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A Versatile Boc Solid Phase Synthesis of Daptomycin and Analogues Using Site Specific, On‐Resin Ozonolysis to Install the Kynurenine Residue
Author(s) -
Xu Buzhe,
Hermant Yann,
Yang SungHyun,
Harris Paul W. R.,
Brimble Margaret A.
Publication year - 2019
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201903725
Subject(s) - daptomycin , residue (chemistry) , chemistry , ozonolysis , antimicrobial , oxindole , kynurenine , threonine , anthranilic acid , stereochemistry , organic chemistry , tryptophan , amino acid , combinatorial chemistry , biochemistry , serine , bacteria , enzyme , staphylococcus aureus , catalysis , biology , vancomycin , genetics
A de novo solid‐phase synthesis of the cyclic lipodepsipeptide daptomycin via Boc chemistry was achieved. The challenging ester bond formation between the nonproteinogenic amino acid kynurenine was achieved by esterification of a threonine residue with a protected tryptophan. Subsequent late‐stage on‐resin ozonolysis, inspired by the biomimetic pathway, afforded the kynurenine residue directly. Synthetic daptomycin possessed potent antimicrobial activity (MIC 100 =1.0 μg mL −1 ) against S. aureus , while five other daptomycin analogues containing ( 2R,3R )‐3‐methylglutamic acid, ( 2S,4S )‐4‐methylglutamic acid or canonical glutamic acid at position twelve prepared using this new methodology were all inactive, clearly establishing that the ( 2S,3R )‐3‐methylglutamic acid plays a key role in the antimicrobial activity of daptomycin.