9 IL-6活性阻害剤Madindolineの不斉全合成と絶対構造の決定(口頭発表の部)

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Interleukin 6 (IL-6) is a multifunctional cytokine that act on immune response, hematopoiesis and the nervous system. Thus, IL-6 plays one of the central regulatory roles in host defense mechanisms. However, it has been demonstrated that IL-6 produced by tumor cells causes cancer cachexia, and also stimulates the proliferation of tumor cells in an autocrine/paracrine manner. Therefore, it may be possible that the inhibition of IL-6 activity relieves cancer cachexia and suppress the growth of IL-6 dependent tumor cells. In the course of a search for inhibitors of IL-6 activity obtained from microoragnisms, madindoline A (MDL-A) and B (MDL-B) were discovered from the fermentation broth of Streptomyces nitrosporeus K93-0711. We describe here the determination of the complete absolute stereochemistries of MDL-A and B and the first total syntheses of these materials. As our point of departure, asymmetric aldol reaction of oxazolidinone 5 with acrolein followed by methanolysis afforded β-hydroxyester 7. Stereoselective aldol reaction of 7 with methacrolein furnished diolefin 8. Ring closing metathesis of 8 afforded cyclopentene 10. Selective silylation of 10 with TBSOTf followed by oxidation provided the α,β-unsaturated ketone 12. Michael addition of 12 with n-Bu_2CuLi, phenylselenylation, oxidative elimination, and isomerization of double bond furnished ketone 14. Selective reduction of 14 followed by silylation and DIBAL reduction afforded 15. Dess-Martin oxidation of 15 followed by reductive N-alkylation with indoline 17 furnished 18. Deprotection of 18, selective silylation, and MnO_2 oxidation followed by acid hydrolysis afforded indole 19. Finally asymmetric oxidative ring closing of 19 afforded 1 and 2. The synthetic 1 was identical in all respects with a sample of the natural MDL-A. Moreover fourtunately single-crystal X-ray diffraction has now been employed to elucidate the abusolute stereochemistry of 1. The first total synthesis of MDL-A has thus been achieved via a highly convergent, efficient strategy.
天然有機化合物討論会の論文
1999-09-01

9 IL-6活性阻害剤Madindolineの不斉全合成と絶対構造の決定(口頭発表の部)

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