8 PI3-キナーゼ阻害剤ワートマンニンの全合成(口頭発表の部)
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Wortmannin (1) is a potent and specific phosphoinositide 3-kinase inhibitor and widely used for the studies on the signal transduction pathways. In spite of the interesting biological activity, 1 has not yet been applied to medical use due to high toxicity. In addition to the medicinal aspect, the challenging structural features of 1 are very attractive from a synthetic point of view. In 1996, we reported the first chemical synthesis of 1 from hydrocortisone as a starting material. Following this primary achievement, we planned to develop a direct total synthesis of 1, hopefully leading to many more derivatives for new types of drugs. Here, we wish to report the first total synthesis of (±)-1. The highly stereoselective construction of allylic quaternary carbon center was achieved (α:β=1:18) using intramolecular Heck reaction with 27. After several elaborations, we found that diosphenol-Claisen rearrangement of 32 was found to be effective for introducing a C-C bond at the sterically hindered neopentyl position. The rearrangement actually proceeded very smoothly under thermal condition and the obtained 33 could be successfully converted into key intermediate lactone 36. After production of 36, furan ring formation remained. The C1 unit for constructing furan ring was introduced by aminomethylenation with HC(NMe_2)_3 and then diosphenol 44 was synthesized by careful transformations. However, unexpectedly, simple acid treatment of 44 only lead to decomposition. Finally, we found clean consumption of 44 by treatment with Et_2NH and successive treatment with 1N HCl afforded furan 46. Final deprotection of TBS and acetylation proceeded to give (±)-1. We are also trying to develop a catalytic asymmetric synthesis of (+)-1. Currently two strategies are being investigated; kinetic resolution using asymmetric Heck reaction and organocatalyst promoted asymmetric cyclization. These results would be also presented.
- 天然有機化合物討論会の論文
- 2002-09-01
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