Total synthesis of Macrocyclic Thiopeptide Antibiotic Constructing Ployheterocyclic Compounds and Unusual Amino Acids

The total syntheses of macrocyclic antibiotics，micrococcins P and P I D21 ii D2(1，2)，were first achieved.These antibiotics have unique structures and are 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 and 2 are slightly different each other.First of all，after constructing the central2，3，6-tristhiazolylsubstituted pyridine skeleton(Fragment A-C segment)(4)from ethyl2-(2-bromoacetyl-6-dimethoxymethyl-3-pyridyl)-thiazole-4-carboxylate(3)in11steps，successive fragment condensations of4with ethyl2-(Z)-1(O-t-butyldiphenylsilyl-L-threoylino1-propenylthiole-4with ethyl2-(Z)-1(O-t-butyldiphenylsilyl-L-threoylino)-L-threoylhyl.Respectively)gave the protected Fragment A-B-C-D segment 6.Subsequent deprotecting of all the protecting groups of 6 with trifluoroacetic acid and then cyclization by using BOP as condensing agent under high dilution gave the expected micrococcin P(1).Furthermore，by various chemical modifications of the synthetic method for 1，the total synthesis of 2was also first accomplished.The synthetic1and2were identical with the natural1and2with respect to the chemical and physical properties.

The total syntheses of macrocyclic antibiotics, micrococcins P and PィイD21ィエD2 (1,2), were first achieved. These antibiotics have unique structures and are 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 and 2 are slightly different each other. First of all, after constructing the central 2, 3, 6-tristhiazolylsubstituted pyridine skeleton(Fragment A-C segment) (4) from ethyl 2-(2-bromoacetyl-6-dimethoxymethyl-3-pyridyl)-thiazole-4-carboxylate (3) in 11 steps, successive fragment condensations of 4 with ethyl 2-(Z)-1(O-t-butyldiphenylsilyl-L-threoylamino)-1-propenylthiazole-4-carboxylate and (S)-1-(O-methoxymethyl-L-threoylamino)-2-(O-methoxymethyl)-2-propanol (5) (the protected Fragment B and C moieties, respectively) gave the protected Fragment A-B-C-D segment 6. Subsequent deprotecting of all the protecting groups of 6 with trifluoroacetic acid and then cyclization by using BOP as condensing agent under high dilution gave the expected micrococcin P (1).Furthermore, by various chemical modifications of the synthetic method for 1, the total synthesis of 2 was also first accomplished. The synthetic 1 and 2 were identical with the natural 1 and 2 with respect to the chemical and physical properties.