Total Synthetic Study of a Few Thiostrepton Macrocyclic Peptides

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Micrococcins P,P_1, and P_2 (1), isolated from the culture of Bacillus pumilus, are unique macrocyclic peptides antibiotics. Many similar macrocyclic antibiotic peptides have been also isolated from various kinds of stains. The peptide (1) includes a characteristic main structure, a 2,3,6-polythiazole-substituted pyridine skeleton called Fragment A with C (A-C) (2) composed of multisubustituted pyridine and thiazole-dehydropeptide moieties. Not only the interesting structure but also the bioactivity of 1 and other similar peptides, which exhibit inhibitory action of bacterial protein synthesis, attracted us to investigate their total synthesis and structure-bioactivity relationship.So far, the total synthesis of any such peptide antibiotics has not been reported. Recently, however, we have reported briefly on the useful synthesis of a very promising precursor Fragment A-C segment (2) from 3-cyano-6-dimethoxymethyl-2-pyridine via 2-bromoacetyl-3- [5-ethoxycarbonyl] thiazole-6-dimethoxymethyl-pyridine in twelve steps.In this report, after the novel syntheses of the two important residual segments, Fragment B and D,the first total synthesis of micrococcin P out of 1 was achieved from 2 via the fragment condensations of the two terminal thiazole carboxylic acids with the obtained two Fragments, and subsequent deprotection and final cyclization.Furthermore, the syntheses of micrococcins P_1 and P_2 are also investigating, besides the convenient syntheses of the central 2,3,6-tri-and 2,3,5,6-tetrasubsti tuted pyridine skeletons of GE 2270 A and nosiheptide.