摘要
天然物(±)-Mersicarpine在2004年由Kam及其團隊從蕊木屬(Kopsia)中分離出來，具有單萜吲哚生物鹼(monoterpene indole alkaloids)之二氫吡啶吲哚酮結構，為非典型之四環結構且具有兩個掌性中心，其中在吲哚3號位具有一個七環亞胺。在本研究中，為了完成Mersicarpine的全合成，我們共探索了兩代不同的合成路徑，依據逆合成分析，我們先將其多環結構分為吲哚(indole)及庚烷骨架，並嘗試在吲哚C-1、C-2、C-3號位建立碳氮鍵及碳碳鍵。 第一代路徑中，我們先將4-氧代庚二酸二乙酯合成五環內酯結構，隨後接上吲哚並嘗試在吲哚C-2號位建立碳碳鍵。然而無論進行酸/鹼水解、還原皆無法製備之後的起始物，且會環化形成最初的內酯結構，吲哚也十分不穩定，容易脫落。因此我們將吲哚改為吲哚啉(indoline)重新嘗試，但仍得到相同的結果，故我們改成先接上醯胺。 之後我們延續第一代的五環內酯結構，直接使用吲哚啉將內酯進行開環，再將吲哚啉氧化生成吲哚。但氧化時羥基會攻擊吲哚啉並形成內酯結構，因此我們決定先將羥基接上保護基以避免此情況發生，然而生成內酯的速率仍較接上保護基快，且發現此結構置於空氣中時會自然合環，因此我們終止五環內酯結構的測試並設計新的合成路徑。 第二代路徑中，我們先將4-氧代庚二酸二乙酯進行威悌反應(Wittig reaction)形成雙鍵後得到關鍵的起始物，並以自由基反應建立C-2號位的碳碳鍵得到關鍵的四級碳中心，再經由幾個步驟之後，最終，我們成功合成(±)-mersicarpine。
並列摘要
(±)-Mersicarpine, a monoterpene indole alkaloids natural product containing a particular dihydropyridoindolone skeleton, was first isolated from the Kopsia (蕊木屬) in 2004 by Kam and co-workers. The unusual tetracyclic framework of mersicarpine possesses two chiral centers and a seven-membered ring imine at the C-3 position of indole. In this research, we explored two different synthetic routes to racemic mersicarpine. Based on our retrosynthetic analysis, we divided the polycyclic structure into indole and heptane skeleton, and endeavored to construct the carbon-nitrogen bond and the carbon-carbon bonds at the C-1, C-2 and C-3 position of indole, respectively. In the first approach, diethyl 4-oxopimelate was converted into a five-membered ring lactone and then the resulting product was connected to indole. we tried to build a carbon-carbon bond on the C-2 position of indole through intramolecular cyclization. Nevertheless, neither hydrolysis nor reduction could generate the desired starting materials for further reaction, and the intermediate always returned to the lactone structure. The indole moiety of the intermediate was also unstable, and tended to dissociate. Hence, we substituted indole with indoline and retried this synthetic approach but faced similar failure. Thus, we shifted to making amide first. Then we continued to use indoline to open the five-membered ring lactone directly before oxidation to indole. Yet, the tertiary hydroxyl group would attack the amide, giving back the lactone under various conditions. To avoid this situation, we decided to install a protecting group on the hydroxyl group, but the reaction rate of lactonization was still faster than the protection of the hydroxyl group. Furthermore, we found this structure would decompose to lactone spontaneously upon storage. Hence, we stopped utilizing lactone and designed a new synthetic pathway. In the second generation, diethyl 4-oxopimelate was subjected to a Wittig reaction to form a carbon-carbon double bond, and the connection of 2-iodoindole was carried out through the amide bond formation. Next, we utilized a radical reaction to form carbon-carbon bond at the C-2 position to construct the key quaternary center. Following a few more steps, we successfully synthesized natural product (±)-mersicarpine.
參考文獻
1. http://gardentia.net/2012/12/06/kopsia-gulabi-tagar-4/.
2. Kam, T.-S.; Subramaniam, G.; Lim, K.-H.; Choo, Y.-M., Mersicarpine, an Unusual Tetracyclic Dihydroindole Alkaloid Incorporating a Seven-Membered Imine Ring. Tetrahedron Lett. 2004, 45, 5995-5998.
3. Magolan, J.; Carson, C. A.; Kerr, M. A., Total Synthesis of (±)-Mersicarpine. Org. Lett. 2008, 10, 1437-1440.
4. Biechy, A.; Zard, S. Z., A Flexible, Convergent Approach to Polycyclic Indole Structures: Formal Synthesis of (±)-Mersicarpine. Org. Lett. 2009, 11, 2800-2803.
5. Desmaéle, D.; d'Angelo, J., Stereocontrolled Elaboration of Quaternary Carbon Centers through the Asymmetric Michael Reaction Using Chiral Imines: Enantioselective Synthesis of (+)-Aspidospermidine. J. Org. Chem. 1944, 59, 2292-2303.