白藜蘆醇

【中文品名】白藜蘆醇 （bái lí lú chún）
【藥效類別】抗腫瘤藥，抗血栓藥
【通用藥名】RESVERATROL
【別　　名】Protykin Resveratrol (Natrol), Resveratrol Antioxidant Protection (Source Naturals)
【化學名稱】 1,3-Benzenediol, 5-[(1E)-2-(4-hydroxyphenyl)ethenyl]
【中文化學名稱】3，4′，5-三羥基-反-均二苯代乙烯（3，4′，5-trihydroxysitlbene)
【CA登記號】[501-36-0]
【結 構 式】

RESVERATROL

【分 子 式】CHNOPS·
【分 子 量】228.24
【來源】葡萄皮葡萄籽、白藜蘆、日本虎杖、金銀花、藍莓、蔓越莓、花生皮、桑白皮、菠蘿蜜、大黃漏蘆、歐洲赤松、云杉、紫荊花、桉樹
【理化性質】為無色無味針狀結晶，難溶于水（0.03 g/L），易溶于乙醚、氯仿、甲醇、乙醇（50 g/L）和丙醇，在波長365nm的紫外光照射下能產生熒光，并能和三氯化鐵-鐵氫化鉀起顯色反應。
【存在形式】順式白藜蘆醇、反式白藜蘆醇、順式白藜蘆醇苷和反式白藜蘆醇苷四種
【收錄藥典】各國藥典
【首次發現】1940年首次從毛葉藜蘆（veratrum grandiflorum）的根部分離得到
【性　　狀】為無色無味針狀結晶

【藥理作用】
（1）抗腫瘤作用
（2）治療心血管病作用
（3）抗氧化、抗自由基作用
（4）保肝作用
（5）雌激素樣作用和影響骨代謝作用
（6）調節免疫
（7）抗病毒
（8）抗細菌及真菌
（9）抗變態反應
（10）輻射防護
（11）預防急性傳染性非典型肺炎
【用　　途】廣泛應用于醫藥、保健品、化妝品和食品添加劑等領域

【推薦合成路線】

白藜蘆醇的合成

一、3,5-二甲氧基芐醇（2）的合成
3,5-二甲氧基苯甲酸(5.0g，27.5mmol)加至無水乙醚(150 ml)中，攪拌下分批加入LiAlH4(1.0g，26.3mmol)，微回流反應18h。緩慢滴加稀鹽酸至無氣泡產生且未分層時停止，得灰色混懸液。過濾，濾液減壓濃縮回收乙醚，殘余物靜置后凝固成白色固體（2）(4.3g，93.2%)，mp 46～47℃。

二、3,5-二甲氧基溴芐（3）的制備
（2）(1.g，11.3mmol)加至甲苯(10 ml)中，攪拌下加入40%氫溴酸(5ml)，于60～80℃油浴中反應3h后，減壓濃縮回收甲苯。濾出析出的固體，水洗至中性，甲醇重結晶，得棕色片狀晶體（3）(1.58g，56.6%)，mp 71～72℃。

三、3,5,4′-三甲氧基二苯乙烯（5）的制備
（3）(2.2g，9.7 mmol)和亞磷酸三乙酯(5ml)于攪拌下回流反應1h，減壓蒸除過量的亞磷酸三乙酯，得淡黃色液體磷酸3,5-二甲氧基芐基二乙酯

（4），直接用于下一步反應。
所得（4）溶于DMF(7ml)，于冰水浴中加入甲醇鈉(1.2g，22.2mmol)并攪拌15min。向上述反應液中加入茴香醛(2.3g，16.9mmol)，冰水浴中反應1h，室溫反應過夜。所得黃色混懸液傾至冷水(60 ml)中，過濾，濾餅用水洗滌，再分別用95%乙醇、無水乙醇二次重結晶，得白色片狀晶體（5）(1.92g，73%)，mp 56.5℃。元素分析(C17H18O3)實測值(計算值,%)：C 75.82(75.53)，H 6.80(6.71)。
四、白藜蘆醇（1）的合成

（5）(0.27g，1mmol)加至二氯甲烷(5ml)中，攪拌至溶解。滴加1mol/L的BBr3的二氯甲烷溶液(10ml)，室溫攪拌反應2h，TLC跟蹤反應[展開劑為丙酮—正己烷(1:2)]。反應液傾至冰水(30ml)中，用乙酸乙酯萃取(20ml×2)，合并有機層，用無水硫酸鎂干燥，過濾后減壓蒸除溶劑，得淡黃色固體。用50%乙醇重結晶，得白色結晶（1）(0.20g，90%)，mp 256～257℃。

【光譜數據】
1HNMR(DSMO-d6)：δ6.11(1H, t, H-4)，6.38(2H, d, H-2,6)， 6.75(2H, d, H-3′,5′)，6.81, 6.93(each 1H, d, -CH=CH-)，7.39(2H, d, H-2′,6′)，9.18(2H, s, OH-3,5)，9.54(1H, s, OH-4′)
【其它合成路線】

Wittig反應通過Wittig試劑(磷Ylide等)與醛、酮的羰基發生親核加成反應，形成烯烴。此方法簡便，但產率較低。目前，已有很多利用Wittig反應合成白藜蘆醇的報道。

【白藜蘆醇的生物合成】

白藜蘆醇作為芪類次生代謝物廣泛存在于種子植物中，其主要通過苯丙氨酸代謝途徑合成的；其中最為關鍵的調節酶是二苯乙烯合酶，也叫做稱芪合酶（Stilbenesynthase，簡稱STS）。

植物芪類次生代謝物生物合成途徑

芪合酶在植物中多以基因家族存在，到目前為止，已克隆的芪合酶可分為2種類型：一種為白藜蘆醇合成酶（Resveratrolsynthase，簡稱RS）（EC2.3.1.95），又被稱為3，4′，5-三羥基二苯乙烯合酶，主要存在與花生以及葡萄中，以丙二酰輔酶A和4-香豆酰輔酶A為底物合成白藜蘆醇；第二種為赤松素合成酶（EC2.3.1.146），以丙二酰輔酶A和肉桂酰輔酶A為底物合成赤松素（Pinosylvin）。研究表明，白藜蘆醇合成酶是白藜蘆醇合成代謝途徑中最后一個起作用的關鍵酶，也是整個合成途徑中唯一必需的合成酶。

詳細有關白藜蘆醇的生物合成信息請參考[41]

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