Studies on the synthesis of peptides containing dehydrovaline and dehydroisoleucine based on copper-mediated enamide formation

Abstract

SummaryThe preparation of peptide fragments containing dehydrovaline and dehydroisoleucine moieties present in the antibiotic myxovalargin is reported. Peptide formation is based on a copper-mediated C–N cross-coupling protocol between an acyl amide and a peptidic vinyl iodide. The presence of a neighboring arginine in the vinyl iodide posed a challenge with respect to the choice of the protecting group and the reaction conditions. It was found that ornithine – a suitable precursor – is better suited than arginine for achieving good yields for the C–N cross-coupling reaction. The optimized conditions were utilized for the synthesis of peptides 32, 33, 39 and 40 containing a neighboring ornithine as well as for the tripeptide 44 containing dehydroisoleucine with the correct stereochemistry.

The Myxobacterial Antibiotic Myxovalargin: Biosynthesis, Structural Revision, Total Synthesis, and Molecular Characterization of Ribosomal Inhibition

“…We also observed density that we attributed to seven water molecules (W 1 –W 7 ) (Figure f and Figure S7-7c–f). The density for MyxA was consistent with the stereochemistry of Val7 and Val10 having D- and L-configurations (Figure S7-7l), as determined here (Figure ), rather than L- and D-configurations, as suggested previously. ,, Despite the lower resolution, the cryo-EM density of MyxB-SRC was well-resolved and suggested an analogous mode of interaction with the ribosome as MyxA (Figure g), consistent with the high conservation in their chemical structures (Figure ).…”

“…Two different strategies were used for the introduction of the olefinic double bonds. For the generation of dehydrovaline, base-promoted elimination of the nitro group in β-nitrovaline 1 was the method of choice, while dehydroisoleucine was introduced into the peptide backbone by a copper-mediated Goldberg reaction of acylamide 5 with vinyl iodide 4 . The synthesis of unusual amino acids such as 4-hydroxyphenyl-β-alanine S7 and β-nitrovaline 1 as well as vinyl iodide 4 and amidinating agent 7 are described in the Supporting Information.…”

The myxobacterial antibiotic myxovalargin: Biosynthesis, structural revision, total synthesis and molecular characterization of ribosomal inhibition

“…2), rather than L-and D-conformations, as suggested previously (Fig. 4e, f) 6,7,17 . The overall conformation of MyxA on the ribosome is oriented with the MBA moiety positioned at the PTC and the AG extending down the NPET towards ribosomal protein L22 (Fig.…”

“…Two different strategies were used for the introduction of the olefinic double bonds. For the generation of dehydrovaline, base-promoted elimination of the nitro group in β-nitrovaline 1 was the method of choice 16 , while dehydroisoleucine was introduced into the peptide backbone by a coppermediated Goldberg reaction of acylamide 5 with vinyl iodide 4 17 . The synthesis of unusual amino acids such as 4-hydroxyphenyl-β-alanine S7 and β-nitrovaline 1 as well as vinyl iodide 4 and amidinating agent 7 are described in the supporting information.…”

Discovery of recombinases enables genome mining of cryptic biosynthetic gene clusters in Burkholderiales species

“…S13 ). Therefore, glidopeptin A was characterized to be a linear 12-amino acid lipopeptide containing a rare C-terminal Dhv that was only found in the myxobacterial nonribosomal peptide myxovalargin ( 50 , 51 ).…”