Useful Synthesis of the Longer Array Oxazole Rings for Telomestatin

Abstract

The convenient syntheses of the precursors of the constituting Fragments A, B, A-B, and its macrocyclic compounds for telomestatin, which exhibits strong antitumor activity, were first achieved.A metabolite telomestatin (1), 1,2 isolated from the culture of Streptomyces anulatus 3533-SV4, has a very unique macrocyclic structure constituting of oxazole and thiazoline rings only, as shown in Figure 1.Not only the interesting structure but also the bioactivity of 1, exhibiting strong antitumor activity, attracted us to investigate its total synthesis and structure-bioactivity relationships.So far, it has been already known that various oxazole-4-carboxylates are derived from hydroxylated α-amino acid, 3-5 its dipeptide, 5,6 α-dehydroamino acid, 5,7 its dehydropeptide 7 and so on.However, the synthesis of 2-(1-amino-2-hydroxyalkyl)polyoxazole-4-carboxylates by the oxazolation of dehydropeptide has not been reported yet.Here, for the total synthesis of 1, the promising precursors of the protected Fragment A and B, benzyl 2-(2-{2-[1-(N-Boc)amino-2-(O-TPS)hydroxyethyl]-5-methyloxazol-4-yl}-5-methyloxazol-4-yl)oxazole-4-carboxylate (17) [(P)-2] and methyl 2-(2-{2-[1-(N,O-Isop-N-Cbz)amino-2-hydroxyethyl]oxazol-4-yl}oxazol-4-yl)oxazole-4-carboxylate (24) [(P)-3] were first synthesized.