Synthesis of IB-01211, a Cyclic Peptide Containing 2,4-Concatenated Thia- and Oxazoles, via Hantzsch Macrocyclization

Abstract

[structure: see text] An efficient and versatile convergent synthesis of IB-01211 based on a combination of peptide and heterocyclic chemistry is described. The key step in the synthesis is macrocyclization through intramolecular Hantzsch formation of the thiazole ring. Dehydration of a free primary alcohol to furnish the exocyclic methylidene present in the natural product was applied during the macrocyclization.

Preparation of penta-azole containing cyclopeptides: challenges in macrocyclization

“…The total syntheses of YM-216391, 13 telomestatin, 14 and IB-01211 15 have recently been described. The three procedures possess a common feature, a macrocyclization of flexible precursors (Scheme 1).…”

“…17 The bis-oxazole derivative 5a was obtained by cyclization of the proper Ser peptide followed by oxidation of the resulting oxazolines, as previously described by our group. 15 However, reaction of 7a with the Lawesson reagent to produce the thioamide 7b gave a complex mixture from which no product could be isolated.…”

Naturally Occurring Oxazole-Containing Peptides

“…X-ray crystallographic studies and 2D NMR revealed that 41 is a macrocycle with a peptidic nature composed of dehydroalanine, Val and Ile, and five continuum azoles (oxazoles and thiazole) [60]. Compound 41 has a similar structure to that of IB-01211 [61] isolated from the closely related marine microorganism strain ES7-008. Inactive against cancer cells, 42 is a linear congener of the antitumor active 41.…”

α,β-Dehydroamino acids in naturally occurring peptides

“…Furthermore, oxazole- and 5-methyl-oxazole-dehydroamino acids such as oxazole-dehydroalanine, 5-methyl-oxazole-dehydroalanine, oxazole-dehydrobutyrine, 5-methyl-oxazole-dehydrobutyrine, oxazole-dehydrohomobutyrine, 5-methyl-oxazole-dehydrohomobutyrine, oxazole-dehydroleucine, and 5-methyl-oxazole-dehydrohomoserine were found in geninthiocin 62 (Yun et al 1994a , b , c ), berninamycins (Liesch and Rinehart 1977 ; Abe et al 1988 ; Kodani and Ninomiya 2013 ), sulfomycins 63 (Egawa et al 1969 ; Kohno et al 1996 ; Vijaya Kumar et al 1999 ), promoinducin (Yun and Seto 1995 ), thiotipin (Yun et al 1994a , b , c ), A10255 64 (Boeck et al 1992 ; Debono et al 1992 ; Favret et al 1992 ), tioaxamycin (Yun et al 1994a , b , c ), radamycin (Castro Rodríguez et al 2002 ), and TP-1161 (Engelhardt et al 2010 ). Oxazole-dehydroalanine and oxazole-dehydrobutyrine were also found, respectively, in mechercharmycin A 65 (IB-01211) (Kanoh et al 2005 ; Hernández et al 2007a , b ) [226–228] and urukthapelstatin A (Matsuo et al 2007 ), a new class of thiopeptides of antitumour activity, which does not have six-membered heterocyclic moiety.…”