26 Type III分泌機構阻害剤Guadinomine類の不斉全合成、及び絶対構造決定(口頭発表の部)

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Enteropathogenic Escherichia coil (EPEC) belong to a family of related bacterial pathogens, including enterohemorrhagic E. coli (EHEC) O157: H7 and other human and animal diarrheagenic pathogens that form attaching and effacing lesions on host epithelial surfaces. Intimate attachment requires the type III-mediated secretion of bacterial proteins, several of which are translocated directly into the host cell. Therefore, it may be possible that the interruption of type III-mediated secretion relieves infectious diarrhea without elimination of microbial pathogens. In the course of a search for inhibitors of the type III-mediated secretion system in microorganisms, Guadinomine C_1 (1), C_2 (2) and K01-0509 B (3) were discovered from the fermentation broth of Streptmyces sp. K01-0509. Due to the significant activity and the unique structure of 1 and 2, we undertook their total synthesis. We achieved the asymmetric total synthesis and determination of absolute configuration of Guadinomine C_2 (56), involving asymmetric syntheses of 3'-epi-Guadinomine C_2(49) and K01-0509 B (13) and simple piperazinone compounds (24, 30, 32). The total synthesis of 3, a plausible biosynthetic intermediate of 1 and 2, features Sharpless asymmetric epoxidation and the stereocontrolled introduction of the cyclicguanidine with asymmetric nitroaldol reaction, followed by iodine-mediated redox cyclization. These reactions allowed the cyclic guanidine part and the adjacent hydroxy group to be assembled effectively. The syntheses of model compounds including the piperazinone and peptide unit of 1 and 2 feature Evans aldol reaction, regioselective azidolysis, S_N2 cyclization and condensation. By using these successive reactions, we established the synthetic route to the piperazinone moiety and elucidated its stereochemistry. Finally, we completed the efficient synthesis of Guadinomine C_2 and its epimer through the enantioselective preparation of diol, entailing asymmetric α-aminooxylation and diastereoselective nucleophilic addition. Piperazinone and peptide units plus the cyclic guanidine part were built up as well as model compounds and K01-0509 B. The synthetic strategy enabled us to complete the first asymmetric total synthesis and determination of absolute configuration of Guadinomine C_2.
天然有機化合物討論会の論文
2006-09-15

26 Type III分泌機構阻害剤Guadinomine類の不斉全合成、及び絶対構造決定(口頭発表の部)

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