synthetic study on thiostrepton macrocyclic peptide antibiotics containing many heterocyclic rings.

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Recently, many kinds of thiostrepton macrocyclic peptide antibiotics, A10255G and J (1), berninamycin A (2), micrococcin P_1 (3), nosiheptide (4) and son have been obtained from the cultures of various strains. All of the peptides are characterized by comprising polythiazole- and -oxazole-dehydropeptide substructure (Fragment A), 2,3,6-trithiazole-substituted pyridine or 2-oxazole-3-thiazole-substituted pyridine-6-carboxylic acid moiety (Fragment B). Furthermore, interestingly, a wide variety of linear oligo-dehydroalanine or its amide segments (Fragment C) link invariably to the peptide ring. However, there is no report on the synthesis of the partial skeleton as well as the total synthesis, except for a few trisubstituted pyridine skeleton.The peculiar structures and the bioactivities attracted and prompted us to study the total synthesis and the structure-bioactivity relationship. Here, the convenient syntheses of three components called Fragments A,B,and C constituting 1-3 and 4 are described. In particular, we would like to report in detail the general syntheses of Fragments A and C starting from alpha, beta-unsaturated alpha-amino acid (alpha-dehydroamino acid) via N-carboxy alpha-dehydroamino acid anhydride. Moreover, the new synthetic methods for the Fragments B from 3-cyano-6-dimethoxymethyl-2-pyridone have been also explored.