(1)催化劑控制的化學環化反應合成吲哚/吡咯稠合二氮雜草和喹喔啉(2)通過氮雜克萊森型重排金屬催化區域選擇性合成異喹啉[1,2-a]異喹啉(3)自由基皮克特－施彭格勒反應合成四氫異喹啉的雜環小分子衍生物

(1)Catalyst-Controlled Chemodivergent Annulation to Indolo/Pyrrolo- Fused Diazepine and Quinoxaline(2)Metal-catalyzed regioselective synthesis of isoquino [1,2-a] isoquinolines via Aza-Claisen type rearrangement(3)Synthesis of Tetrahydroisoquinoline Heterocyclic Small Molecule Derivatives via Radical Pictet-Spengler Reaction

邱偉榕(Wei-Jung Chiu)

指導教授 ： 孫仲銘

國立交通大學/理學院/應用化學系所/碩士(2019年)

摘要

第一部分:
含有雜原子的化合物是在大量銷售的市售藥物中最為突出的實體。在所有雜原子分子中，苯並咪唑，苯並硒唑，吲哚和吡咯被認為是醫藥和藥物發現的特權核心。特別地，這些生物學上重要的雜環稠合/連接的雜環分子被認為是醫藥和藥物發現研究中的著名支架。因此，稠合和連接的雜環分子的合成是必須被關注。本論文涉及生物學上有趣的稠合和連接的雜環的設計和合成。
報導催化劑控制的化學反應環化策略，以便從易取得的鄰位-吲哚苯胺與重氮酯作為偶聯配偶體的反應中獲得二氮雜草[1,7-a]吲哚和吲哚並[1,2-a]喹喔啉。在 Rh（III）催化劑下，反應通過胺基輔助的 C2-H 活化進行，然後酰胺化，以高選擇性方式得到二氮雜草[1,7-a]吲哚。在 Ru（II）催化劑下，反應包括了 Ru-卡賓配合物的形成，然後通過金屬-烯類反應以及 β-氫脫去反應，最後進行 -NH2 基團的插入和級聯環化，得到吲哚並[1,2-a]喹喔啉。
這種新開發的催化劑控制策略廣泛適用於一系列產率極高的吲哚稠合二氮雜草/喹喔啉以及吡咯並稠合的二氮雜草/喹喔啉支架的構建。我們相信這種方法可以開闢催化和有機合成領域的新途徑。
第二部分:
我們成功開發出具有區域選擇性的合成異喹啉[1,2-a]異喹啉的方法。首先，以皮克特－施彭格勒反應合成具有四氫異喹啉骨架的化合物，再與烯丙基溴反應後，在一價金催化劑存在下進行了六元環的環化及重排的級聯反應。該級聯反應的過程涉及到金屬催化環化反應，及烯丙基由氮原子遷移到乙烯的過程。
第三部分:
為了得到具有生物活性的 2-硫代乙内酰脲(2-thiohydantoin)環(B)，我們以自由基的方式進行皮克特－施彭格勒反應，先形成具有抗菌及抗腫瘤活性的四氫異喹啉骨架化合物後，再與異硫氰酸酯反應後，得到具有生物活性的雜環小分子結構。

關鍵字

二氮雜草 ； 喹喔啉 ； 金屬催化 ； 四氫異喹啉

並列摘要

The first part:
Compounds containing heteroatoms are the most prominent entities in commercially available drugs that are sold in large quantities.Among all heteroatom molecules, benzimidazole,benzoselenazole, guanidine and pyrrole are considered to be the privileged core of drug and drug discovery.In particular, these biologically important heterocyclic fused/linked heterocyclic molecules are considered to be well known scaffolds in medical and drug discovery research. Therefore, the synthesis of fused and linked heterocyclic molecules must be taken care of this paper deals with the design and synthesis of biologically interesting fused and linked heterocycles.A catalyst-controlled chemical reaction cyclization strategy was reported to obtain diazepam [1,7-a] fluorene and hydrazine from the reaction of the readily available ortho-anisidine and diazonium ester as coupling partners.And [1,2-a] quinoxaline.Under Rh(III) catalyst, the reaction is carried out by amine-assisted C2-H activation followed by amidation to obtain diazepam [1,7-a]pyrene in a highly selective manner.Under the Ru(II) catalyst, the reaction involves the formation of a Ru-carbene complex, followed by a metal-olefin reaction and a β-hydrogen removal reaction, and finally the insertion of the -NH2 group and the cascade cyclization to obtain a ruthenium. Indole [1,2-a] quinoxaline.This newly developed catalyst control strategy is broadly applicable to the construction of a series of very high yields of ruthenium diazide/quinoxaline and pyrrole fused diazapest/quinoxaline scaffolds.We believe this approach opens up new avenues in the fields of catalysis and organic synthesis.
The second part:
We have successfully developed a regioselective method for the synthesis of isoquinoline [1,2-a]isoquinolines.First of all, the tetrahydroisoquinoline skeleton is synthesized by a Pictet-Spengler reaction, and then reacted with allyl bromide to carry out cyclization and rearrangement of a six-membered ring in the presence of a monovalent gold catalyst.The process of this cascade involves a metal catalyzed cyclization reaction and a process in which the allyl group migrates from the nitrogen atom to ethylene.
The third part:
In order to obtain the biologically active 2-thiohydantoin ring (B), we perform the Pictet-Spengler reaction by radical to form a tetrahydroisoquinoline skeleton compound having antibacterial and antitumor activity, and then it will react with isothiocyanate, a biologically active heterocyclic small molecule structure is obtained.

並列關鍵字

Diazepine ； Quinoxaline ； Metal-catalyzed ； Tetrahydroisoquinoline

參考文獻

(1) (a) Battaglia, S.; Boldrini, E.; Settimo, F.D.; Dondio, G.; Motta, C.L.; Marini, A.M.; Primofiore, G. Eur. J. Med. Chem. 1999, 34, 93. (b) Przhevalskii, N.M.; Magedov, I.V.; Drozd, V. N. Chem. Heterocycl. Comp. 1997, 33, 1475. (c) Hiari, Y. M. A.; Qaisi, A. M.; Abadelah, M. W.; Voelter, W. Chemie. 2006, 137, 243. (d) Tan, D.X.; Chen, L.D.; Poeggeler, B.; Manchester, L. C.; Reiter, R. J. Endocr. J., 1993, 1, 57. (e)Suzen, S.; Buyukbingol, E. II Farmaco, 1998, 53, 525. El-Gendy Adel, A.; Abdou Naida, A.; El-Taber, Z. S.; El-Banna Hosny, A. Alex. J. Pharm. Sci. 1997, 7, 99. (f)Kumar, A.; Archana, Sharma, S.; Malik, N.; Sharma, P.; Kushik, K.; Saxena, K. K.; Srivastava, V. K. Indian J. Chem. B., 2004, 43, 1532. (g) Smith, A. L.; Stevenson, G. I.; Swain, C. J.; Castro, J. L. Tetrahedron Lett., 1998, 39, 8317.

(2) (a) Singh, T. P.; Singh, O. M. Mini-Rev. Med. Chem .2018, 18, 9. (b) Zhang, M. Z.; Chen, Q.; Yang, G. F,; Eur. J. Med. Chem. 2015, 89, 421. (c) Chen, H.; Bai, J.; Fang, Z. F.; Yu, S. S.; Ma, S. G.; Xu, S.; Li, Y.; Qu, J.; Ren, J. H.; Li, L.; Si, Y. K.; Chen, X. G. J. Nat. Prod. 2011, 74, 2438.

(3) Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. J. Med. Chem. 2014, 57, 5845.

(4) (a) Bhardwaj, V.; Gumber, D.; Abbot, V.; Dhiman, S.; Sharma, P. RSC Adv., 2015, 5, 15233. (b) Kaur, R.; Rani, V.; Abbot, V.; Kapoor, Y.; Konar, D.; Kumar, K. J. Pharm Chem Chem Sci. 2017, 1, 17. (c) Wilkerson, W. W.; Copeland, R. A.; Covington, M.; Trzaskos, J. M. J. Med. Chem. 1995, 38, 3895. (d) Wurz, R. P.; Charette, A. B.; Org. Lett., 2005, 7, 2313. (e) Lee, H.; Lee, J.; Lee, S.; Shin, Y.; Jung, J. H.; W.; Kim, K. Park, K. Kim, Cho, H. S.; Ro, S. Bioorg. Med. Chem. Lett., 2001, 11, 3069.

(5) (a) Beke, G.; Eles, J.; Boros, A.; Farkas, S.; Keseru, G. M. PCT WO 2016/166684A1, 2016. (b) Fuk-Wah, S.; John, D.; Efren, D. S.; George, G.; Marvin, R.; Xumei, D.; Albright, J. D.; Peter, C.; Joseph, C.; Xun, R.; Hossein, M.; Trina, S. Bioorg. Med. Chem. Lett. 2009, 19, 627.