Synthetic Study on Antitumor Antivacterial Marine Alkaloid Manzamine A

抗肿瘤抗菌海洋生物碱曼扎明A的合成研究

• 批准号: 04671283
• 负责人: TORISAWA Yasuhiro
• 金额: $ 1.28万
• 依托单位: Chiba University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1992
• 资助国家: 日本
• 起止时间: 1992 至 1993
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-04671283/
• 关键词: manzamine A; dihydropyridiones; Diels-Alder reaction; pyrroloisoquinoline; azocin lactam; Wittig reaction; PFP ester; Diels-Alder(D-A)反応; アゾシンラクラム; 脱ベンゼンスルホニル; PEPエステル; 中心4環性化合物; β-カルボリン環; 3環性重要中間体; Pictet-Spenglar反応

For the challenging construction of the complex azacyclic core structure of manzamine A, we have been investigating a viability of the Diels-Alder reaction of 3-alkyldihydropyridinones. Thus, after various attempts on the search for a suitable dienophile partner as well as on the practical reaction conditions, we have found the high-pressure D-A reaction of 1 with Danishefsky diene, which furnished the tricyclec core structrue (2) of manzamine A.After this initial success, we have developed another moer practical and efficient D-A reaction of the two new dienophiles (3), which have NCOCF_3 group at the side chain. With this dienophiles, D-A reaction proceeded under normal pressure to afford the enone (4). Utilizing this key reaction, the new tricyclic ley intermediate (5) was prepared, which was efficiently converted to the alchohol (6). Oxidation of 6 followed by the Witting reaction allorded the acid (7) which was then purified by the PFP ester (8). Careful deprotection and base treatment of 8 furmished the tetracyclic core (9) of manzamine A.

对于具有挑战性的建设复杂的氮杂环核心结构的manzamine A，我们一直在研究的可行性的Diels-Alder反应的3-烷基二氢吡啶酮。因此，经过对寻找合适的亲双烯体配偶体以及实际反应条件的各种尝试，我们发现了1与Danishefsky二烯的高压D-A反应，该反应提供了Manzamine A的三环核心结构（2）。在这一初步成功之后，我们开发了两种新的亲双烯体的另一种更实际和有效的D-A反应（3），其侧链上具有NCOCF_3基团。与此亲双烯体在常压下进行D-A反应，得到烯酮（4）。利用这一关键反应，合成了新的三环类中间体（5），并将其高效地转化为醇（6）。6经氧化后进行Witting反应得到酸（7），然后用PFP酯（8）纯化。对8进行仔细的脱保护和碱处理，得到了manzamine A的四环核心（9）。

项目成果

M.Nakagawa et al: "Dihydropyridinone Approach to Manzamines:An Expedient Construction of the Tetracyclic Core of Manzamine A." Tetrahedron Letters. 34. 4543-4546 (1993)

M.Nakakawa 等人：“Manzamines 的二氢吡啶酮方法：Manzamine A 四环核心的便捷构建”。

M.Nakagawa et al: "Efficient Michael Addition Reactions of the N-Arylsulfonyl-3-Phenylthiopiperidones.Synthesis of 3-Substituted Dihydropyridinones" Heterocycles. 35. 1157-1170 (1993)

M.Nakakawa 等人：“N-芳基磺酰基-3-苯基硫代哌啶酮的高效迈克尔加成反应。3-取代的二氢吡啶酮的合成”杂环。

Y.Torisawa: "Synthetic Studies on Manzamine A II:A Novel Diels-Alder Approach to the pyrrolo[2,3-j]isoquinolire Skeleton." Tetrahedron Letters. 31. 3195-3198 (1990)

Y.Torisawa：“Manzamine A II 的合成研究：吡咯并[2,3-j]异喹啉骨架的新颖 Diels-Alder 方法。”

T.Hino: "Synthesis of Bioactive Nitrogen Heterocycles from Marine Orgasms" Journal of Heterocyclic Chemistry. 31. (1994)

T.Hino：“从海洋性高潮中合成生物活性氮杂环”杂环化学杂志。

Y.Torisawa: "Diels-Alder Reactions of Dihydropyridinones:Synthetic Entry to the Manzamine A Tricyclic Core" Journal of Organic Chemistry. 57. 5741-5747 (1992)

Y.Torisawa：“二氢吡啶酮的狄尔斯-阿尔德反应：曼扎明三环核心的合成”有机化学杂志。