15 Norzoanthamineの全合成研究(口頭発表の部)  [in Japanese] 15 Synthetic Studies of Norzoanthamine  [in Japanese]

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Zoanthamine (1) and norzoanthamine (2) are marine alkaloids with significant biological activities. In particular, norzoanthamine and its hydrochloride suppress decrease in bone weight and strength in ovariectomized mice without increase of the uterine weight, and are considered to be a promising candidate for an ostcoporotic drug. In addition to their potential medicinal interest, zoanthamine and norzoanthamine are challenging target molecules from a synthetic point of view due to their complex heptacyclic ring system including aminal structure. During the course of our studies directed toward total synthesis of norzoanthamine, we examined an enantioselective route to the fully functionalized heterocyclic aminal core 3. Pentacyclic heterocyclic 3 contains four of the five quaternary chiral centers, including three contiguous ones, in zoanthamine and norzoanthamine. Our basic strategy is to construct the pentacyclic 3 from monocyclic precursor 5 by sequential cyclization. As a cyclization precursor we selected 6 in which cyclohexanone is protected as ethyleneketal and aminoalcohol moiety is protected as Cbz- or Boc- substituted N,O-acetal. The synthesis of the key intermediate 6 was accomplished by the coupling of the aldehyde 7 and sulfone 8, which were prepared from (+)-Wieland-Miescher ketone and D-glutamic acid, respectively. It should be noted that the stereochemical control of contiguous quaternary chiral centers in 7 was achieved by the stereoselective cuprate addition to W.-M. ketone. After a number of experiments, N-substituted aminal 19a and 19b were isolated in good yields when 6a and 6b were treated with 2N HCl in THF. N-Cbz aminal 19a was then subjected to a hydrogenolysis, and the pentacyclic aminal 3 was isolated in 71% yield after treatment of the reaction mixture with MS3A. The pentacyclic aminal core 3 was also obtained from Boc derivative 19b by stirring in aqueous acetic acid at 100℃ followed by the Na_2SO_4 treatment. The structure of 3 was supported by ^1H- and ^<13>C-NMR spectra which were in good accordance with those of norzoanthamine. Finally, one-step cyclization of Boc derivative 19b to 3 was achieved in 89% yield. This is the first example of the synthesis of the characteristic moiety of zoanthamine/norzoanthamine family. Concerning the cyclization of monocyclic precursor, we observed that the (R)-methyl isomer 6c gave only spiroketal 21, and 6c did not cyclize to pentacyclic aminal 22 by aqueous acetic acid treatment. We believe that the present methodology developed here could be applicable to the total synthesis of norzoanthamine, and are currently doing effort toward this goal.


  • Symposium on the Chemistry of Natural Products, symposium papers

    Symposium on the Chemistry of Natural Products, symposium papers (41), 85-90, 1999-09-01

    Symposium on the chemistry of natural products


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