Totalsynthese des antiviralen Peptidantibiotikums Feglymycin

Abstract

Hochkonvergent verlief die stereoselektive Totalsynthese von Feglymycin (1) und dessen Enantiomer durch Kupplung sich in der Struktur wiederholender Peptidfragmente. Nur schwach basische Reaktionsbedingungen während des gesamten Syntheseverlaufs unterdrückten eine Epimerisierung empfindlicher Arylglycine. 1 zeigt nicht nur eine bemerkenswerte Anti‐HIV‐Aktivität, sondern, entgegen früheren Ergebnissen, auch eine beachtliche antibakterielle Aktivität gegen Staphylococcus aureus.

Alanine Scan of the Peptide Antibiotic Feglymycin: Assessment of Amino Acid Side Chains Contributing to Antimicrobial Activity

“…Thus the direct influence of Ala-exchange on the secondary structure of the peptide would be minimized. The synthetic strategy, which was based on the total synthesis published previously by our group, [10] was adapted to the requirements of the alanine scan. Accordingly, the [6+7] fragment coupling of the 13-mer peptide was further partitioned into coupling of Ala-containing di-and tripeptides to readily available building blocks.…”

“…[9] The first total synthesis of feglymycin was recently developed by our group and is based on a [6+7] fragment coupling strategy (Scheme 1). [10] One of the main challenges of the synthesis was establishing suitable coupling conditions to suppress racemization and epimerization of phenylglycines and phenylglycine-containing peptides. Furthermore, phenolic protecting groups caused severe solubility problems in the later stages of the peptide assembly, thus requiring an appropriate condensation strategy and suitable protecting groups for mild final deprotection.…”

Biosynthesis of the Peptide Antibiotic Feglymycin by a Linear Nonribosomal Peptide Synthetase Mechanism

“…The emergence of bacterial resistance against “last resort” antibiotics, such as vancomycin, increases the urgency for new antibacterials, preferably with new modes of action . In the search for new lead structures for the development of antibacterial substances, we have focused on peptide antibiotics of both ribosomal and nonribosomal origin; these often have a dedicated and preferred role in inhibition of the bacterial cell wall biosynthesis. Thus, we became interested in feglymycin, a peptide antibiotic that was discovered in a screening program by the Hoechst company in the late 1990s .…”

“…Apart from its linear primary sequence, X‐ray crystallographic studies of feglymycin showed that the molecule forms a β‐helical dimeric structure that is reminiscent of that of gramicidin A, with head‐to‐head dimerization. In order to understand the structure–activity relationships, we synthesized feglymycin by a total synthesis route . Alanine scanning of all 13 amino acids revealed the positions, particularly of Hpg residues, with a strong effect on MurA/MurC inhibition and antibacterial activity against S. aureus .…”

Intramolecular Suzuki–Miyaura Reaction for the Total Synthesis of Signal Peptidase Inhibitors, Arylomycins A2 and B2

“…However, extensive epimerization observed during the attempted coupling of acid 36 with l-Ala-OMe prompted us to modify this sequence. [49] Thus, coupling of arylglycine 12 with l-Ala-OMe in the presence of HOAt [34] and EDC·HCl afforded dipeptide 37 in 82 % yield without epimerization (Scheme 7). Methylation of 37 by action of TMSCHN 2 in a 3:1 mixture of CH 2 Cl 2 /MeOH afforded 38 in 96 % yield.…”