Total Synthesis of a Macrocyclic Antibiotic, Micrococcin P

Abstract

Abstract The first total synthesis of a macrocyclic antibiotic, micrococcin P (1), was accomplished. After constructing the central 2,3,6-tristhiazolyl-substituted pyridine skeleton [Fragment A—C segment] (21) from ethyl 2-(2-bromoacetyl-6-dimethoxymethyl-3-pyridyl)thiazole-4-carboxylate (15) in 11 steps, successive fragment condensations of 21 with ethyl 2-[(Z)-1-(O-t-butyldiphenylsilyl-l-threonylamino)-1-propenyl]thiazole-4-carboxylate (29) and (S)-1-(O-methoxymethyl-l-threonylamino)-2-(O-methoxymethyl)-2-propanol (25) [the protected Fragments B and D moieties, respectively] gave the protected Fragment A–B–C–D segment 34. Subsequent deprotection of all the protecting groups of 34 with trifluoroacetic acid and then cyclization by using BOP as condensing agent under high dilution conditions gave the expected micrococcin P (1). The synthetic 1 was identical with the natural 1 with respect to the chemical and physical properties.