Total Synthetic Study of a Few Thiostrepton Macrocyclic Peptides

几种硫链丝菌素大环肽的全合成研究

• 批准号: 08640698
• 负责人: SHIN Chung-gi
• 金额: $ 1.6万
• 依托单位: Kanagawa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08640698/
• 关键词: Thiostrepton antibiotics ;; alpha-Dehydroamino acid ;; Dehydropeptide ;; 2,3,6-tri-and 2,3,5,6-tetrasubstituted pyridine ;; Micrococcins P,P_1 and P_2 ;; GE 2270 A ;; Nosiheptide.; ベルニナマイシン; ミクロコッシンP_1; チオストレプトン抗生物質

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.

从短小芽孢杆菌（Bacilluspumilus）培养物中分离得到的微球菌素P_1、P_2（1）是一类独特的大环肽类抗生素。许多类似的大环抗生素肽也已从各种菌株中分离出来。肽（1）包括一个特征性的主要结构，一个2，3，6-聚噻唑取代的吡啶骨架，称为片段A与C（A-C）（2），由多取代的吡啶和噻唑-脱氢肽部分组成。1及其他类似肽类抗生素不仅具有有趣的结构，而且具有抑制细菌蛋白质合成的生物活性，这吸引了我们对其全合成及其构效关系的研究，但迄今为止，此类肽类抗生素的全合成还未见报道。然而，最近，我们简要地报道了一个非常有前途的前体片段A-C片段（2）的合成，该片段由3-氰基-6-二甲氧基甲基-2-吡啶经2-溴乙酰基-3- [5-乙氧羰基]噻唑-6-二甲氧基甲基-吡啶经十二步合成。由2经两个末端噻唑羧酸与得到的两个片段缩合、脱保护、环合，首次实现了1中微球菌素P的全合成，并对微球菌素P_1和P_2的合成进行了研究，此外，GE 2270 A和那西肽的中心2，3，6-三取代和2，3，5，6-四取代吡啶骨架的方便合成。

项目成果

C.Shin et.al.: "A Convenient Synthesis of Fragment E of Antibiotic,Nosiheptide" Heterocycles. 43. 891-898 (1996)

C.Shin 等人：“抗生素、那西肽”杂环化合物片段 E 的便捷合成。

Y.Yonezawa et.al.: "Total Syntheses of Naturally Occurring Bis(methylthio)silvatin and its Three Stereoisomers." Heterocycles. 44. 1151-1159 (1997)

Y.Yonezawa 等人：“天然存在的双（甲硫基）西伐汀及其三种立体异构体的全合成”。

K.Umemura et.al.: "Synthesis of Central Heterocyclic Skeleton of Antibiotic,A10255." Chem.Lett.1203-1204 (1997)

K.Umemura 等人：“抗生素中央杂环骨架的合成，A10255”。

C.Shin et.al.: "Total Synthesis of Antibiotic,Micrococcin P,from 2,3,6-Polythiazolesubstituted Pyridine Skeleton[Fragment A-C]" Chem.Lett.139-140 (1998)

C.Shin 等人：“从 2,3,6-聚噻唑取代的吡啶骨架[片段 A-C] 抗生素微球菌素 P 的全合成”Chem.Lett.139-140 (1998)

C.Shin et.al.,: "Total Synthesis of Antibiotic,Micrococcin P,from 2,3,6-Polythiazolesubstituted Pyridine Skeleton[FragmentA-C]" Chem.Lett.,. 139-140 (1998)

C.Shin 等人，：“从 2,3,6-聚噻唑取代的吡啶骨架 [片段 A-C] 抗生素微球菌素 P 的全合成”Chem.Lett.，。