Total Synthesis of Thiostrepton. Retrosynthetic Analysis and Construction of Key Building Blocks

Abstract

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.

Identification and Analysis of the Biosynthetic Gene Cluster Encoding the Thiopeptide Antibiotic Cyclothiazomycin in Streptomyces hygroscopicus 10-22

“…Early in vitro investigations of these special heterocycles of thiopeptides were performed by organic chemists and included stereoselective synthesis of a ␥-lactam acidic hydrolysate of cyclothiazomycin (4) and total synthesis of thiostrepton (21). Extensive research on microccins (5,19) and lantibiotics (6,29) described biosynthesis of the thiazole-and dehydroamino acidcontaining polypeptides that were derived from ribosomally synthesized prepeptides.…”

Totalsynthese von Nosiheptid

“…[98,106,115,217,218] 63 Für die Synthese des Pyridylthiazols 160 wurde das aus L-Cystein abgeleitete Thioamid 47 [98] mit dem -Bromketon 161 [219] …”

Recent Progress in the Discovery of Macrocyclic Compounds as Potential Anti-Infective Therapeutics

“…Using an integrated combinatorial and medicinal chemistry program, researchers at Vicuron discovered analogues of GE2270A with more favorable physico-chemical properties. [22] The total syntheses of six members of the class have been reported, including those of thiostrepton, [23] promothiocin A, amythiamicin D, [24] GE2270A, [25] GE2270T, [26] and siomycin A.…”