Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

A novel microwave-assisted solid-phase peptide synthesis utilizing N-Fmoc-protected(α-aminoacyl)benzotriazoles was applied in the preparation of tri-, tetra-, penta-, hexa-, and heptapeptides in 71% average crude yield.

The B3LYP/6-31 + G(d) molecular geometry optimized structures of 17 five-membered heterocycles were employed together with the gauge including atomic orbitals (GIAO) density functional theory (DFT) method at the B3LYP/6-31 + G(d,p), B3LYP/6-311 + + G(d,p) and B3LYP/6-311 + G(2d,p) levels of theory for the calculation of proton and carbon chemicals shifts and coupling constants. The method of geometry optimization for pyrrole (1), N-methylpyrrole (2) and thiophene (7) using the larger 6-311 + + G(d,p) basis sets at the B3LYP/6-31 + G(d,p), B3LYP/6-311 + + G(d,p), B3LYP/6-31 + G(2d,p) and B3LYP/cc-pVTZ levels of theory gave little difference between calculated and experimental values of coupling constants. In general, the ¹H and ¹³C chemical shifts for all compounds are in good agreement with theoretical calculations using the smaller 6-31 basis set. The values of ⁿJ_HH(n = 3, 4, 5) and ^rmnJ_CH(n = 1, 2, 3, 4) were predicted well using the larger 6-31 + G(d,p) and 6-311 + + G(d,p) basis sets and at the B3LYP/6-31 + G(d,p), B3LYP/6-311 + + G(d,p), B3LYP/6-31 + G(2d,2p) levels of theory. The computed atomic charges [Mülliken; Natural Bond Orbital Analysis (NBO); Merz-Kollman (MK); CHELP and CHELPG] for the B3LYP/6-311 + + G(d,p) geometry optimized structures of 1–17 were used to explore correlations with the experimental proton and carbon chemical shifts. Copyright © 2007 John Wiley & Sons, Ltd.

The GIAO (Gauge Including Atomic Orbitals) DFT (Density Functional Theory) method is applied at the B3LYP/6–31+G(d,p)//B3LYP/6–31+G(d), B3LYP/6–311++G(d,p)//B3LYP/6–31+G(d), B3LYP/6–311+G (2d,p)//B3LYP/6–31+G(d) and B3LYP/6–311++G(d,p)//B3LYP/6–311++G(d,p) levels of theory for the calculation of proton and carbon chemicals shifts and coupling constants for 25 nitro-substituted five-membered heterocycles. Difference (1D NOE) spectra in combination with long-range gHMBC experiments were used as tools for the structural elucidation of nitro-substituted five-membered heterocycles. The assigned NMR data (chemical shifts and coupling constants) for all compounds were found to be in good agreement with theoretical calculations using the GIAO DFT method. The magnitudes of one-bond (¹J_CH) and long-range (ⁿJ_CH, n > 1) coupling constants were utilized for unambiguous differentiation between regioisomers of nitro-substituted five-membered heterocycles. Copyright © 2006 John Wiley & Sons, Ltd.

Dipeptides 3a–g, (3a + 3a′), (3d + 3d′), (3l + 3l′)^a and tripeptides 6a–e, (6b + 6b′), (6e + 6e′) incorporating Z^ε-Lys were prepared in high yields (70–95%) and enantiopurity (≥97%) in partially aqueous acetonitrile solution by coupling using (i) Z^ε-Lys with N-(Z- and Fmoc-aminoacyl)benzotriazoles 1a–g, (ii) Z^ε-Lys with N-Z-dipeptidoylbenzotriazoles 5a–c, and (iii) N-Fmoc^α-Z^ε-l-Lys-Bt 1h and amino acids 2a,c–e. Unnatural dipeptides 3h–j, (3h + 3h′) and tripeptides 6f were similarly prepared from Z^α-Lys. Retention of chirality was demonstrated by parallel experiments involving l-Ala, dl-Ala, l-Met, and dl-Met by NMR and HPLC analysis.

Aspartic and glutamic acids were selectively extended at each of the alternative C-terminals under mild conditions to afford diverse natural and unnatural N-protected dipeptides and tripeptides in yields of 73–96%. The reactions between N-protected (α-aminoacyl)benzotriazoles and free amino acids or dipeptides proceeded with complete retention of chirality as supported by parallel experiments involving d-Ala, l-Ala, and dl-Ala in the preparation of dipeptides and tripeptides, monitored by NMR and HPLC analyses.

Twenty-eight novel salts with tetramethyl-, tetraethyl-, and tetrabutylammonium and 1-butyl-3-methylimidazolium cations paired with 3,5-dinitro-1,2,4-triazolate, 4-nitro-1,2,3-triazolate, 2,4-dinitroimidazolate, 4,5-dinitroimidazolate, 4,5-dicyanoimidazolate, 4-nitroimidazolate, and tetrazolate anions have been prepared and characterized by using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and single-crystal X-ray crystallography. The effects of cation and anion type and structure on the physicochemical properties of the resulting salts, including several ionic liquids, have been examined and discussed. Ionic liquids (defined as having m.p.<100 °C) were obtained with all combinations of the 1-butyl-3-methylimidazolium cation ([C₄mim]⁺) and the heterocyclic azolate anions studied, and with several combinations of tetraethyl or tetrabutylammonium cations and the azolate anions. The [C₄mim]⁺ azolates were liquid at room temperature exhibiting large liquid ranges and forming glasses on cooling with glass-transition temperatures in the range of −53 to −82 °C (except for the 3,5-dinitro-1,2,4-triazolate salt with m.p. 33 °C). Six crystal structures of the corresponding tetraalkylammonium salts were determined and the effects of changes to the cations and anions on the packing of the structure have been investigated.

An operationally straightforward and efficient benzotriazole-based method for the guanylation of diverse amines by use of the new reagent classes (bis-benzotriazol-1-yl-methylene)amines 13a–13f and benzotriazole-1-carboxamidines 17a–17i is described. The preparation is described for a variety of both acyclic and cyclic 1,2,3-trisubstituted guanidines in high yields.

¹H and ¹³C NMR data for N-substituted morpholines 1–20 were measured using 1D (DEPT, 1D NOE difference) and 2D NMR spectroscopic methods including ¹H–¹H COSY, long-range ¹H–¹H COSY, NOESY, gHMBC and gHMQC experiments. At room temperature the ¹H NMR spectra of protonated compounds 2 and 9 show the chair conformation for the morpholine ring. Spin–spin coupling constants were deduced from the resolution-enhanced proton spectra. Copyright © 2005 John Wiley & Sons, Ltd.

The temperature-dependent ¹H and ¹³C NMR spectra of 2-(2-butynyl)-10-methyl-1,2,3,4-tetrahydropyrazino[1,2-a]indole (4) (as a representative example of 1–9) in CFCl₃ + CD₂Cl₂ solution are described and discussed. Below 183 K, the hexahydropyrazine ring inversions become slow on the NMR time-scale and 4 exists in principle as two conformational diastereomers. In fact, only one was observed with the N-2 substituent in an equatorial position as shown by a low-temperature NOESY experiment. The energy barrier for conformational interchange was calculated from NMR data to be 8.3 kcal mol⁻¹ (1 kcal = 4.184 kJ), in agreement with quantum chemical calculations. Unambiguous assignments for all proton and carbon resonances of 1–9 were made using 1D (APT, DEPT, NOE difference) and 2D (COSY, NOESY, gHMQC, gHMBC) NMR techniques. Copyright © 2005 John Wiley & Sons, Ltd.

Regioselective addition of allylthiol at the C-3 position adjacent to the nitrogen carrying the phenyl group of the 1,4-phenylenediamine moiety of compounds 1–4 was rigorously confirmed by 1D NOE difference in combination with gHMBC experiments. The structures of 1,4-phenylenediamines 1–4, allylsulfanyl-N¹-alkyl-N⁴-phenyl-1,4-phenylenediamines 5–8 and cyclization products 9–14 were completely analyzed in both CDCl₃ and DMSO-d₆ solutions. The ¹H and ¹³C NMR spectra of 10 and 11, which contain two chiral centers, exhibit duplication for several signals, indicating the existence of two diastereomeric forms. The full structures of 5 and 9 were unambiguously confirmed by x-ray crystallography. The ¹H and ¹³C NMR spectra of all compounds were assigned using one- and two-dimensional NMR techniques (APT, DEPT, 1D NOE difference, COSY, NOESY, HETCOR, gHMQC and gHMBC). Copyright © 2004 John Wiley & Sons, Ltd.

Nucleophilic addition of alkyl- and benzylthiols to benzoquinone diimine (1) gave the corresponding 3-alkylthio- or 3-benzylthio-1,4-phenylenediamines (2–5). However, addition of aryl- or heteroarylthiols to 1 formed 2-arylthio- or 2-heteroarylthio-1,4-phenylenediamines (6–14). The structures of 2–14, obtained in 55–91% yields, were confirmed in CDCl₃ or DMSO-d₆ solution using 1D (NOE difference, coupled ¹³C NMR spectra, APT and DEPT) and 2D NMR techniques [DQCOSY, NOESY, HETCOR and heteronuclear multiple bond coherence (HMBC)] that resulted in unambiguous proton and carbon NMR resonance assignments. The substituent-induced ¹³C NMR chemical shift differences were calculated in 2–14 relative to carbon atoms in the model compound N¹-(1,3-dimethylbutyl)-N⁴-phenyl-1,4-phenylenediamine (DMBPPD) (15) (a reduced form of benzoquinone diimine). Copyright © 2004 John Wiley & Sons, Ltd.

The ¹H and ¹³C NMR spectra of compounds 1–11 and 16–22 in CDCl₃ and DMSO-d₆ solutions allowed structural assignment to regioisomers 1/5 and 2/6 and their regioselective cyclization products 16–18 utilizing one- and two-dimensional NMR techniques (APT, DEPT, NOE difference, COSY, NOESY, HETCOR and gHMQC, gHMBC). Temperature-dependent ¹H NMR spectra of 8-anilino-5-(4-methyl-2-pentyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (18) indicated a free energy of activation (ΔG^‡) of ca 17 kcal mol⁻¹ for interconversion between rotamers. The ¹H and ¹³C NMR spectra of 20 and 22 containing two chiral centers exhibit duplication of several signals, indicating the existence of two diastereomeric forms. The structure of 4 was unambiguously confirmed by x-ray crystallography. Copyright © 2004 John Wiley & Sons, Ltd.

Assignments of the proton and carbon NMR signals for 2-(benzotriazol-1-yl)tetrahydrofurans 1–6 are based on ¹H–¹H COSY, NOESY, ¹H–¹³C heteronuclear HETCOR, ¹H–¹³C heteronuclear long-range HETCOR-LR and nuclear Overhauser enhancement experiments, and supported by selective spin decoupling experiments. The electronic and steric effects of the 2-benzotriazolyl substituent on the ¹H and ¹³C NMR chemical shifts are evaluated and discussed. Conformational isomers cis and trans are distinguished by the magnitude of the J_{(H−2,H−3)} coupling constant, by one-bond ¹J_{(C−2, H−2)} coupling constants and by ¹³C chemical shifts of the C-2 anomeric carbon. The benzotriazol-1-yl group prefers the pseudo-axial orientation in each of 1–6. The stereochemistry and conformation of 6 are rigorously demonstrated by an x-ray structure. Copyright © 2003 John Wiley & Sons, Ltd.

The overall five-parameter QSAR correlation [ in terms of log(IGC₅₀⁻¹)] based on CODESSA-PRO methodology for the aquatic toxicity of 97 substituted nitrobenzenes to the ciliate Tetrahymena pyriformis supports previous conclusions that hydrophobicity and electrophilic reactivity control nitrobenzene toxicity. Correcting for the ionization of acidic species (picric and nitrobenzoic acids) improves the results: . Consideration of the total set of 97 compounds suggests two mechanisms of toxic action. A subset containing 43 compounds favorably disposed to reversible reduction of nitro group with respect to the single occupied molecular orbital energy, E^SOMO correlated well with just four theoretically derived descriptors: . Another set of 49 substances predisposed to aromatic nucleophilic substitution modeled well () with five descriptors. Copyright © 2003 John Wiley & Sons, Ltd.

The oxidation of symmetrical disulfides [D,L-cystine (1) and 3,3′-dithiobis(propionic acid) (2)] with hydrogen peroxide in D₂O–NaOH solution (pH 10–11) was studied by NMR spectroscopy. Assignments of the proton and carbon NMR signals of starting materials (1 and 2) and products of oxidation are based on conventional 1D NMR methods (DEPT, selective spin decoupling). Formation of C—S bond cleavage products or, in case of 2, partially oxidized intermediates was not detected. The accelerating effect of Cu²⁺ cations, but not Fe³⁺ cations, on the oxidation rate of 1 in basic medium was demonstrated. Copyright © 2002 John Wiley & Sons, Ltd.

Structure elucidation of compounds in the benzisoxazole series (1–6) and naphtho[1,2-d][1,3]- (7–10) and phenanthro[9,10-d][1,3]oxazole (11–14) series was accomplished using extensive 2D NMR spectroscopic studies including ¹H–¹H COSY, long- range ¹H–¹H COSY, ¹H–¹³C COSY, gHMQC, gHMBC and gHMQC-TOCSY experiments. The distinction between oxazole and isoxazole rings was made on the basis of the magnitude of heteronuclear one-bond ¹J_{C2, H2} (or ¹J_{C3, H3}) coupling constants. Complete analysis of the ¹H NMR spectra of 11–14 was achieved by iterative calculations. Gradient selected gHMQC-TOCSY spectra of phenanthro[9,10-d][1,3]oxazoles 11–14 were obtained at different mixing times (12, 24, 36, 48 and 80 ms) to identify the spin system where the protons of phenanthrene ring at H-5, H-6 and at H-9 and H-7 and H-8 were highly overlapping. Copyright © 2003 John Wiley & Sons, Ltd.