6 ゲルセミンの合成研究(口頭発表の部)
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Gelsemine (1), an alkaloid isolated from Gelsemium sempervirens (Carolina jasmine), has been a popular target for synthetic chemists because of its challenging, close-packed structure. While three total syntheses of (±)-gelsemine via its minor congener, 21-oxogelsemine (2), were reported in 1994, none of these groups has succeeded in controlling the stereochemistry of the spiroindolinone moiety. Herein we report a stereocontrolled total synthesis of (±)-21-oxogelsemine (2). As illustrated in our retrosynthetic analysis of gelsemine (Scheme 1), we planned to construct the critical bicyclo[3.2.1] system 3 by means of a divinylcyclopropane rearrangement of 4 with a complete control of the stereochemistry of the spiroindolinone. The requisite intermediate 7 could be prepared easily by following the protocol reported by Kondo et al. for their prostaglandin synthesis. While condensation of 7 with oxindole furnished a 4:1 mixture of E-and Z-isomers, 8 and 9, use of 4-iodooxindole 10 gave the desired Z-isomer 11 as the sole product. When heated at 90℃ for 30min, the divinylcyclopropane 12 underwent a smooth rearrangement to give exclusively the desired bicyclic product 13 in 98% yield. Since the endo-side of 15 is completely blocked by the indolinone, the Michael addition of MeNH_2 to the α,β-unsaturated ester occurred entirely from the less hindered, exo-side to give the trans-isomer 16. The amine 16 was then converted to the relatively stable carbamoyl chloride 20 in an eight-step sequence. Upon treatment with AgOTf and Ag_2CO_3 in CH_2Cl_2 at 45℃, 20 underwent cyclization to give the lactam 21, which, on acid hydrolysis, provided the aldehyde 22. Olefination with Tebbe reagent followed by oxymercuration^<4b> with Hg(OTf)_2 furnished the 6-membered ether 24. Incidentally, attempted oxymercuration prior to the construction of the lactam ring resulted in the exclusive formation of the undesired 5-membered ether. A two-step deprotection of the N-MOM group yielded (±)-21-oxogelsemine (2), which was identical with an authentic sample (^1H and ^<13>C NMR). Since 21-oxogelsemine can be reduced to gelsemine (1) with AlH_3 or DIBAL, our present work constitutes a formal total synthesis of (±)-gelsemine.
- 天然有機化合物討論会の論文
- 1995-09-01
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