38(D-8) 細胞毒性ポリ環状エーテル・ギムノシン-Aの全合成(口頭発表の部)

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Gymnocin-A (1) is a polycyclic ether toxin, isolated from the notorious red-tide forming dinoflagellate Karenia mikimotoi. The toxin molecule displays in vitro cytotoxicity against P388 lymphocytic leukemia cells (EC_<50>=1.3μg/mL). Structurally, gymnocin-A is characterized by 14 contiguous and saturated ether rings and a 2-methyl-2-butenal side chain. The number of contiguous ether rings is the largest among the polycyclic ethers hitherto known. Herein, we describe a convergent and efficient total synthesis of gymnocin-A by using our developed B-alkyl Suzuki-Miyaura coupling-based methodology. We planned to assemble the polycyclic ether backbone of 1 by a particularly challenging Suzuki-Miyaura cross-coupling between the ABCD and FGHIJKLMN fragments (2 and 3, respectively). The symmetry elements of fragment 3 allowed further division into two fragments, the GHI and KLMN (4 and 5, respectively) rings, both of which would be derived from a common precursor 6. Common precursor 6 was synthesized by using B-alkyl Suzuki-Miyaura coupling-based methodology, then converted into the GHI (4) and KLMN (5) ring fragments. Hydroboration of 4 followed by Suzuki-Miyaura reaction with 5 provided cross-coupled product 20 in good yield. Ring-closure of the J ring by radical reduction of fused thioketal 22 and formation of the F ring generated the FGHIJKLMN ring fragment 2. Synthesis of the ABCD ring fragment 3 started with tricyclic ether 7, which was elaborated to α,β-epoxy ketone 26. Selenium-mediated reduction of 26 installed the C10 hydroxyl group, and the tetrahydrofuran ring A was constructed by radical cyclization of β-alkoxyacrylate 28 to give ester 29. A further eight-step sequence was required to complete the synthesis of 3. Hydroboration of 3 with 9-BBN and cross-coupling with enol triflate 2 in the presence of aqueous Cs_2CO_3 and Pd(PPh_3)_4 in DMF at room temperature proceeded smoothly to furnish the desired cross-coupled product 31 in excellent yield (81%). The C17 hydroxyl group was installed by stereoselective OsO_4 oxidation of the silyl enol ether, derived from ketone 32. The E ring was formed by radical reduction of fused thioketal 35 to generate tetradecacyclic polyether skeleton 36. Finally, incorporation of a side chain completed the first total synthesis of gymnocin-A (1). The synthetic gymnocin-A was identical to the natural sample by 1^H and <13>^C NMR and MS spectra, thus confirming the structure of gymnocin-A. Moreover, cytotoxicity of synthetic gymnocin-A was comparable to that of natural sample.
天然有機化合物討論会の論文
2004-10-01

38(D-8) 細胞毒性ポリ環状エーテル・ギムノシン-Aの全合成(口頭発表の部)

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