28 (+)-ビンブラスチンの全合成(口頭発表の部)

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Vinblastine (1), isolated from Catharanthus roseus, has been widely used in cancer chemotherapy, and a variety of derivatives have been derived from vinblastine to search for more efficient drugs. In addition, its complex structure has attracted a great deal of attension of many synthetic chemists, and several total syntheses have been reported, which, however, employed natural vindoline (2) as starting material. For the effective preparation of a range of derivatives, total synthesis of the whole vinblastine is essential. Herein, a total synthesis of (+)-vinblasitne, including (-)-vindoline, is reported. We planned to prepare the two indole parts, which constitute vinblastine, and couple these indole parts near the last stage of the synthesis. The preparation of the bottom part, vindoline (2), which we have already reported, has been improved for a large-scale preparation. The requisite indole fragment was synthesized utilizing radical cyclization of thioanilide 7, followed by Mannich reaction of malonate to give acrylate derivative 9. The preparation of 2,4-dinitrobenzensulfonamide 10 was carried out via enzymatic resolution of the cyanohydrin intermediate. The upper part of vinblastine was prepared as indoloazacycloundecane 42. The stereoselective introduction of the tertially alcohol was performed by a combination of 1,3-dipolar cycloaddition of nitrile oxide and Baeyer-Villiger oxidation (29 to 33). The indole nucleus was formed utilizing radical cyclization of thioamide 36. Construction of the 11-membered ring was successfully achieved by macrocyclization of nosyl amide 40. The coupling of 42 with (-)-vindoline (2) occurred with the desired stereochemistry to afford 45 as a sole isomer and further manipulations afforded (+)-vinblastine (1), whose spectroscopic data were identical to those of the natural sample.
天然有機化合物討論会の論文
2001-09-01

28 (+)-ビンブラスチンの全合成(口頭発表の部)

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