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Amino Acids: The Forum for Amino Acid, Peptide and Protein Research (v.29, #2)
Ethynylglycine synthon from Garner’s aldehyde: a useful precursor for the synthesis of non-natural amino acids by G. Reginato; P. Meffre; F. Gaggini (pp. 81-87).
The ethynylglycine synthon, namely (R)-2,2-dimethyl-3-(tert-butoxycarbonyl)-4-ethynyl-oxazolidine, can be obtained through the synthetic elaboration of naturally occurring serine. This compound has been exploited as a helpful and versatile non-racemic building block to be used for the design and synthesis of biologically important compounds, mainly non-natural α-amino acids. Taking advantage of the terminal acetylene moiety several synthetic applications can be designed. Metalation followed by trapping with electrophiles or Cu/Pd catalysed coupling with aromatic halogenides are shown to deliver useful precursors of ethynylglycine derivatives. Additions of bimetallic reagents like stannyl- or silylcuprates are useful entries for the regio- and stereoselective functionalization of the lateral chain, aimed at the synthesis of modified vinylglycine precursors.An overview of our recent work in the field will be given, and the use of ethynylglycine synthon in the synthesis of non-racemic saturated and unsaturated non-natural amino acids will be briefly reviewed.
Keywords: Keywords: Amino acids – Synthesis – Precursors – Organometallics – Ethynylglycine
Alicyclic β-amino acids in Medicinal Chemistry by A. Kuhl; M. G. Hahn; M. Dumić; J. Mittendorf (pp. 89-100).
The structural element of alicyclic β-amino acids shows some remarkable biological effects: For some 5- and 6-membered β-amino acids a unique anti fungal activity has been observed, 7-membered β-amino acid derivatives have been investigated for neurological disorders. The application of 5-, 6- and 7-membered alicyclic β-amino acids in Medicinal Chemistry will be reported. Caption of figure
Keywords: Keywords: Beta-amino acid – Medicinal chemistry – Antifungal – Cispentacin – Icofungipen – Asymmetric synthesis
Recent advances in asymmetric synthesis of pipecolic acid and derivatives by C. Kadouri-Puchot; S. Comesse (pp. 101-130).
This review covers the literature relating to asymmetric syntheses of pipecolic acid derivatives from 1997 to present. This review is organized according to the position and the degree of substitution of the piperidinic cycle. In a first section, syntheses of pipecolic acid itself are described. Then, successively, syntheses of C-3, C-4, C-5, C-6 substituted pipecolic acid derivatives are reported. Finally, syntheses of unsaturated pipecolic acid derivatives are presented before the last part devoted to the polysubstituted pipecolic acid derivatives.
Keywords: Keywords: Pipecolic acid – Pipecolic acid derivatives – Amino acids – Asymmetric syntheses – Asymmetric catalysis
Synthesis of modular dipeptide mimetics on the basis of diazabicycloalkanes and derivatives thereof with sulphur containing side chains by D. C. Grohs; W. Maison (pp. 131-138).
We present the synthesis of new modular dipeptide mimetics based on diazabicycloalkane backbones. These diazabicycloalkanes are ligands for the prostate specific membrane antigen (PSMA), a well known tumor marker. Our previously described synthetic route to enantiomerically pure diazabicycloalkanes is extended to yield polyfunctional diazabicycloalkanes with a modular character using a new ring closing methodology. This, finally, allows us to attach linker moieties to different positions of the diazabicycloalkane scaffold providing conjugation sites to other functional molecules such as markers or cytostatic compounds. Furthermore, successful synthesis of sulphur-containing dipeptide analogues as for example CysXAA- or HCysXAA-mimetics on the basis of diazabicycloalkanes is described.
Keywords: Keywords: Prostate cancer – PSMA – Diazabicycloalkanes – Stereoselective synthesis
Method for the synthesis of phosphinic acids from hypophosphites V. The synthesis of pseudo-α,α-dipeptides by L. F. Rozhko; V. V. Ragulin (pp. 139-143).
The method for the synthesis of 2-substituted 2-hydroxycarbonylethyl-1-aminoalkylphosphinic acids (I) (pseudo-α,α-dipeptides) from ammonium and potassium hypophosphites (II) is described. The proposed route to the synthesis of pseudo-α,α-dipeptides consists in addition hypophosphite to acrylic compounds and formation of the first phosphorus–carbon bond with following addition of aminoacid fragment and formation of the second phosphorus–carbon bond. The key intermediates of the synthesis – phosphonous acids (III) and their silylic esters (IV) were obtained at the first stage of the process as the result of the addition of the bis(trimethylsilyl)hypophosphite in situ to suitably substituted acrylates. The modificated procedure for the Kabachnik-Fields reaction of 2-substituted 2-alkoxycarbonylethyl phosphonous acids (III), acetamide, benzaldehyde in acetic anhydride with following hydrolysis results in 2-substituted 2-hydroxycarbonylethyl-α-aminobenzyl phosphinic acids (Ia–c) (pseudo-phenylglycylpeptides). Bis(trimethylsilyl) 2-substituted 2-alkoxycarbonylethylphosphonites (IV) in situ were added to N-tritylmethanimine and following alcoholysis and acid hydrolysis of addition products gave 2-substituted 2-hydroxycarbonylethyl-aminomethylphosphinic acids (Id–f) (pseudo-glycylpeptides).
Keywords: Keywords: Pseudo-α,α-dipeptides – Phosphinic acid peptides – 2-Substituted 2-alkoxycarbonylethylphosphonous acids – Potassium and Ammonium hypophosphites – Amino phosphinic acids
Norleucine, a natural occurrence in a novel ergot alkaloid γ-ergokryptinine by L. Cvak; A. Jegorov; P. Sedmera; I. Císařová; J. Čejka; B. Kratochvíl; S. Pakhomova (pp. 145-150).
A novel natural peptide ergot alkaloid γ-ergokryptinine containing norleucine has been isolated from ergot sclerotia of the field-growing parasitic fungus Claviceps purpurea CCM 8059. Its structure was deduced from the NMR and mass spectral data. The final structural proof was provided by the crystal structure determination, which is the first X-ray structure of a natural Nle-containing secondary metabolite. The conformations of three ergopeptinines: γ-ergokryptinine, ergoladinine, and α-ergokryptinine were compared.
Keywords: Keywords: Norleucine – Ergot alkaloids – γ-Ergokryptinine – Crystal structure determination
Synthesis and utilization of 13C and 15N backbone-labeled proline: NMR study of synthesized oxytocin with backbone-labeled C-terminal tripeptide amide by M. Budαěšínský; U. Ragnarsson; L. Lankiewicz; L. Grehn; J. Slaninová; J. Hlaváček (pp. 151-160).
The 13C and 15N backbone-labeled proline was prepared using Oppolzer’s method based on application of a sultam as chiral auxiliary. This isotopomer was used in the synthesis of the 13C, 15N backbone-labeled C-terminal tripeptide amide fragment of neurohypophyseal hormone oxytocin. Finally, this tripeptide amide was coupled by segment condensation with N-Boc- or N-Fmoc-tocinoic acid, followed by N-deprotection with TFA or piperidine. The labeled oxytocin exhibited biological activity identical with that of natural oxytocin. A detailed 1H, 13C and 15N NMR study confirmed the assigned oxytocin conformation containing a β-turn in the cyclic part of the molecule, stabilized by H-bond(s) that can be perturbed by the C-terminal tripeptide amide moiety as indicated by comparison of NMR data for both the tocine ring in oxytocin and tocinoic acid.
Keywords: Keywords: Labeled proline – Oxytocin isotopomer – Peptide synthesis – Segment condensation – Protected tocinoic acid – Bioassay – NMR study