Total Syntheses of Thiostrepton Macrocyclic Antibiotics Constructing of Unusual Amino Acid Residues and Heterocyclic Ring Moieties

异常氨基酸残基和杂环结构的硫链丝菌素大环抗生素的全合成

• 批准号: 12640529
• 负责人: SHIN Chung-gi
• 金额: $ 2.3万
• 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: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12640529/
• 关键词: Thiostrepton antibiotics; Dehydropeptide; Thiazolylthiazole derivative; GE 2270 A; Cyclothiazomycin; Berninamycin A,B; Thiocillines; ベルニナマイシン

The synthetic studies of a few macrocyclic thiostrepton antibiotics, GE 2270 A, berinamycins A and B, thiocillines, nosiheptide, and cyclothiazomycin have proceeded extensively. For examples, synthesis of the protected linear precursor [Fragment A-B-C'] of GE 2270 A was achieved by coupling of a 2,3,6-tristhiazolyl-substituted pyridine skeleton [Fragment A-C'] with a thiazolylthiazole segment [Fragment B]. The Fragment B was synthesized from an appropriate thioamide and β-bromo-α-oxoalkanoate, the latter of which was first derived by consecutive β-bromonation and hydrolytic removal of the α-(N-Boc)amino group of α-dehydroamino acid ester. Furthermore, with regard to the synthesis of cyclothiazomycin, first, the 2-[2-(2-thiazol-4-yl)thiazol-4-yl]thiazoline-4-carboxylate [Fragment A], attached to the 6-substituent of the main pyridine skeleton, was synthesized by two consecutive thiazolations of the protected Ser thioamide derivative with bromopyruvate and then thiazolination of the C-terminal Ser residue of the sequence. Secondly, a synthesis of the central (1'R)-2-{2-[2-(1-aminoethylpyridin-6-yl]thiazol-4-yl}thiazoline-4-carboxylate [Fragment B] was also achieved by thiazolation of the formyl group of the 2-(1-amino)ethyl-6-formylpyridine derivative and then thiazolation. Thirdly, a synthesis of the protected dehydrotetrapeptide [Fragment C], which is bound to the 2-substituent of the pyridine skeleton, was attained by the stepwise elongation of the appropriate α-amino acids and β-elimination of a Thr residue of the sequence. Finally, the fragment condensation of the three Fragments gave the protected Fragment A-B-C.

几种大环硫链丝菌素类抗生素GE 2270 A、berinamycins A和B、硫代西林、那西肽和环噻唑霉素的合成研究已经广泛进行。例如，GE 2270 A的受保护的线性前体[片段A-B-C ']的合成是通过将2，3，6-三噻唑基取代的吡啶骨架[片段A-C']与噻唑基噻唑片段[片段B]偶联来实现的。片段B是由适当的硫代酰胺和β-溴-α-氧代链烷酸酯合成的，后者首先通过连续的β-溴化和水解除去α-脱氢氨基酸酯的α-（N-Boc）氨基得到。此外，关于环噻唑霉素的合成，首先，通过用溴丙酮酸盐将受保护的Ser硫代酰胺衍生物进行两次连续噻唑化，然后将该序列的C-末端Ser残基噻唑化，合成了连接至主吡啶骨架的6-取代基的2-[2-（2-噻唑-4-基）噻唑-4-基]噻唑啉-4-羧酸酯[片段A]。其次，通过2-（1-氨基）乙基-6-甲酰基吡啶衍生物的甲酰基的噻唑化，然后噻唑化，也实现了中心（1 ′ R）-2-{2-[2-（1-氨基乙基吡啶-6-基]噻唑-4-基}噻唑啉-4-羧酸酯[片段B]的合成。第三，通过逐步延长适当的α-氨基酸和β-消除序列的Thr残基，合成了与吡啶骨架的2-取代基结合的受保护的脱氢四肽[片段C]。最后，三个碎片的碎片凝聚，得到了被保护的碎片A-B-C。

项目成果

A.Okabe, C.Shin, et al.: "Convenient Synthesis of a Central Antibiotic, 2,3,6-Trissubstituted Pyridine of a Macrocyclic Skeleton Antibiotic Cyclothiazomycin"Chem.Lett.,. 380-381 (2001)

A.Okabe、C.Shin 等人：“大环骨架抗生素环噻唑霉素的中心抗生素 2,3,6-三取代吡啶的便捷合成”Chem.Lett.，。

Y. Yonezawa, H. Saito, S. Suzuki, and C. Shin: "A Synthesis of a Hydroxyvalie-derived Thiazole-4-carboxylate Constituting an Antibiotic, Thiocilline I"Heterocycles. (in press).

Y. Yonezawa、H. Saito、S. Suzuki 和 C. Shin：“羟基缬氨酸衍生的噻唑-4-羧酸酯的合成，构成抗生素硫代青霉素 I”杂环。

T.Suzuki, C.Shin, et al.: "Convenient Synthesis of a Fragment B and Linear Main Skeleton [Frabment A-B-C'] Derivatives of an Antibiotic, GE 2270 A"Heterocycles. 835-840 (2001)

T.Suzuki、C.Shin 等人：“抗生素 GE 2270 A 片段 B 和线性主骨架 [片段 A-B-C] 衍生物的便捷合成”杂环。

T. Yamada, K. Okumura, Y. Yonezawa, and C. Shin: "Useful Synthesis of the Main Dehydrohexapeptide Segment of a Macrocyclic Antibiotic, Berninamycin B"Chem. Lett.. 102-103 (2001)

T. Yamada、K. Okumura、Y. Yonezawa 和 C. Shin：“大环抗生素 Berninamycin B 的主要脱氢六肽片段的有用合成”Chem。

T.Suzuki, C.Shin, et al.: "Convenient Synthesis of a Frabment B and Linear Main Skeleton [Frabment A-B-C'] Derivatives of an Antibiotic, GE 2270 A"Heterocycles. 835-840 (2001)

T.Suzuki、C.Shin 等人：“抗生素 GE 2270 A 片段 B 和线性主骨架 [片段 A-B-C] 衍生物的便捷合成”杂环。