MOOC 药物合成反应 人名反应选讲 Birch 还原反应 主讲人：孟歌

Arthur John Birch Australia organic chemist 1915~1995 From University of Sydney to Oxford PhD It is fitting that the first original experiments performed by Arthur Birch - distillation of eucalyptus leaves - were done on equipment bought from the legacy of a grandmother who called him professors as a child. His family was very poor and only after winning a scholarship at the University of Sydney did he find himself at Oxford to complete a PhD. After a successful research career at Oxford and Cambridge, where he formulated a breakthrough procedure in synthetic organic chemistry now known as the Birch Reduction, he was appointed to the Chair of Organic Chemistry at the University of Sydney. One of the world's great masters in organic chemistry, Birch's research formed the foundation for the manufacture of antibiotic drugs. From 1967-80 he was a foundation Professor at the Research School of Chemistry at the ANU and a leading science administrator and policy adviser. He was President of the Australian Academy of Science and one of the founders of the Australian Science and Technology Council. Birch was made a companion of the Order of Australia. He died, still actively engaged in science and writing, in 1996.

Birch 还原反应的定义 芳香族化合物在醇的存在下在液氨中用钠(锂或钾)还原，生成非共轭二烯的反应称为Birch还原反应。

Birch 还原反应式 反应原理

Birch还原反应的底物延伸 杂环化合物，如吡啶、吡咯和呋喃，也在这种情况下也能被还原。 当芳香化合物被取代时，还原反应的区域选择性取决于取代基的性质：如果取代基是供电子体，还原速度比非取代的化合物慢，取代基可以在新产物的非还原部分找到。在吸电子取代基的情况下，结果是相反的。 共轭烯烃，α,β-不饱和羰基化合物、环内炔烃、和苯乙烯衍生物也是可以被还原的。

Birch 还原反应通式

Birch还原的局限性 普通的烯烃不受Birch还原条件影响，双键如果没有与芳香环共轭不会被还原而存在。 富电子的杂环需要有至少含有一个吸电子的取代基。 所以呋喃和噻吩不会被还原，除非有吸电子取代基的存在。

Birch 还原机理 Typical free radical mechanism If R=EDG then the product is: If R=EWG then the product is: 给电子基产物：1-取代-1,4-环己二烯 吸电子基的产物：1-取代-2,5-环己二烯 Typical free radical mechanism

在Na+EtOH条件下Bouveault-Blanc Reduction还原反应 和在醇钠（EtONa）催化条件下的Claisen缩合反应。 有关Birch 还原条件的知识联想 说明： 1. 醇可是乙醇、异丙醇或仲丁醇等。 2. 区分Na+NH3和NaNH2两个体系 Na+NH3提供电子，还原 NaNH2为强碱，夺氢 联想类比： 在Na+EtOH条件下Bouveault-Blanc Reduction还原反应 和在醇钠（EtONa）催化条件下的Claisen缩合反应。

Birch 还原的影响因素 当苯环上有取代基时： 阴离子自由基 EWG：COOH，EDG：Me

在药物合成中的应用 18-甲基炔诺酮（Norgestrel）中间体的合成： The Birch Reduction enables the modification of steroids. In 1948 Birch published the first total synthesis of a male sex hormone (19-nortestosterone), as the first member of a new structural series. This series later comprised the first oral contraceptive pill, which was made by others. The Birch reduction also allows for the development of other steroid drugs and antibiotics The first simple synthesis of the ring A-B structure of cholesterol..

在有机合成中的应用 2. 取代环己酮衍生物的制备： 环己酮衍生物的合成可以用Birch还原反应制备，可能的原料为：取代苯环衍生物，如苯甲醚和苯胺类。

在有机合成中的应用

在有机合成中的应用 紫杉醇全合成

延伸阅读 Enzymatic Birch Reduction The Birch reduction is a widely used synthetic tool in organic chemistry that achieves 1,4-dihydro additions to benzenoid and other aromatic compounds. The reaction proceeds by alternate electron transfer and protonation steps to the aromatic ring and requires solvated electrons, which are usually generated by dissolving an alkali metal in liquid ammonia. Considering these nonphysiological conditions it is remarkable that a similar reaction exists in biology: the dearomatizing benzoyl-coenzyme A reductase (BCR) plays a key role in the anaerobic degradation of aromatic compounds.

Dearomatizing benzoyl-coenzyme A reductase (BCR) In anaerobic bacteria many low-molecular aromatic growth substrates are converted to the central intermediate benzoyl-CoA (BCoA), which serves as substrate for BCR. The enzyme catalyzes the reduction of BCoA (1) to cyclohexa-1,5-diene-1-carboxyl-CoA (dienoyl-CoA, 2) rather than the kinetically favored 2,5-dienoyl-CoA isomer.

Enzymatic Mechanism A mechanism similar to the classical Birch reduction has been suggested in which the rate limiting first electron transfer yields a radical anion. The CoA ester moiety is considered to stabilize this intermediate by formation of a relatively stable thioester ketyl radical. Remarkably, BCR couples electron transfer to the aromatic ring from the donor reduced ferredoxin (Fd) to a stoichiometric ATP hydrolysis, a reaction that has long been considered as an exclusive feature of nitrogenase. The oxygen sensitive BCR has so far only been isolated from the facultatively anaerobic bacterium Thauera aromatica. Barbel Thiele, Oliver Rieder, Bernard T. Golding, Michael Mu ller, Matthias Boll Mechanism of Enzymatic Birch Reduction: Stereochemical Course and Exchange Reactions of Benzoyl-CoA Reductase，J. AM. CHEM. SOC. 2008, 130, 14050–14051

课后思考题 1. Birch 是哪个国家的有机化学家？ A. 澳大利亚； B. 英国； C. 奥地利； D. 美国； E. 比利时。

课后思考题 2. 下面什么底物能发生Birch 反应？ A. 非共轭的二烯类； B. 含有吸电子取代基的芳香族类化合物； D. 含有供电子基的呋喃环； E. 羰基化合物或取代烯烃类化合物。

课后思考题 3. 下列什么条件下能进行Birch还原么？ A. 冷的氨水中； B. 无水条件下； C. 冷液氨，钠和醇溶液中； D. 水溶液中； E. 室温条件下。

课后思考题 4. 在苯环上含有吸电子取代基的情况下进行Birch 还原反应，吸电子取代基可以在新产物的那部分结构中找到？ A. 非还原的结构部分找到； B. 未参与反应的原料中找到； C. 参与反应的原料中找到； D. 被还原的结构部分找到； E. 副产物的结构中找到。

课后思考题 5. 环己酮衍生物的合成是否可以用Birch还原反应制备，如果可以，请给出可能的原料。 提示： 取代苯环衍生物包括苯甲醚和苯胺类。 答案：ABCD

The end!