98(P-30) プロリンを用いた不斉触媒α-アミノオキシ化反応を鍵反応とするfumagillin,RK-805,FR65814の効率的全合成(ポスター発表の部)

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Fumagillin, TNP-470, fumagillol, RK-805 are angiogenesis inhibitors and are promising lead compounds for the treatment of angiogenesis-related diseases such as cancer and rheumatoid arthritis, while FR65814 is a structurally similar immunosuppressant. Structurally these compounds possess a cyclohexane framework, two epoxides and five or six contiguous chiral centers, three or four of which are on the cyclohexane ring. Because of their novel structure and important biological properties, these compounds have proved attractive targets for many research groups, and several total syntheses have been accomplished, among them pioneering work of Corey. We will disclose a concise, flexible and highly diastereoselective asymmetric total syntheses of RK-805, fumagillol and FR65814 using our recently developed proline mediated α-aminoxylation of carbonyl compounds as a key step. The initial aminoxylation controls the absolute and relative stereochemistry of the subsequently generated chiral centers formed by the following noteworthy diastereoselective transformations: 1) A highly diastereoselective formation of bis-silyl cyanide involving kinetic discrimination. 2) A diastereoselective Michael reaction by the use of vinyl zincate. 3) A stereoselective epoxidation 4) The importance of the order of the two epoxidations for the high diastereoselectivity. 5) A stereoselective reduction.
天然有機化合物討論会の論文
2004-10-01