Total synthesis of the thiopeptide antibiotic amythiamicin D.
The thiopeptide (or thiostrepton) antibiotics are a class of sulfur containing highly modified cyclic peptides with interesting biological properties, including reported activity against MRSA and malaria. Described herein is the total synthesis of the thiopeptide natural product amythiamicin D, which utilizes a biosynthesis-inspired hetero-Diels-Alder route to the pyridine core of the antibiotic as a key step. Preliminary studies using a range of serine-derived 1-ethoxy-2-azadienes established that hetero-Diels-Alder reaction with N-acetylenamines proceeded efficiently under microwave irradiation to give 2,3,6-trisubstituted pyridines. The thiazole building blocks of the antibiotic were obtained by either classical Hantzsch reactions or by dirhodium(II)-catalyzed chemoselective carbene N-H insertion followed by thionation, and were combined to give the bis-thiazole that forms the left-hand fragment of the antibiotic. The key Diels-Alder reaction of a tris-thiazolyl azadiene with benzyl 2-(1-acetylaminoethenyl)thiazole-4-carboxylate gave the core tetrathiazolyl pyridine, which was elaborated into the natural product by successive incorporation of glycine and bis-thiazole fragments followed by macrocyclization.
Hughes
Rachael A
RA
School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom.
Thompson
Stewart P
SP
Alcaraz
Lilian
L
Moody
Christopher J
CJ
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis; D003500:Cyclization; D005998:Glycine / Q000737:chemistry; D047028:Macrocyclic Compounds / Q000138:chemical synthesis*; D011725:Pyridines / Q000737:chemistry; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry
D000900:Anti-Bacterial Agents; D047028:Macrocyclic Compounds; D011725:Pyridines; D013844:Thiazoles; C088501:amythiamicin D; C023666:pyridine; D005998:Glycine