Total Synthesis of the Antiviral Peptide Antibiotic Feglymycin

Abstract

An adaptable approach: The first highly convergent stereoselective synthesis of feglymycin (see structure) and its enantiomer is based on the coupling of repeating peptide fragments. The use of weakly basic conditions throughout the synthesis suppressed the epimerization of sensitive aryl glycine units. Feglymycin has strong anti-HIV activity as well as potent (previously identified as weak) antibacterial activity against Staphylococcus aureus.

Total synthesis of feglymycin based on a linear/convergent hybrid approach using micro-flow amide bond formation

“…The structure of obtained feglymycin ( 1 ) was confirmed by 1 H and 13 C NMR, IR, and HRMS spectra, as well as by specific rotation. The observed spectra were consistent with the previously reported data12.…”

“…The biological activity of feglymycin involves strong anti-HIV activity8 and moderate antimicrobial activity910, and its unique helical conformation11 makes it an attractive lead compound for drug development. In 2009, the Süssmuth group reported the first total synthesis of feglymycin based on a highly convergent approach, in which D -Dpgs were coupled with the neighbouring C-terminal side of amino acids at an initial stage12. This amidation of the D -Dpgs with amino acids was performed using a coupling agent, 3-(diethyloxyphosphoryloxy)-1,2,3-benzotriazin-4(3 H )-one (DEPBT).…”

“…However, the Süssmuth group reported that the coupling of D -Dpgs with longer peptides based on a linear approach resulted in severe racemization of the D -Dpgs and provided an inseparable mixture of diastereomers even when using DEPBT. The Süssmuth group concluded that a linear approach for the hexapeptide and the heptapeptide containing D -Dpgs was not possible12. The development of peptide chain elongation based on a linear approach is important not only for the synthesis of feglymycin and related compounds, but also for the synthesis of other arylglycines-containg biologically active oligopeptides.…”

Enantioselective Synthesis of α-Bromonitroalkanes for Umpolung Amide Synthesis: Preparation of tert-Butyl ((1R)-1-(4-(benzyloxy)phenyl)-2-bromo-2-nitroethyl)carbamate

“…The coupling of aryl glycines using conventional dehydrating agents and a carboxylic acid donor is subject to competitive epimerization of the α-stereocenter. 13 Preservation of this stereochemical integrity is a key advantage of UmAS due to its unique mechanism which avoids an electrophilic active ester and acidic α-C–H bond.…”

Enantioselective Synthesis of D‐α‐(Uracil‐5‐yl)glycine Derivatives and Their Racemization‐Free Incorporation into a Model ­Peptide

“…Incorporation of enantiopure (R)-7a (95 % ee) into the model peptide gave the tripeptide with a de of only 8 %, which proved our hypothesis on the potential epimerization of the C-α position under this standard peptide-coupling protocol ( Table 1, entry 1). The use of DEPBT, an alternative coupling reagent commonly used with epimerization-sensitive aryl glycines, together with diisopropylethylamine (DIPEA) as a base, [27][28][29] resulted in a higher diastereomeric excess of the model tripeptide, but racemization was still significant (Table 1, entry 2). …”