Synthesis and NMR studies of malonyl-linked glycoconjugates of N-(2-aminoethyl)glycine. Building blocks for the construction of combinatorial glycopeptide libraries

Four glycoconjugate building blocks for the construction of combinatorial PNA like glycopeptide libraries were prepared in 75–79% yield by condensing tert-butyl N-[2-(N-9-fluorenylmethoxycarbonylamino)ethyl]glycinate (AEG) 5 with 3-oxo-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosylamino)- (6a), 3-oxo-3-(β-D-galactopyranosylamino)- (6b), 3-oxo-3-(2-acetamido-2-deoxy-3,4,6-tetra-O-acetyl-β-D-glucopyranosylamino)- (6c) and 3-oxo-3-(2-acetamido-2-deoxy-3,4,6-tetra-O-acetyl-β-D-galactopyranosylamino)propanoic acid (6d), respectively. The resulting AEG glycoconjugates 1a–d were converted into the corresponding free acids 2a–d in 97–98% yield by treatment with aqueous formic acid. The Fmoc group of compound 1c was removed and the intermediate amine 9 was condensed with 2a to afford the corresponding glycosylated AEG dipeptide 4 in 58% yield. All glycoconjugate building blocks showed the presence of cis and trans rotamers. Compounds 1a, 1b and 4 were subjected to temperature dependent 1H NMR spectroscopy in order to determine the coalescence temperature which resulted in calculated rotation barriers of 17.9–18.3 kcal/mol for the rotamers.

Rhodium-catalyzed asymmetric reactions with a dynamic library of chiral tropos phosphorus ligands

Nineteen chiral tropos phosphorus ligands, based on a flexible (tropos) biphenol unit and a chiral P-bound alcohol (11 phosphites) or secondary amine (8 phosphoramidites), were screened, individually and as a combination of two, in various Rh-catalyzed asymmetric reactions. In the Rh-catalyzed asymmetric conjugate addition of phenylboronic acid to cyclic enones, enantiomeric excesses (ee's) up to 95 % were obtained with a 1:1 mixture of a phosphite [derived from (1R,2S)-2-(1-methyl-1-phenylethyl)cyclohexanol] and a phosphoramidite [derived from (S,S)-2,5-diphenylpyrrolidine]. In the mixed Rh precatalyst, which was characterized via 31P-NMR, the biphenol-derived phosphite is free to rotate (tropos) while the biphenol-derived phosphoramidite shows a temperature-dependent tropos/atropos behavior (coalescence temperature = 310 K). The ligands were also screened in the hydrogenation of dehydro-α-amino acids and dehydro-β-amino acids. Ee's up to 98% were obtained for the dehydro-α-amino acids, using the combination of a phosphite [derived from (1R,2S)-2-phenyl-1-cyclohexanol] and a phosphoramidite [derived from (S,S)-bis(α-methylbenzyl)amine]. The reaction was optimized by lowering the phosphite/phosphoramidite ratio to 0.25:1.75 with a resulting improvement of the product ee.

Determination of the Accurate Values of the Rate Constant and Thermodynamic Parameters for the Rotation About the C(sp2)-C(aryl) Bond; Adamantan-1-yl 3-Bromo-2,4,6-trimethylphenyl Ketone

Four programs for the 1H NMR line shape analysis: two commercial - Winkubo (Bruker) and DNMR5 (QCPE 165) and two written in our laboratory - Newton (in Microsoft Excel) and Simtex (in Matlab) have been tested in order to get highly accurate rate constants of the hindered rotation about a single bond. For this purpose four testing criteria were used, two of them were also developed by us. As supplementary determinations the rate constants obtained for the coalescence temperature and for the thermal racemization of chromatographically separated enantiomers were used which fitted well the temperature dependence of the rate constants determined by the line shape analysis. As a test compound adamantan-1-yl 3-bromo-2,4,6-trimethylphenyl ketone was prepared and studied. It was shown that supermodified simplex method used in our algorithm (Simtex), though time consuming, gives the most accurate values of the rate constants and consequently the calculated thermodynamic parameters Ea, ∆H≠, and ∆S≠ lay in relatively narrow confidence intervals.

Keto-Enol Tautomerism of Dimedone Studied by Dynamic NMR

The keto-enol tautomeric equilibrium of dimedone has been investigated by high-resolution 13C NMR spectroscopy. Kinetic information of the solution keto-enol tautomerism for dimedone in DMSO, in the temperature range of 25–85 °C, was derived from line shape measurements in a 75-MHz spectrometer. A value of 3.43 Kcal/mol was found for the Arrhenius activation energy Ea and of 1.07 × 106 s−1 for the pre-exponential factor A. With the use of the observed chemical shifts in the high-resolution 13C-NMR spectra of dimedone in the solid state, an estimate coalescence temperature of 240 K for dimedone in DMSO was obtained by extrapolation of the experimental curve. The estimated free energy of activation at the coalescence temperature, Δ Gc≠, is 10.8 Kcal/mol. Finally, the 13C spin-lattice relaxation times, T1(13C), in solid dimedone were measured as a function of temperature in the range of 25 to 90 °C. The data are discussed in terms of the different motional environments that result from the geometric restrictions imposed by hydrogen bonding in the crystal structure.

Proton nuclear magnetic resonance studies of nucleosides: hindered internal rotation in N-dimethylaminomethylene derivatives of adenosine, guanosine, and cytidine

Studies of the internal rotation about the C—N bond of the dimethylaminomethylene (DMAM) group of DMAM-adenosine, 1, DMAM-guanosine, 2, and DMAM-cytidine, 3, was determined by high-resolution 1H NMR spectroscopy. Arrhenius plots (ln k = ln A − Ea/RT) were used to determine the barriers to internal rotation, Ea, of the compounds. They were found to be 58.0 ± 2.4 kJ mol−1, 71.2 ± 1.4 kJ mol−1, and 62.8 ± 2.4 kJ mol−1 for 1, 2, and 3, respectively. At the same time the coalescence temperatures, tc, for the compounds were determined and found to be 93.5 °C for 1, 124.7 °C for 2, and 119.6 °C for 3 in DMSO. In D2O, compound 1 was found to have a tc of 104.5 °C. The compound decomposed so rapidly at this temperature that the barrier to internal rotation could not be determined. The results indicate that the oxo function in the nucleobase has a considerable effect on the barrier to internal rotation and coalescence temperature.