Von Aminosäuren zu Heteroarenen – Thiopeptid‐Antibiotika als heterocyclische Peptide aus der Natur

Abstract

Aminosäuren, die Bausteine der Proteine, sind zugleich auch Vorstufen für viele andere Naturstoffe wie Alkaloide, Antibiotika und, Thema dieses Aufsatzes, heterocyclische Peptide. Einfache α‐Aminosäuren werden dabei zu komplexen Anordnungen aus heteroaromatischen Ringen zusammengefügt, die sich ihrerseits durch interessante, hohe biologische Aktivität auszeichnen. Ein Beispiel dafür sind die Thiopeptid‐Antibiotika mit ihrer komplexen Molekülarchitektur. In diesem Aufsatz zeigen wir auf, wie Organiker innovative Methoden zur Synthese des heterocyclischen Ringsystems entwickelt haben, die teilweise auch durch die jeweiligen Biosyntheserouten inspiriert waren. Zielführend war dabei die geschickte Anwendung von orthogonalen Schutzgruppen und Kupplungsstrategien.

Biomimetic Synthesis of Azole‐ and Aryl‐Peptide Alkaloids

“…While it is certainly too early to generalize, this trend has gained momentum in recent years, when RPS was shown to be involved with the Lissoclinum peptides, the patellamides (4), and the thiopeptide antibiotics as well (9)(10)(11)(12)(13). In all cases a serine, threonine, or cysteine peptide is dehydrated (cyclodehydratase, McbB for 6) and then sometimes further oxidized (dehydrogenase, McbC for 6) to generate peptide-embedded heterocycles [8].…”

“…Mechanistically, the dehydratase enables a nucleophilic side-chain attack at an amide carbon (Scheme 9.2), which is not easily induced with chemical reagents. These typically activate the side chain [9,10]. However, for thiazolines such a condensation was achieved with oxophilic Lewis acids such as TiCl 4 [11] or Tf 2 O-activated triphenylphosphine oxide in a biomimetic fashion [12], leading directly to peptide heterocycles (Scheme 9.2).…”

“…Surprisingly, genetics studies conclusively established that all important thiopeptide antibiotics (thiostrepton, thiocillin, siomycin, thiomuracin, nosiheptide) [31][32][33] are derived from RPS [2,[33][34][35]. One of the most complex members, thiostrepton (9), was isolated in the 1950s from Streptomyces azureus. It was identified as a very potent antibiotic with strong activity against Gram-positive bacteria (Figure 9.3) [7].…”

“…The X-ray structure of 9 revealed a globular structure reminiscent of folded protein domains [9]. Thiostrepton inhibits bacterial protein biosynthesis by binding tightly to the GTPase-associated region (GAR) on the 70S ribosome.…”

Total Synthesis and Stereochemical Assignment of Baringolin

“…[1,2] These natural products have drawn the attention of many research groups mainly owing to their interesting antibiotic activities [3] and their challenging structures. [1,2] These natural products have drawn the attention of many research groups mainly owing to their interesting antibiotic activities [3] and their challenging structures.…”