Total synthesis of a macrocyclic antibiotic, micrococcin P-1

The first total synthesis of a macrocyclic antibiotic, micrococcin P-1 (1), was achieved. This antibiotic has a unique structure and is constructed of four components called Fragments A, B, C, and D. In particular, the struct ures of the central pyridine skeleton (Fragment A) and the exocyclic side-c hain (Fragment D) of 1 are slightly different from those of a similar antib iotic, micrococcin P (2). By various chemical modifications of the syntheti c method for 2, the synthesis of the central 2,3,6-tris(substituted thiazol yl)pyridine segment [Fragment A-C] 15 from ethyl 2-[6-dimethoxymethyl-2-(1- ethoxyvinyl)-3-pyridyl]thiazole-4-carboxylate (9), followed by coupling of 15 with the Fragments B and D moieties, synthesized independently, gave the protected Fragment A-B-C-D segment. Final intramolecular cyclization by us ing (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphat e as a condensing agent under high-dilution conditions and then deprotectio n of all the protecting groups with trifluoroacetic acid were effected succ essfully to give the expected synthetic 1.