The complex p-[Co(tren){NH(2)CH(2)C(O)CH(3)}](ClO(4))(3).H(2)O was produced stereoselectively from [Co(tren)(O(3)SCF(3))(2)]O(3)SCF(3) () and 2-(aminomethyl)-2-methyl-1,3-dioxolane. The structure of was determined by X-ray crystallography. The complex is the first aminoacetone chelate to be reported and the first structurally characterized example of a non-conjugated ketone moiety coordinated to cobalt(iii). The robust complex was stable to aquation in strong acid and behaved as an acid with pK(a) = 4.99(1) indicative of a strong activation of the aminoacetone ligand towards deprotonation. The complex constitutes a structural model for a proposed substrate binding mode relevant for substrate activation of the zinc(ii)-dependent enzyme 5-aminolaevulinic acid dehydratase.
Peptidyl privileged structures have been widely used by many groups to discover biologically active molecules. In this context, privileged substructures are used as "hydrophobic anchors", to which peptide functionality is appended to gain specificity. Utilization of this concept has led to the discovery of many different active compounds at a wide range of biological receptors. A synthetic approach to these compounds has been developed on a "safety-catch" linker that allows rapid preparation of large libraries of these molecules. Importantly, amide bond formation/cleavage through treatment with amines is the final step; it is a linker strategy that allows significant diversification to be easily incorporated, and it only requires the inclusion of an amide bond. In addition, chemistry has been developed that permits the urea moiety to be inserted at the N-terminus of the peptide, allowing the same set of amines (either privileged substructures or amino acid analogues) to be used at both the N- and C-termini of the molecule. To show the robustness of this approach, a small library of peptidyl privileged structures were synthesized, illustrating that large combinatorial libraries can be synthesized using these technologies.
A new versatile synthetic route is presented for the cyclization of tripeptides on solid support using nucleophilic aromatic substitution in the cyclization step. Identification of all conformers within a limit of 3 kcal/mol from the identified global minimum conformations by Monte Carlo conformational searching reveals that five out of six synthesized compounds have well-defined peptide backbone conformational properties. This was determined by clustering the identified conformers against a filter of seven to nine torsion angles in the peptide backbone. Thus, the results meet our goal to find synthetic routes to peptides that are conformationally sufficiently locked to serve as convenient leads for further development of pharmacophoric models. The strategy is based on Fmoc-peptide chemistry on a N-aminoethyl-substituted glycine bound to the commercially available Rink amide PS-resin. After deprotection of the N-terminus of the tripeptide, it is acylated with a fluoronitrobenzoic acid. Subsequently, a Boc group on the N-bound aminoethyl substituent is selectively deprotected allowing cyclization from the head (N-terminus) to the backbone substituent, thereby leading to the desired cyclized tripeptides. A number of representative examples of peptides cyclized by this method have been synthesized and characterized by NMR. Protecting groups that allow the incorporation of side chain functionalized amino acids have been found. Thus, the route provides access to generic libraries of conformationally restricted peptide sequences expressing a range of proteinogenic pharmacophores.
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