利用D-(-)-quinic acid合成(+)-Lycoricidine和 Polyhydroxylated Fluoroazepanes

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Title:	利用D-(-)-quinic acid合成(+)-Lycoricidine和 Polyhydroxylated Fluoroazepanes
Other Titles:	Total syntheses of (+)-Lycoricidine and Polyhydroxylated Fluoroazepanes from D-(-)-quinic acid
Authors:	吳昆達;Wu, Kuen-Da
Contributors:	淡江大學化學學系碩士班施增廉;Shih, Tzenge-Lien
Keywords:	生物鹼;醣水解酵素抑制劑;石蒜西定;奎寧酸;分子內赫克反應;氮雜環庚烷;二乙胺基三氟化硫;含氟氮雜環庚烷;alkaloids;Glycosidase inhibitors;(+)-lycoricidine;D-(-)-quinic acid;intramolecular Heck reaction;Azasugars;Azepanes;DAST;fluoroazepanes;fluoropiperidines
Date:	2011
Issue Date:	2011-12-28 18:06:36 (UTC+8)
Abstract:	近年來，許多關於生物鹼(alkaloid)及醣水解酵素抑制劑(glycosidase inhibitors)的設計與合成被廣泛報導，並引起學術界和工業界的濃厚興趣。因為這些分子被認為可用於治療癌症、糖尿病、病毒感染等疾病。石蒜科(Amaryllidaceae)植物中，含有許多種類的生物鹼。而生物鹼擁有相當好的生物活性，但其在植物中的含量相當少。所以我們選擇(+)-Lycoricidine作為合成目標，以D-(-)-quinic acid為起始物當作C環的來源，主要是利用分子內赫克反應(intramolecular Heck reaction)，經過12個步驟合成出(+)-Lycoricidine分子。七圓環之azasugars(或稱為azepanes)醣水解酵素抑制劑較五圓環與六圓環之醣類衍生物在結構上更具可變性(flexibility)。將氟原子引入azasugars分子中，有助於改變其生物特性。於是我們以D-(-)-quinic acid為起始物，使用DAST引入氟原子並產生重排反應(rearrangement)，可以得到一系列的polyhydroxylate fluoroazepanes和polyhydroxylate fluoropiperidines。另一方面，研究中發現具N-alkyl之azepanes有助於提升其生物活性。基於這個原因，我們也將氟原子加入N-alkyl azepanes，期望能有效提高活性。 Recently, the syntheses of alkaloids and glycosidase inhibitors have attracted a great deal of attention in academies and industries. These molecules are potential in the treatment of cancers, diabetes and viral infections. Some naturally occurring alkaloids possess interesting biological activities but obtained in minute amounts from plants. The plant of Amaryllidaceae family produced many alkaloids. Among them, we describe a new total synthesis of (+)-lycoricidine in twelve steps from D-(-)-quinic acid which constructed the C ring. The key step involved a intramolecular Heck reaction. On the other hand, the seven-membered azasugars are more flexible than five and six-member rings in structures. The introduction of a flurorine atom into azasugars can profoundly alter their biological properties. From this point of view, we define a new approach to synthesize a series of polyhydroxylate fluoroazepanes and fluoropiperidines. It is worth noting that the fluoropiperidines were obtained from the corresponding azepanes that mediated rearrangement by DAST. In addition, the N-alkyl azepanes were also investigated that may be potentially enhanced biological activities. During this course, the flurorine atom was also introduced into the N-alkyl azepanes in order to evaluate their activities.
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