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

The total syntheses of macrocyclic antibiotics, micrococcins P and P D21 D2 (1,2)，这些antibiotics有独特的结构，并且是四个组成部分的结构。called Fragments A， B， C, and D. In particular，the structures of the central pyridine skeleton（Fragment A）和the exocyclic side-chain（Fragment D）1和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 ethyl2-(2- brooketyl -6-dimethoxymethyl-3-pyridyl)-thiazole-4-carboxylate (3) in 11 steps，successive fragment condensations of 4 with ethyl2 -(z)- 1 (- o - t - butyldiphenylsilyl - l - threoylamino)- 1 - propenylthiazole - 04 - carboxylate and(S)-1-(O-methoxymethyl- threoylamino)-2-(O-methoxymethyl)-2-propanol (5) （the protected Fragment B）and C moieties，A-B-C-D segment 6. Subsequent deprotecting of all theprotecting groups of 6 with trifluoroacetic acid and then cyclization by using BOP as condensingagent under high dilution gave the expected micrococcin P (1).Furthermore，various chemical modifications of the synthetic方法1，总synthesis of 2也是第一个accomplished. synthetic 1和2是identical with thenatural 1 and 2 with 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.