Total Synthetic Study of a Few Thiostrepton Macrocyclic Peptides

微球菌素P、P_1和P_2(1)是从短小芽孢杆菌培养物中分离得到的一种独特的大环肽类抗生素。从各种菌株中也分离到了许多类似的大环抗菌肽。该肽(1)包括一个特征的主结构，一个被称为片段A的2，3，6-多噻唑取代的吡啶骨架，C(A-C)(2)由多取代的吡啶和噻唑脱氢多肽部分组成。1及其类似的多肽具有抑制细菌蛋白质合成的作用，其有趣的结构和生物活性吸引了我们对其全合成和构效关系进行研究。迄今为止，尚未有此类多肽抗生素的全合成报道。然而，最近我们简要地报道了以3-氰基-6-二甲氧甲基-2-吡啶为原料，经12步反应，合成了一种非常有前景的前体片段A-C片段(2)。此外，在本报告中，在两个重要的残基片段B和D的新合成之后，通过两个末端的噻唑羧酸与得到的两个片段的片段缩合，以及随后的脱保护和最终的环合，首次从2合成了微球菌素P。此外，除了2，3，6-三和2，3，5，6-四取代吡啶骨架Ge 2270A和诺西肽的简便合成外，微球菌素P_1和P_2的合成也在进行中。

Micrococcins P,P_1, and P_2 (1), isolated from the culture of Bacillus pumilus, are unique macrocyclic peptides antibiotics. Many similar macrocyclic antibiotic peptides have been also isolated from various kinds of stains. The peptide (1) includes a characteristic main structure, a 2,3,6-polythiazole-substituted pyridine skeleton called Fragment A with C (A-C) (2) composed of multisubustituted pyridine and thiazole-dehydropeptide moieties. Not only the interesting structure but also the bioactivity of 1 and other similar peptides, which exhibit inhibitory action of bacterial protein synthesis, attracted us to investigate their total synthesis and structure-bioactivity relationship.So far, the total synthesis of any such peptide antibiotics has not been reported. Recently, however, we have reported briefly on the useful synthesis of a very promising precursor Fragment A-C segment (2) from 3-cyano-6-dimethoxymethyl-2-pyridine via 2-bromoacetyl-3- [5-ethoxycarbonyl] thiazole-6-dimethoxymethyl-pyridine in twelve steps.In this report, after the novel syntheses of the two important residual segments, Fragment B and D,the first total synthesis of micrococcin P out of 1 was achieved from 2 via the fragment condensations of the two terminal thiazole carboxylic acids with the obtained two Fragments, and subsequent deprotection and final cyclization.Furthermore, the syntheses of micrococcins P_1 and P_2 are also investigating, besides the convenient syntheses of the central 2,3,6-tri-and 2,3,5,6-tetrasubsti tuted pyridine skeletons of GE 2270 A and nosiheptide.