- Role of the carbohydrate moieties in chiral recognition on teicoplanin- based LC stationary phases
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For this study, we used the macrocyclic antibiotic teicoplanin, a molecule consisting of an aglycone peptide 'basket' with three attached carbohydrate (sugar) moieties. The sugar units were removed and the aglycone was purified. Two chiral stationary phases (CSPs) were prepared in a similar way, one with the native teicoplanin molecule and the other with the aglycone. Twenty-six compounds were evaluated on the two CSPs with seven RPLC mobile phases and two polar organic mobile phases. The compounds were 13 amino acids or structurally related compounds (including DOPA, folinic acid, etc.) and 13 other compounds (such as carnitine, bromacil, etc.). The chromatographic results are given as the retention, selectivity, and resolution factors along with the peak efficiency and the enantioselective free energy difference corresponding to the separation of the two enantiomers. The polarities of the two CSPs are similar. It is clearly established that the aglycone is responsible for the enantioseparation of amino acids. The difference in enantioselective free energy between the aglycone CSP and the teicoplanin CSP was between 0.3 and 1 kcal/mol for amino acid enantioseparations. This produced resolution factors 2-5 times higher with the aglycone CSP. Four non amino acid compounds were separated only on the teicoplanin CSP. Six and five compounds were better separated on the teicoplanin and aglycone CSPs, respectively. Although the sugar units decrease the resolution of α-amino acid enantiomers, they can contribute significantly to the resolution of a number of non amino acid enantiomeric pairs.
- Berthod, Alain,Chen, Xianghong,Kullman, John P.,Armstrong, Daniel W.,Gasparrini, Francesco,D'Acquarica, Ilaria,Villani, Claudio,Carotti, Angelo
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- First and second generation-total synthesis of the teicoplanin aglycon
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Full details of studies leading to the total synthesis of the teicoplanin aglycon are provided. Key elements of the first generation approach (26 steps from constituent amino acids, 1% overall) include the coupling of an EFG tripeptide precursor to the common vancomycin/teicoplanin ABCD ring system and sequential DE macrocyclization of the 16-membered ring with formation of the diaryl ether via a phenoxide nucleophilic aromatic substitution of an o-fluoronitroaromatic (80%, 3:1 atropisomer diastereoselection) followed by 14-membered FG ring closure by macrolactamization (66%). Subsequent studies have provided a second generation total synthesis which is shorter, more convergent, and highly diastereoselective (22 steps, 2% overall). This was accomplished by altering the order of ring closures such that FG macrolactamization (95%) preceded coupling of the EFG tripeptide to the ABCD ring system and subsequent DE ring closure. Notably, DE macrocyclization via diaryl ether formation on substrate 57, the key intermediate in the latter approach incorporating the intact FG ring system, occurred with exceptional diastereoselection for formation of the natural atropisomer (> 10:1, 76%) without problematic C23 epimerization provided the basicity of the reaction is minimized.
- Boger,Seong Heon Kim,Mori,Weng,Rogel,Castle,McAtee
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p. 1862 - 1871
(2007/10/03)
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- Thermal atropisomerism of teicoplanin aglycon derivatives: Preparation of the P,P,P and M,P,P atropisomers of the teicoplanin aglycon via selective equilibration of the DE ring system
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The degradation of teicoplanin to a series of key aglycon derivatives, including those containing a cleaved FG ring system, and a study of their thermal atropisomerism are detailed. In all cases, selective equilibration of the DE ring system was observed to provide a 1:1 mixture of P:M atropisomers under conditions in which the AB and CD atropisomer stereochemistry were unaffected. The DE atropisomer equilibration was found to occur with an E(a) of 29.3 and 24.8-25.2 kcal/mol for 6a (FG ring system intact) and 10/12 (cleaved FG ring system), respectively, which is comparable to that of a vancomycin aglycon DE ring system (E(a) = 23.6 kcal/mol) and more facile than the CD (E(a) = 30.4 kcal/mol) or O-methylated AB ring system (E(a) = 37.8 kcal/mol). Consistent with intuitive expectations, the intact teicoplanin FG ring system slowed the rate of isomerization, contributing ca. 4.0 kcal/mol to the E(a) (6a vs 10), and the bulky C23 substituent on teicoplanin acyclo FG derivatives had a much less significant effect, contributing only 1-1.5 kcal/mol to the E(a) relative to the vancomycin aglycon. Neither precludes selective equilibration of the DE ring system, and neither had an effect on the thermodynamic ratio of the resulting atropisomers (1:1). Resynthesis of the teicoplanin aglycon (P,P,P-2) from 8 as a prelude to the synthesis of the teicoplanin aglycon unnatural DE atropisomer (M,P,P-17) from 13 is described and provides the final stages of a teicoplanin aglycon total synthesis and a key structural analogue. The comparative evaluation of 2 and 17 revealed that the DE atropisomer stereochemistry substantially impacts the antimicrobial activity (2 > 17, 50-fold) and the binding affinity for N,N'-Ac2-L-Lys-D-Ala-D-Ala (2 > 17, K(a) = 2.4 x 106 vs 1.9 x 104 M-1, 125 times).
- Boger,Weng,Miyazaki,McAtee,Castle,Kim,Mori,Rogel,Strittmatter,Jin
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p. 10047 - 10055
(2007/10/03)
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- Kinetics and thermodynamics of binding of a model tripeptide to teicoplanin and analogous semisynthetic antibiotics
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The thermodynamics and kinetics of binding of model tripeptides ε-N-acetyl-α-N-dansyl-L-Lys-D-Ala-D-Ala (ADLAA) or α-N,ε-N-diacetyl-L-Lys-D-Ala-D-Ala (AALAA) to teicoplanin (1a) and a series of semisynthetic derivatives with (1b-f) or devoid of (2a-g) the glycidic side arms and modified at the terminal amino acids of the peptide backbone have been studied by fluorescence or UV spectroscopy. The binding process is suggested to occur via a two-step mechanism. The first, fast process is likely governed by an electrostatic interaction between the C- and N-termini of the peptide chain of the substrate and of the antibiotic, respectively, while the second slower one, accounts for the formation of the hydrogen bonds responsible of the major contribution to the overall binding energy. The binding constants with all modified derivatives are smaller than that with native teicoplanin. Larger modification of the overall binding constant are observed when the sugar residues are removed and, to a lower extent, when the N-terminus of the peptide chain is acylated. The kinetic process is very little affected by the modifications introduced.
- Scrimin, Paolo,Tecilla, Paolo,Tonellato, Umberto,Verzini, Massimo,Andreini, Bianca Patrizia,Coutant, John E.,Zerilli, Luigi F.
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p. 6268 - 6272
(2007/10/03)
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- Structure Elucidation of the Teicoplanin Antibiotics
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By a combination of chemical, 1H and 13C NMR, and mass spectrometric studies, the structures of the five major components of the antibiotic teicoplanin, produced by Actinoplanes teichomyceticus, have been elucidated.The components all have structures closely related to those of the glycopeptide antibiotics of the vancomycin group.The teicoplanin components are differentiated from one another by the presence of various N-acylglucosamine moieties, where the acyl group is a C10 or C11 fatty acid.Such groups are not present in any other known member of the vancomycin group.
- Barna, Jennifer C. J.,Williams, Dudley H.,Stone, David J. M.,Leung, T.-W. Christina,Doddrell, David M.
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p. 4895 - 4902
(2007/10/02)
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