Total synthesis of thiostrepton. Retrosynthetic analysis and construction of key building blocks.
The first phase of the total synthesis of thiostrepton (1), a highly complex thiopeptide antibiotic, is described. After a brief introduction to the target molecule and its structural motifs, it is shown that retrosynthetic analysis of thiostrepton reveals compounds 23, 24, 26, 28, and 29 as potential key building blocks for the projected total synthesis. Concise and stereoselective constructions of all these intermediates are then described. The synthesis of the dehydropiperidine core 28 was based on a biosynthetically inspired aza-Diels-Alder dimerization of an appropriate azadiene system, an approach that was initially plagued with several problems which were, however, resolved satisfactorily by systematic investigations. The quinaldic acid fragment 24 and the thiazoline-thiazole segment 26 were synthesized by a series of reactions that included asymmetric and other stereoselective processes. The dehydroalanine tail precursor 23 and the alanine equivalent 29 were also prepared from the appropriate amino acids. Finally, a method was developed for the direct coupling of the labile dehydropiperidine key building block 28 to the more advanced and stable peptide intermediate 27 through capture with the highly reactive alanine equivalent 67 under conditions that avoided the initially encountered destructive ring contraction process.
Nicolaou
K C
KC
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. kcn@scripps.edu
Safina
Brian S
BS
Zak
Mark
M
Lee
Sang Hyup
SH
Nevalainen
Marta
M
Bella
Marco
M
Estrada
Anthony A
AA
Funke
Christian
C
Zécri
Frédéric J
FJ
Bulat
Stephan
S
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry; D019281:Dimerization; D013237:Stereoisomerism; D013883:Thiostrepton / Q000138:chemical synthesis* / Q000737:chemistry
D000900:Anti-Bacterial Agents; D013883:Thiostrepton