Synthesis of novel nocathiacin-class antibiotics. Condensation of glycolaldehyde with primary amides and tandem reductive amination of amadori-rearranged 2-oxoethyl intermediates.
Nocathiacin I (1) and nocathiacin IV (2) are novel indole-containing thiazolyl peptide antibiotics, which exhibit potent activity against key Gram-positive bacterial pathogens, including multi drug-resistant Staphylococcus aureus, Streptococcus pneumoniae, and Enterococcus faecium. New nocathiacins 7-12 were prepared from 2 by a condensation with glycolaldehyde followed by tandem reductive amination of the 2-oxoethyl intermediate 4. The latter was formed via Amadori rearrangement from initial 2-hydroxyethylideneamide 3. This transformation readily tolerates the complex architecture of nocathiacins and allows selective incorporation of water solubilizing groups to the primary amide in 2 without protecting group manipulation.
Hrnciar
Peter
P
Bristol-Myers Squibb Co., Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, Connecticut 06492, USA.
Ueda
Yasutsugu
Y
Huang
Stella
S
Leet
John E
JE
Bronson
Joanne J
JJ
D000079:Acetaldehyde / Q000031:analogs & derivatives* / Q000737:chemistry*; D000577:Amides / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002384:Catalysis; D020650:Combinatorial Chemistry Techniques; D024901:Drug Resistance, Multiple, Bacterial; D016984:Enterococcus faecium / Q000187:drug effects; D036341:Intercellular Signaling Peptides and Proteins; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D010455:Peptides; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000187:drug effects; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D014867:Water / Q000737:chemistry
D000577:Amides; D000900:Anti-Bacterial Agents; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D010456:Peptides, Cyclic; D013844:Thiazoles; C463319:nocathiacin I; C473548:nocathiacin IV; D014867:Water; D000079:Acetaldehyde; C010972:glycolaldehyde