Total synthesis of a macrocyclic antibiotic, micrococcin P1

Article abstract of DOI:10.1246/bcsj.72.2483

The first total synthesis of a macrocyclic antibiotic, micrococcin P₁ (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 structures of the central pyridine skeleton (Fragment A) and the exocyclic side-chain (Fragment D) of 1 are slightly different from those of a similar antibiotic, micrococcin P (2). By various chemical modifications of the synthetic method for 2, the synthesis of the central 2,3,6-tris(substituted thiazolyl)pyridine segment [Fragment AC] 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 using (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate as a condensing agent under high-dilution conditions and then deprotection of all the protecting groups with trifluoroacetic acid were effected successfully to give the expected synthetic 1.