RESUMEN
The total syntheses of hypomurocin A3 and hypomuricin A5 (HM A3 and HM A5, resp.) in solution phase are described. These syntheses have been successfully achieved by applying the 'azirine/oxazolone method' to introduce the two Aib-Pro units into the backbone of these undecapeptaibols in one step with methyl 2,2-dimethyl-2H-azirine-3-prolinate as the 'Aib-Pro synthon'. The coupling of Z-protected (Z=(benzyloxy)carbonyl) amino acids or peptide acids with amino acid tert-butyl esters and of peptide segments was carried out according to the TBTU (=O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate) and HOBt (=1-hydroxybenzotriazole) protocol. Purification by reversed-phase HPLC gave the peptides in pure form. The products were characterized by optical rotation, NMR and IR spectroscopy, mass spectrometry, and elemental analysis. The crystal structures of HM A3 and of an octapeptide fragment of HM A5 could be obtained. An NMR analysis was also carried out with HM A3 and HM A5 to determine their conformations in solution. A global structural comparison between the three sequences of HM A1, HM A3, and HM A5 was performed, as well as the HPLC correlation of the natural HM A family and the synthetic samples.
Asunto(s)
Oligopéptidos/síntesis química , Peptaiboles/síntesis química , Secuencia de Aminoácidos , Azirinas/química , Cromatografía Líquida de Alta Presión , Cristalografía por Rayos X , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Conformación Molecular , Oligopéptidos/química , Oxazolona/química , Peptaiboles/químicaRESUMEN
The title compounds, O-benzyl-N-(benzyloxycarbonyl)threonyl-2,N-dimethylalaninanilide, C30H35N3O5, and methyl (4R)-4-benzyloxy-N-(benzyloxycarbonyl)valyl-2-(methylalanyl)prolinate, C30H39N3O7, were obtained from the ;azirine coupling' of the corresponding protected amino acids with 2,2,N-trimethyl-2H-azirin-3-amine and methyl (4R)-4-(benzyloxy)-N-(2,2-dimethyl-2H-azirin-2-yl)prolinate, respectively. The Aib unit in each molecule has the greatest turn- or helix-inducing effect on the molecular conformation. Intermolecular N-H...O interactions link the molecules of the tripeptide into sheets and those of the dipeptide into extended chains.
Asunto(s)
Ácidos Aminoisobutíricos/química , Anilidas/química , Dipéptidos/química , Oligopéptidos/química , Azirinas/química , Cristalografía por Rayos X , Enlace de Hidrógeno , Modelos Moleculares , Estructura MolecularRESUMEN
The first total synthesis of Hypomurocin A1 (HM A1) in solution phase is described. As members of the peptaibol family, hypomurocins are constituted by two groups of peptides: six undecapeptides (undecamers) in the HM A group and six octadecapeptides (18-mers) in the HM B group. The synthesis presented has been successfully achieved by the 'azirine/oxazolone method' to introduce the two Aib-Pro sequences included in this undecapeptaibol in one step with methyl 2,2-dimethyl-2H-azirine-3-prolinate as the building block. The coupling reactions of the Z-protected amino acids or peptide acids involved the use of N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) and 1-hydroxybenzotriazole (HOBt), and led to the peptides in good-to-very-good yields. The peptides were purified by reverse-phase HPLC and characterized by NMR spectroscopy (1H, 13C, COSY, TOCSY, HSQC, HMBC, ROESY), ESI-MS, IR, elemental analysis, optical rotation, and X-ray crystallography. An NMR analysis of HM A1 was also carried out in deuterated micelles to perform a structural comparison of the helix in solution and in membranes.
Asunto(s)
Proteínas Fúngicas/síntesis química , Oligopéptidos/química , Oligopéptidos/síntesis química , Secuencia de Aminoácidos , Proteínas Fúngicas/química , Modelos Moleculares , Datos de Secuencia Molecular , Peptaiboles , Péptidos/química , Conformación ProteicaRESUMEN
The protected 11 amino acid segment (6-16) of the peptaibol zervamicin II-2 was synthesized by using the 'azirine/oxazolone method' for the introduction of all Aib residues. Whereas a 2,2-dimethyl-2H-azirin-3-amine was used as the building block for Aib(7), methyl 2,2-dimethyl-2H-azirine-3-prolinate and -3-(3-hydroxyprolinate) proved to be ideally suited as dipeptide synthons for the introduction of Aib-Pro and Aib-Hyp, respectively. The coupling of Z-protected amino acids or peptide acids with the 2H-azirin-3-amines were performed in 75% to quantitative yield.