臺灣博碩士論文加值系統

天然物Citreamicin δ是由檸檬小單胞菌Micromonospora citrea所萃取而得到的，其架構為氧二苯甲酮(xanthone)及異喹啉酮(isoquinlinone)所組成的多芳香環化合物。
在天然物的回溯合成中，我們將Citreamicin δ做切割並分別得到異喹啉酮片段2及氧二苯甲酮片段10兩個重要的中間物。在合成氧二苯甲酮片段10方面，我們可以利用化合物37經由IBX氧化及利用鹼性條件進行分子內環合反應兩步來得到；而化合物37是由商業上可購得的兒茶酚(catechol)及間苯三酚(trihydroxybenzene)分別合成到醛化合物12及四個甲氧基化合物15再做接合而得到。醛化合物12可由兒茶酚經過甲基保護、溴化反應、鋰溴置換引進醛基、Baeyer- Villiger反應，最後選擇性在苯環上引進醛基而得到；而化合物15可以利用間苯三酚作為起始物經由甲基保護、引進醛基再使用過氧化物進行Baeyer- Villiger反應之後在搭配碳酸氫鈉試劑將苯環上的羥基進行甲基保護而得到；最後再-78 ℃低溫條件下利用正丁基鋰將化合物12及15接合而得到化合物37。
另一方面，化合物53可視為異喹啉酮片段2的前趨物。在合成上，我們可以利用4-溴苯甲酸(4-bromobenzoic acid)當作起始物經過醯胺化反應、Sonogashira反應、最後利用第二丁基鋰在苯環上引進醛基等三個步驟而得到。
未來我們希望可以利用合成到的中間產物進而完成天然物Citreamicin δ的合成。

Natural Citreamicin δ, which is isolated by lemon young Shan spore fungus Micromonospora citrea, features a fused aromatic compound consisting of xanthone and isoquinlinone structural moieties.
Retrosynthetic disassembly of Citreamicin δ provides isoquinlinone derivative 2 and xanthone derivative 10 as potential intermediates. The xanthone derivative 10 is accessible from 37 in two steps through an IBX- promoted oxidation and subsequent base-promoted intramolecular coupling of hydroxyarene with aryl ketone. Intermediate 37 was further disconnected into aldehyde 12 and tetramethoxybenzene 15, which are accessible from commercially available cheap catechol and trihydroxybenzene respectively. Aldehyde 12 was produced through base-promoted methylation of catechol, NBS-mediated arene-bromination, n-butyllithium-mediated formylation, application of Baeyer- Villiger reaction, protection of aryloxy, and regioselective formylation of arene. Conventional methylation of trihydroxybenzene, POCl3/DMF mediated arene formylation, H2O2-promoted Baeyer- Villiger reaction, and K2CO3-promoted methylation afforded tetramethoxybenzene 15. Treatment of 15 with n-butyllithium at -78 ℃ followed by quenching with aldehyde 12 produced the desired diarylmethanol 37.
On the other hand, 2-formyl-4-(2-silylethynyl)-N,N-diethylbenzamide 53 might serve as the precursor to the isoquinlinone moiety 2. A facile construction of 53 has been realized by virtue of the development of a three-step strategy involving addition of N,N-diethylamine to the 4-bromobenzoic acid derived benzoyl chloride, palladium-catalyzed direct coupling of arylbromide 51 with trimethyacetylene, and formylation of the aryl anion derived from s-butyllithium-promoted deprotonation of diethylbenzamide. Future efforts will direct toward elaboration of these intermediates into natural Citreamicin δ.

第一章 緒論------------1
第二章 結果與討論-------------4
2-1 Citreamicin δ回溯合成(I)-------- 4
2-2 製備黃酮類化合物----------6
2-3 Citreamicin δ回溯合成(II)--------7
2-4 合成醚類化合物--------------8
2-5 形成酯類化合物-----------9
2-6 合成醛類化合物-----------10
2-7 製備上保護化合物----------11
2-8 合成酮類化合物------------12
2-9 製備黃酮類化合物---------- 13
2-10 合成醇類化合物----------14
2-11 合成黃酮類化合物-----------15
2-12 測試錕類化合物-------------16
2-13 製備炔類化合物------------17
2-14 製備醛類化合物---------- 18
第三章 結論-----------19
第四章 實驗部份---------20
4-1 一般實驗----------20
4-2 儀器------------20
4-3 實驗藥品--------- 21
4-4 縮寫表-------22
4-5 化合物的合成與鑑定--------- 23
第五章 參考文獻---------48
附件一 化合物光譜圖-------S1

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