

Study of the neurotransmitter dopamine and the neurotoxin 6-hydroxydopamine by electrospray ionization coupled with tandem mass spectrometry

Electrospray ionization combined with tandem mass spectrometry has been applied to a study of dopamine and 6-hydroxydopamine, an important neurotransmitter and a well-known neurotoxin, respectively. Both protonated and deprotonated molecules were observed for the two compounds. Upon collision-induced dissociation of protonated and deprotonated 6-hydroxydopamine molecules, the number of fragmentation pathways observed was greater than that observed with protonated and deprotonated dopamine molecules; the greater proclivity to fragment of the former is due to the 6-substituted hydroxyl group, which is para to the 3-OH group and ortho to the CH2CH2NH2 group. Furthermore, 6-hydroxydopamine showed a greater propensity to oxidize than did dopamine when sample solutions were kept uncovered in the air for 24 h prior to mass spectrometric examination. Radical structures of the four main oxidation products of 6-hydroxydopamine have been suggested on the basis of their product ion mass spectra; one or more of these oxidation products may be responsible for the cytotoxic property of 6-hydroxydopamine.     

Synthesis and characterization ofM 2(CCR)4(PMe3)4 dimetallapolyynes

The reaction betweenM ₂Cl₄(PMe₃)₄ (M = Mo, W) and four equivalents of LiCCR (R = Me,i-Pr,t-Bu, SiMe₃, Ph) in dimethoxyethane solution yields alkynyl-substituted, quadruply bonded complexes of the type M₂(CCR )₄(PMe₃)₄ in 10–90% yield. The electronic-absorption and¹H-,¹³ ₁₃C-, and³¹P-NMR spectroscopic data for these dimetallapolyyne complexes indicate that they are uncontaminated by chloride-containing impurities, and that they possess theD _2d geometry expected of compounds of the M₂X₄L₄ type. A single-crystal X-ray diffraction study of Mo₂(CCPr ⁱ )₄(PMe₃)₄ confirms this latter conclusion, and also reveals that the Mo₂ core of the complex is three-way disordered within the ordered quasi-cubic array of ligating atoms.     

CO rebinding to protoheme: investigations of the proximal and distal contributions to the geminate rebinding barrier

The rebinding kinetics of CO to protoheme (FePPIX) in the presence and absence of a proximal imidazole ligand reveals the magnitude of the rebinding barrier associated with proximal histidine ligation. The ligation states of the heme under different solvent conditions are also investigated using both equilibrium and transient spectroscopy. In the absence of imidazole, a weak ligand (probably water) is bound on the proximal side of the FePPIX-CO adduct. When the heme is encapsulated in micelles of cetyltrimethylammonium bromide (CTAB), photolysis of FePPIX-CO induces a complicated set of proximal ligation changes. In contrast, the use of glycerol-water solutions leads to a simple two-state geminate kinetic response with rapid (10-100 ps) CO recombination and a geminate amplitude that can be controlled by adjusting the solvent viscosity. By comparing the rate of CO rebinding to protoheme in glycerol solution with and without a bound proximal imidazole ligand, we find the enthalpic contribution to the proximal rebinding barrier, H(p), to be 11 +/- 2 kJ/mol. Further comparison of the CO rebinding rate of the imidazole bound protoheme with the analogous rate in myoglobin (Mb) leads to a determination of the difference in their distal free energy barriers: DeltaG(D) approximately 12 +/- 1 kJ/mol. Estimates of the entropic contributions, due to the ligand accessible volumes in the distal pocket and the xenon-4 cavity of myoglobin ( approximately 3 kJ/mol), then lead to a distal pocket enthalpic barrier of H(D) approximately 9 +/- 2 kJ/mol. These results agree well with the predictions of a simple model and with previous independent room-temperature measurements of the enthalpic MbCO rebinding barrier (18 +/- 2 kJ/mol).     

Separation characteristics of alkylated guanines in high-performance liquid chromatography

The retention behavior of thirteen alkylated guanines on normal-phase silica gel and amino columns and on reversed-phase ODS and phenyl columns was studied. The larger the alkyl substituent at the same position of guanine the weaker was the retention in the normal-phase chromatographic system and the greater the retention during reversed-phase chromatography. O6-Derivatives possess the lowest polarity in each set of isomers. An amino column was found to be of highest efficiency in terms of separation of the set of ethylguanine isomers and of benzylguanines studied. A phenyl column provided the best resolution of methylated guanines.     

Tandem mass spectrometry with online high-flow reversed-phase extraction and normal-phase chromatography on silica columns with aqueous-organic mobile phase for quantitation of polar compounds in biological fluids

In this work, high-flow online reversed-phase extraction was coupled with normal phase on silica columns with aqueous-organic mobile phase liquid chromatography/tandem mass spectrometry (LC/MS/MS) to quantify drug candidates in biological fluids. The orthogonal separation effect obtained from this configuration considerably reduced matrix effects and increased sensitivity for highly polar compounds as detected by selected reaction monitoring. This approach also significantly improved the robustness and limit of detection of the assays. An evaluation of this system was performed using a mixture of albuterol and bamethan in rat plasma. Assay validation demonstrated acceptable accuracy (< 8% difference) and precision (< 6% CV) for these model compounds. The system has been used for the quantitation of polar ionic compounds in biological fluids in support of drug discovery programs. This assay was used to analyze samples for a BMS proprietary compound (A) in a rat pharmacokinetic study and is shown as an example to demonstrate the precision, accuracy, and sufficient sensitivity of this system.     

Transition metal ion complexes of thiosemicarbazones derived from 2-acetylpyridine. Part 7. Chemical and antifungal properties of 2-acetylpyridine4 N-ethylthiosemicarbazone and its metal complexes

Summary Spectral and thermal information, as well as activity againstAspergillus niger, have been obtained for 2-acetylpyridine⁴ N-ethylthiosemicarbazone and its iron(III), cobalt(II,III), nickel(II) and copper(II) complexes.     

Total assignment of the proton and carbon NMR spectra of the alkaloid quindoline — utilization of HMQC-TOCSY to indirectly establish protonated carbon-protonated carbon connectivities

The reisolation of the indoloquinoline alkaloid quindoline (also known as norcryptolepine) from Cryptolepis sanguinolenta is reported. The structure was unequivocally confirmed by two-dimensional nmr methods; the proton and carbon spectra were assigned for the first time. Because of congestion in the proton spectrum HMQC-TOCSY was used as an alternative to the more familiar COSY experiment. In addition to establishing proton-proton connectivities, HMQC-TOCSY affords the added benefit of providing, in an indirect sense, connectivity information between protonated carbons.