Total Synthesis of Thiopeptide Antibiotics GE2270A, GE2270T, and GE2270C1

Abstract

The total syntheses of the thiopeptide antibiotics GE2270A (7), GE2270T (8), and GE2270C1 (9) are described. The original synthetic strategies employed utilized the hetero-Diels-Alder reaction to construct the pyridine core of the target molecules and relied on a macrolactamization process to construct the macrocycle. The hetero-Diels-Alder-based strategy finally evolved allows the introduction of all four thiazole units attached to the pyridine ring and a one-pot sequence for macrocyclization and side-chain extension, culminating in highly convergent and expedient syntheses of these molecules as exemplified by a 24-step synthesis of GE2270C1 (9).

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] …”

Biomimetic Synthesis of Azole‐ and Aryl‐Peptide Alkaloids

“…Synthetically, GE2270 allows us to compare biomimetic and non-biomimetic strategies. Two distinct syntheses for this molecule have been worked out: one with biomimetic key steps [52,53] and the second making extensive use of non-biological Pd-mediated sp 2 -couplings [54,55], even for the macrocyclization (Figure 9.7). …”

“…In Nicolaou's biomimetic synthesis [52,53], GE2270A and some of its variants were prepared. The strategy used to obtain the pyridine core was similar to that employed in their earlier synthesis of thiostrepton.…”

“…In their total synthesis of sanjonine G1 (52), Zhu et al used an intramolecular S N Ar reaction of a 4-fluoro-3-nitroaryl-derivative with a β-hydroxy amino acid residue (53) and subsequent reductive removal of the activating nitro-group from 54 via the diazonium intermediate to obtain the desired cyclopeptide scaffold 55 (Scheme 9.13) [80][81][82][83].…”

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.…”