124(P-82) Cystothiazole Aおよびその立体配座固定型類縁体の合成と抗真菌活性(ポスター発表の部)

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Cystothiazoles and Melithiazoles are potent antifungal β-methoxyacrylate antibiotics (MOAs) isolated from nature in 1998-1999. These compounds having the aromatic ring-containing chain structures extended from their β-position of β-methoxyacrylate moieties. This structural feature is in interesting contrast to well-known and studied α-substituted MOAs such as Strobilurins and Oudemansins. Since then, extensive synthetic studies of β-substituted MOAs have been carried out and total syntheses of Cystothiazole A were already reported by four academic groups. On the other hand, in the course of our synthetic and pharmacological SAR studies on MOAs, 9-methoxystrobilurin-type β-substituted MOA was designed and synthesized as an artificial conformationally-locked model compound. Interestingly, this compound showed more potent antifungal activity than the Oudemansin-type β-substituted MOA having the Cystothiazole-like saturated-type substructure on the same 4-5 position. This result strongly suggested the pharmacological superiority of the conformationally-locked analogue of Cystothiazole A which has not yet been reported. We report here the total synthesis and antifungal activities of Cystothiazole A and its two types of conformationally-locked analogues. Total synthesis of Cystothiazole A was successfully achieved by the original synthetic strategy based on the Lewis acid-catalyzed asymmetric Mukaiyama aldol reaction. Unfortunately, the synthesis of methyl enol ether-type analogue was not completed by the first approach due to the difficulty of the construction of methyl enol ether moiety at the 4-5 position. Then, our efforts have been directed toward a development of new synthetic route including the construction of this moiety at an early stage of the synthesis. The desired methyl enol ether-type analogue was successfully obtained via Claisen condensation of a thiol ester intermediate bearing the methyl enol ether moiety. A convergent synthesis was planned for the aromatic-type analogue, then an efficient preparation of intermediate aromatic aldehyde bearing the β-methoxyacrylate moiety was developed. The Wittig reaction of the aldehyde with bisthiazole-type phosphorous ylide was carried out and the desired aromatic-type analogue was obtained stereoselectively. Antifungal activities of synthesized compounds against representative five kinds of strains were examined by disk-diffusion assay. The methyl enol ether-type analogue showed the most potent activity, and the predicted superiority of the conformationally-locked analogue is clearly proved. In contrast, the aromatic-type analogue was less effective than Cystothiazole A. These results indicated the importance of further development of more chemically stable and potent substructure for the 4-5 position of β-substituted MOAs.
天然有機化合物討論会の論文
2004-10-01

124(P-82) Cystothiazole Aおよびその立体配座固定型類縁体の合成と抗真菌活性(ポスター発表の部)

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