Novel Synthesis of the Main Central 2,3,6-Trisubstituted Pyridine Skeleton [Fragment A-B-C] of a Macrobicyclic Antibiotic, Cyclothiazomycin

Abstract

Abstract The useful synthesis of the main central 2,3,6-trisubstituted pyridine skeleton [the protected Fragment A-B-C] of a macrobicyclic antibiotic, cyclothiazomycin, was first accomplished. First, the 2-[2-(2-substituted thiazol-4-yl)]-4,5-dihydrothiazole-4-carboxylate [Fragment A derivative], attached to the 6-substituent of the main pyridine skeleton, was synthesized by two consecutive thiazolations of the protected Ser thioamide derivative with 3-bromopyruvate, and then thiazolination of the C-terminal Ser residue of the sequence. Secondly, an efficient synthesis of the central 2-(2-{2-[(1R)-1-aminoethyl]pyridin-6-yl}thiazol-4-yl)-4,5-dihydrothiazole-4-carboxylate [Fragment B derivative] was also achieved by thiazolation of the formyl group of the 2-(1-aminoethyl)-6-formylpyridine derivative, and then thiazolination. Thirdly, a convenient synthesis of the protected dehydrotetrapeptide [Fragment C derivative], which is bound to the 2-substituent of the pyridine skeleton, was attained by the usual stepwise elongation of the appropriate α-amino acids and β-elimination of a Thr residue of the sequence. Finally, the facile fragment condensation of the three Fragments thus obtained gave the protected Fragment A-B-C derivative via Fragment A-B. Furthermore, the configurational structures of the three Fragments (A, B, and C) were also investigated.