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)
スポンサーリンク
概要
- 論文の詳細を見る
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
著者
-
佐々木 誠
東京大学大学院工学系研究科博士課程
-
佐々木 誠
東北大院生命科学
-
佐々木 誠
東北大学大学院生命科学研究科
-
塚野 千尋
東北大学大学院生命科学研究科分子生命科学専攻・博士後期課程
-
海老根 真琴
東北大院生命科学
-
塚野 千尋
東北大院生命科学
関連論文
- 超高層分譲マンションの住戸平面計画および住棟計画上の特徴
- P-72 鈴木-宮浦カップリング反応を基盤とする天然物全合成(ポスター発表の部)
- ポリエーテル系天然物全合成の最近の進歩
- 39 海産ポリエーテル系天然物ブレベナールの全合成と構造改訂(口頭発表の部)
- 64(P-47) 海産毒ガンビ***ールの多様な構造改変体の全合成と構造活性相関(ポスター発表の部)
- ポリエーテル系天然物の化学合成 : 新しい中員環エーテル構築法とエーテル環連結法の開発
- 5615 首都圏に暮らす単身女性の住空間・ライフスタイルの実態 : 22のケーススタディを通して(女性と家族の住まい,建築計画II)
- 5640 隣接グラフによるコーポラティブ住宅の住戸平面構成の分析(シェア居住・コレクティブ・コーポラティブ(2),建築計画II)
- 5659 自由設計型集合住宅における計画の枠組みと入居者に関する考察(集合住宅の内部空間計画,建築計画II)
- 首都圏で供給される民間分譲マンション大型住戸の建築計画上の特徴