Total Syntheses of Thiostrepton Macrocyclic Antibiotics Constructing of Unusual Amino Acid Residues and Heterocyclic Ring Moieties

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The synthetic studies of a few macrocyclic thiostrepton antibiotics, GE 2270 A, berinamycins A and B, thiocillines, nosiheptide, and cyclothiazomycin have proceeded extensively. For examples, synthesis of the protected linear precursor [Fragment A-B-C'] of GE 2270 A was achieved by coupling of a 2,3,6-tristhiazolyl-substituted pyridine skeleton [Fragment A-C'] with a thiazolylthiazole segment [Fragment B]. The Fragment B was synthesized from an appropriate thioamide and β-bromo-α-oxoalkanoate, the latter of which was first derived by consecutive β-bromonation and hydrolytic removal of the α-(N-Boc)amino group of α-dehydroamino acid ester. Furthermore, with regard to the synthesis of cyclothiazomycin, first, the 2-[2-(2-thiazol-4-yl)thiazol-4-yl]thiazoline-4-carboxylate [Fragment A], attached to the 6-substituent of the main pyridine skeleton, was synthesized by two consecutive thiazolations of the protected Ser thioamide derivative with bromopyruvate and then thiazolination of the C-terminal Ser residue of the sequence. Secondly, a synthesis of the central (1'R)-2-{2-[2-(1-aminoethylpyridin-6-yl]thiazol-4-yl}thiazoline-4-carboxylate [Fragment B] was also achieved by thiazolation of the formyl group of the 2-(1-amino)ethyl-6-formylpyridine derivative and then thiazolation. Thirdly, a synthesis of the protected dehydrotetrapeptide [Fragment C], which is bound to the 2-substituent of the pyridine skeleton, was attained by the stepwise elongation of the appropriate α-amino acids and β-elimination of a Thr residue of the sequence. Finally, the fragment condensation of the three Fragments gave the protected Fragment A-B-C.