一、重氮化合物與亞胺分子製備全取代之1,2,3-三唑 二、有機催化連鎖Michael加成/半縮醛化反應 三、(±)-Viroallosecurinine的全合成

Abstract

本論文有三個研究主題，第一部分為全取代之1,2,3-三唑分子的合成。1,2,3-三唑是具生物活性分子的重要架構，文獻中，以炔類及疊氮分子為反應物，進行[3+2]環加成反應而合成之；然而，合成全取代之1,2,3-三唑的方法，有的步驟繁複，或者需金屬催化劑的參與及高溫條件，反應方可進行。在此，我們開發新穎的反應類型，以重氮化合物與亞胺分子為起始物，在DBU的作用下，於溫和的反應條件，一步反應得到[3+2]環加成產物－1,4,5-全取代-1,2,3-三唑，產率為60-95%；歸納實驗結果，推測合理的反應機構；此外，產物之雜環架構中的四號位置為酯基，可經由不同的化學反應，轉換為多樣化之官能基，為此反應增添合成上的應用性。 第二部分以不對稱有機催化之連鎖反應，合成高鏡像選擇性之苯色烯衍生物。含氧原子的六員雜環架構，常見於天然物及藥物分子，有效建構它們的立體選擇性，在合成化學領域非常重要。本論文發展新穎的連鎖Michael加成 ∕ 半縮醛化反應，以-四氫萘酮和,-不飽和醛類為起始物，在L-脯胺酸衍生之有機催化劑的作用下，於最佳化的反應條件，製備苯色烯衍生物，高達99%之產率及80-96% ee的鏡像選擇性；將產物進一步氧化為-環戊內酯後，經X-ray單晶解析，確認新建立之立體中心為(S)-form，並推測了合理的反應機構，此連鎖反應提供合成高鏡像選擇性之含氧六員雜環分子的新途徑。 第三部分為天然物(±)-Viroallosecurinine的全合成，由美國Colorado State University的John L. Wood教授指導完成。以-環戊內酯為起始物，經由15個步驟，成功合成天然物(±)-Viroallosecurinine，總產率約為5%；其中，與苯基丙烯醇的連鎖銠催化之O－H嵌入 ∕ Claisen rearrangement ∕ 1,2-allyl轉移反應，可建構具有立體中心的三級醇，有效控制其立體化學，進而合成所有的Securinega生物鹼，此為本合成策略之優勢，最終合成之(±)-Viroallosecurinine的NMR光譜，與文獻比對後確認之。

There are three parts of research topics in this thesis. The first topic is an alternative and direct access to fully-substituted 1,2,3-triazoles. Treatment of diazo compound with 4-methoxyaniline derived aryl imines in the presence of DBU provided ethyl 1-(4-methoxyphenyl)-5-phenyl-1H-1,2,3-triazole-4-carboxylate in good to high yields. A reasonable mechanism is proposed that involves the addition of an imine nitrogen atom to the terminal nitrogen atom of the diazo compound, followed by aromatization to give the 1,2,3-triazole. The presence of the 4-carboxy group is advantageous as it can be easily transformed into other functional groups. The second topic is the synthesis of benzo[f]chromenols via asymmetric organocatalytic domino Michael/Hemiacetalization process. Treatment of -tetralones with ,-unsaturated aldehydes in the presence of diphenylprolinol silyl ether gave 2,3,5,6-tetrahydro-1-alkyl/aryl-1H-benzo[f]chromen-3-ol derivatives with high to excellent chemical yields (50-99%) and high levels of enantioselectivities (up to 96% ee). The stereochemistry of newly generated stereogenic center is determined as (S)-form by X-ray analysis of oxidized chromenol. A reasonable mechanism is proposed that undergoes iminium ion-catalyzed Michael addition followed by hemiacetalization to complete the domino sequence. The third topic is the total synthesis of (±)-Viroallosecurinine, which is supervised by Professor J. L. Wood in Colorado State University. Total Synthesis of (±)- Viroallosecurinine is described that utilize a rhodium carbenoid-initiated O-H insertion/Claisen rearrangement/1,2-allyl migration domino process for the stereoselective introduction of the tertiary alcohol moiety. The strategy is flexible and allows access to other members of the Securinega alkaloids. (±)-Viroallosecurinine is synthesized from -valerolactone in 15 steps with 5% overall yield.