Total Synthesis of the Peptaibols Hypomurocin A3 and Hypomurocin A5, and Their Conformation Analysis

• Published in: Chemistry & biodiversity 2012-11, Vol.9 (11), p.2528-2558
• Main Authors: Pradeille, Nicolas, Tzouros, Manuel, Möhle, Kerstin, Linden, Anthony, Heimgartner, Heinz
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Amino acids; Azirine/oxazolone method; Azirines - chemistry; Chromatography, High Pressure Liquid; Crystallography, X-Ray; Hypomurocins; Ions; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Conformation; Oligopeptides - chemical synthesis; Oligopeptides - chemistry; Oxazolone - chemistry; Peptaibols; Peptaibols - chemical synthesis; Peptaibols - chemistry; X-Ray crystallography
• ISSN: 1612-1872; 1612-1880
• DOI: 10.1002/cbdv.201200285

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.