Eine Totalsynthese des bismakrocyclischen Thiopeptidantibiotikums Nosiheptid gelang durch den Aufbau einer voll funktionalisierten linearen Vorstufe und konsekutive Makrocyclisierungen. Schlüsselmerkmale waren eine kritische Makrothiolactonisierung und eine milde Entschützungsstrategie für den 3-Hydroxypyridin-Kern. Der Naturstoff war mit isoliertem authentischem Material im Hinblick auf spektroskopische Daten und antimikrobielle Aktivität identisch.

Total synthesis of the bismacrocyclic thiopeptide antibiotic nosiheptide was achieved through the assembly of a fully functionalized linear precursor followed by consecutive macrocyclizations. Key features are a critical macrothiolactonization and a mild deprotection strategy for the 3-hydroxypyridine core. The natural product was identical to isolated authentic material in terms of spectral data and antibiotic activity.

Macrocyclic natural products (NPs) and analogues thereof often show high affinity, selectivity, and metabolic stability, and methods for the synthesis of NP-like macrocycle collections are of major current interest. We report an efficient solid-phase/cyclorelease method for the synthesis of a collection of macrocyclic depsipeptides with bipartite peptide/polyketide structure inspired by the very potent F-actin stabilizing depsipeptides of the jasplakinolide/geodiamolide class. The method includes the assembly of an acyclic precursor chain on a polymeric carrier, terminated by olefins that constitute complementary fragments of the polyketide section and cyclization by means of a relay-ring-closing metathesis (RRCM). The method was validated in the first total synthesis of the actin-stabilizing cyclodepsipeptide seragamide A and the synthesis of a collection of structurally diverse bipartite depsipeptides.

D-/L-Peptides such as gramicidin A (gA) adopt unique dimeric β-helical structures of different topologies. To overcome their conformational promiscuity and enrich individual components, a dynamic combinatorial approach assisted by thiol tags was developed. This method led to identification of the preferential formation of antiparallel dimers under a broad range of conditions, which was independent of peptide side-chain polarity. Exclusive formation of an antiparallel cyclic dimer was achieved in the presence of cesium ions.

Intramolecular aza-Wittig ring closures were applied to synthesize thiazolines, oxazolines, and imidazolines from β-azido thioester, ester, and amide precursors. The cyclization precursors were obtained from amino acid derivatives. Optimized conditions for diazo transfer with a fast rate and racemization suppression, (thio)esterification, and amide coupling reactions are described. The ring closure reaction can be executed with PPh₃ under neutral conditions and was found to be highly chemoselective for five-membered rings. If amide groups were activated with tosyl groups, smooth intramolecular ring closure of iminophosphoranes furnished enantiopure imidazoline products with position-specific tosyl protection. This aza-Wittig-based azoline synthesis was then extended to double azoline ring closures to furnish catenated azoline building blocks common to peptide natural product building blocks and their analogues.

Growing resistance to antibiotics, as well as newly emerging pathogens, stimulate the investigation of antimicrobial peptides (AMPs) as therapeutic agents. Here, we report a new library design concept based on a stochastic distribution of natural AMP amino acid sequences onto half-length synthetic peptides. For these compounds, a non-natural motif of alternating D- and L-backbone stereochemistry of the peptide chain predisposed for β-helix formation was explored. Synthetic D-/L-peptides with permuted half-length sequences were delineated from a full-length starter sequence and covalently recombined to create two-dimensional compound arrays for antibacterial screening. Using the natural AMP magainin as a seed sequence, we identified and iteratively optimized hit compounds showing high antimicrobial activity against Gram-positive and Gram-negative bacteria with low hemolytic activity. Cryo-electron microscopy characterized the membrane-associated mechanism of action of the new D-/L-peptide antibiotics.