药物合成讲稿重排反应药物合成反应讲义课件

1、Chapter 5重排反应(Rearrangement RXN)MGABMGABMG（Migrating Group）: 迁移基团；A及B为迁移的起点和终点原子1By Xioawen XueChina Pharmaceutical University定义：指在同一分子内， 某一原子或基团从一个原子迁移 至另一个原子而形成新分子的反应。2分类：根据迁移起点及终点原子之间的位置，可分为1, 2迁 移、1, 3迁移根据迁移起点及终点原子的种类，可分为从碳原子到碳 原子的重排、从碳原子到杂原子的重排以及从杂原子到 碳原子的重排。根据反应机理， 可分为亲核重排、亲电重排、自由基 重排及协同反应（迁移重

2、排）。3NucleophilicElectrophilic4CH35CH3PhCCH2 CHOCH3 PhCCH2CH3CH3CCH2Ph CH3CH3HCCH2Ph CH3（tBuO)2Free radical协同反应 Concert65.1 亲核重排7主要介绍从C原子到C原子的亲核重排以及从C原子到N原子的亲核重排一. Wagner-Meerwein Rearrangement定义：有机分子在催化剂作用下生成碳正离子，其结构 中的烷基、芳基或氢从一个碳原子通过过渡态迁 移至相邻带正电荷碳原子的反应称 Wagner- Meerwein Rearrangement。Mechanism8a. 反

3、应物结构：凡能生成正碳离子的化合物，如醇、卤 烃、 烯烃、胺及环氧化物等反应影响因素OH9NHTsOPPh3NHTsNHTs HNHTsArCO2PPh3DEAD 2ArCO - CH3 CH3CH3CH3CH3CH3CH3CH3CH3 CH3H3C TsOH10b. 基团迁移：1. 形成更稳定的碳正离子（ SN1 ）环张力 （环状体系）反式共平面规则（环状体系，SN2 ）11MeOMeOHHH3COHNH2NaNO2 / HOAc12在药物合成中的应用13KW-2189a DNA minor groove-binding agentEgor Egorovich Vagner. Born 18

4、49, in Kazan; died 1903, in Warsaw. Russian organic chemist.In 1874, Vagner graduated from the University of Kazan. From 1882 he was a professor at Novoaleksandr Institute of Agriculture, and from 1886 he was a professor at Warsaw University. In 1888 he developed a general method of oxidizing ethyle

5、ne bonds with permanganate. His name is associated with the Wagner- Meerwein rearrangement (1899).14Hans Meerwein (1879-1965). Born in Hamburg, he studied chemistry at the Fresenius chemistry schoolbefore going to Bonn. After taking his doctorate at the polytechnic in Berlin- Charlottenburg, he retu

6、rned to Bonn. He later held Chairs at Knigsberg and Marburg.Meerweins main interest was carbonium ion chemistry. In 1914, during his study of the pinacol-pinacolone rearrangement, he generalised Egor Vagners mechanism for the conversion of a-pinene into bornyl chloride (Wagner-Meerwein rearrangement

7、).Meerweins name is also associated with theMeerwein-Ponndorf-Verley reduction (1925-6).15二. Pinacol重排定义：在酸催化下，邻二叔醇失去一分子水，重排成醛或酮的反应称Pinacol重排。16MechanismNotes: (1). 哪一个羟基脱水通常是由所形成的碳正离子的 稳定性所决定；也可使用特定方法有选择性地将 其中一个脱去形成碳正离子(2). 哪一个基团迁移则由基团的迁移能力、进攻 时的立体化学及产物稳定性多方面因素所决定。 17影响因素a. 反应选择性1819b. 基团的迁移顺序：一般来说

8、，芳基 烷基，带给电子 基的芳基 带吸电子基的芳基MeMe PhCCPhOHOHMeMe PhCCPhOHOMeMeCCPhPhp-MeO-Ph20OHOHPh PhCCPh-OMe-pOPh-OMe-p PhCCPh-OMe-pPhH+OHMeMeOH OH2Me transCOCH3 CH3H+c. 环状化合物中，与离去基团处于反式的基团优先迁移。OH2Me OHMeMeMeOOHMe OHMe cisMeOH21H+d. Semipinacol 重排ORROHLOHRL = X, NH2 etc2223三. 二苯基乙二酮二苯基乙醇酸型重排(Benzil - Benzilic Acid R

9、earrangement）定义：二酮（一般为芳基二酮）用强碱处理发生重排， 生成羟基乙酸盐的反应称为二苯基乙二酮二 苯基乙醇酸型重排 。后反应范围扩展到脂环二酮。24Mechanism25OOSCOOHS1. KOH2. HCl反应影响因素26a. 反应物结构以芳二酮和脂环酮为主，可以是对称的，也可以 是不对称的。对称二酮反应， 产物单一。不对称二 酮反应，也可得到单一产物。OHOOOMeMeHHHOMeHHHKOH, MeOHMe COOHOH60-70%27b. 碱及溶剂所用的碱通常为KOH, NaOH等无机碱，溶剂为水或含水乙 醇。如用醇的碱金属盐为碱，反应产物为酯。28在药物合成中的应

10、用29抗癫痫药苯妥英钠四. Beckmann 重排定义：醛肟（Oxime）或酮肟在酸性催化剂作用下重排 成取代酰胺的反应称Beckmann 重排。30Mechanism31Usually，the group anti to hydroxy group shifts.反应影响因素：a. Catalysts (1). 无机酸（H2SO4、HCl、PPA）有机酸（三氟磺酸）Lewis acids (BX3、AlCl3 、TiCl4 、ZnCl2) (4). 酰化剂（POCl3、PCl5、SOCl2、MeSO2ClTsCl etc）无机酸和有机酸为质子酸，有时会引发异构化。因此， 为避免异构化，可选用

11、Lewis acids 或酰化剂来催化。3233另外，当肟结构中含有对酸敏感的基团时，同样可选用Lewis 酸或酰化剂来催化。OONOHOONHOCH3SO2Cl34TEABF 3110oCb. 溶剂当用质子酸催化，极性质子溶剂常使肟发生异构 化，重排后得混合物。为防止异构化的发生， 可选用非极性或极性小的 非质子溶剂，同时用酰化剂为催化剂。35c. 温度温度对异构化的产生具有较大影响，通常较高的温度 更容易导致异构化。36d. 立体化学那个基团迁移？手性迁移基团在重排后构型保持不变。37在药物合成中的应用38Ernst Otto Beckmann (1853-1923), German ch

12、emist. Beckmann studied chemistry and pharmacy at Leipzig. He taught pharmacy and chemistry at the Technische Hochschule in Brunswick, before moving back to Leipzig as an assistant to Wislicenus. He was briefly a Professor of Physical Chemistry at Leipzig and Giessen in turn before moving to Erlange

13、n.He then became Director of the Laboratory of Applied Chemistry at Leipzig, and finally, Director of the new Kaiser Wilhelm Institute for Physical Chemistry and Electrochemistry in Berlin-Dahlem. His name is associated with the Beckmann thermometer, and the Beckmann rearrangement of oximes to amide

14、s (1886).39五. Hofmann 重排定义：伯酰胺用卤素（溴或氯）及碱处理，脱羧生成比反 应物少一个碳的伯胺的反应称为Hofmann重排。40Mechanism41反应影响因素a.反应所用试剂及溶剂一般使用Br2 / NaOH或NaOCl/NaOH。当大于七个碳的脂 肪酰胺反应时应选用碱性更强的NaOR/ROH，但生成的产物为氨基甲酸酯。42当反应物对碱敏感时，可用其他氧化剂，如NBS、Pb(OAc)4 或高价碘试剂 PhI(OAc)2 或 PhI(OCOCF3)243RNCO44H2OPhI(CF3CO2)2F3COPhOIOI OPhOCF3ORNH2F3COPhOIOIPhNR

15、 OHRNH2b.反应物结构-若酰胺的碳原子为手性碳，那么重排后它的构型保留。45-当酰胺羰基的 或位具有羟基或氨基时，反应产物为环状的氨基甲酸酯或脲。46在药物合成中的应用47August Wilhelm von Hofmann (1818-1892). Born in Giessen and studied under Liebig. Professor at the Royal College of Chemistry in London (1845-1865), and then Berlin (1865- 1892). Associated with the Hofmann reac

16、tion(1881), Hofmann degradation (sometimes mistakenly given to the unrelated Hofmann reaction), Hofmann primary amine test (carbylamine reaction), Hofmann rule, Hofmanns violet, Hofmann method of vapour densities, and the Hofmann voltammeter, which is surely more than enough for one person, even one

17、 as ambitious as AW.48六. Wolff重排、Curtius重排及Schmidt重排简介Wolff重排：-重氮酮在加热、光照或过渡金属催化剂 存在下，重排生成烯酮及其后续衍生物的 反应。初始生成的烯酮与水、醇或胺反应 分别转变成羧酸、酯或酰胺。49ExamplesArndt-Eistert Reaction50Curtius重排：酰基叠氮受热分解生成异氰酸酯的反应。 如反应是在水、醇或胺中进行，那么产物 则分别为胺、氨基甲酸酯和脲。5152在酸存在下，羧酸、酮或醛与叠氮酸 反应，生成胺、酰胺或腈的反应。尽管Schmidt反应的底物范围较宽，但应用最多的是酮，羧 酸与叠氮酸的

18、反应因为类似于Curtius重排，应用相对较少， 而醛与叠氮酸的反应则少之又少。Schmidt重排：53Ludwig Wolff(1857-1919), German chemistry. He studied chemistry at the University of Strasbourg where he received his Ph.D. from Rudolph Fittig in 1882. He became Professor at the University of Jena in 1891 and held this position till his death in

19、1919. The Wolff rearrangement was first reported in 1902. In 1912 he also published a new reaction now known as the Wolff-Kishner reduction.Julius Wilhelm Theodor Curtius (27 May 1857 8 February 1928) was professor of Chemistry at Heidelberg University and elsewhere. He published the Curtius rearran

20、gement in 1890/1894 and also discovered diazoaceticacid, hydrazine and hydrazoic acid.55Karl Friedrich Schmidtno biographical information5.2 亲电重排56主要介绍从C原子到C原子的亲电重排（Favorskii重排） 以及从N原子到C原子的亲电重排（Stevens & Sommelet Rearrangements），这类反应涉及碳负离子的形成。一. Favorskii重排定义：-卤代酮在碱作用下与亲核试剂作用，生成羧酸或其衍生物的反应，称为Favorski

21、i重排。Mechanism57Notesa. -卤代酮可以是链状的，也可以是环状的58b. 当-卤代酮羰基的另一侧没有-氢时，在碱作用下 亦可得到相应的Favorskii重排产物。这个反应与 经典的Favorskii重排不同，称为准Favorskii重排（quasi-Favorskii rearrangement）。c. 除了-卤代酮外，在-位带有其它离去基团（如- 磺酸酯基和,-环氧基等）的酮，也能发生 Favorskii重排。在药物合成中的应用61Alexey Yevgrafovich Favorskii (20 February 1860 - 8 August 1945 ), Russi

22、an Chemist.Favorskii studied chemistry at the imperial University of Saint Petersburg from 1878 to 1882.He joined Alexander Butlerovs laboratory for several years, and in 1891 became a lecturer. In 1895, Favorksii received his PhD and became professor for technical chemistry. He discove- red the Fav

23、orskii rearrangeme- nt in 1894.62二. Stevens 重排定义：季铵盐在碱作用下生成叶立德，氮原子上的一个烃 基发生1,2-迁移，生成叔胺的反应称为Stevens重排63MechanismNotes：EWG(Z): COR, COOR, Ph, 烯烃基及炔烃基等Bases: NaNH2, LDA, RONa, NaOH (KOH) 等区域选择性 (Regioselectivity)：当反应物结构中具有俩个或以上的CH在碱作用下能形成 ylide，那么酸性大的那个优先生成ylide。同时，还应根 据基团的迁移能力来决定迁移基。一般来说，烯丙基、苄 基或吸电子基取

24、代的烷基要比普通的伯烷基优先迁移。644. 改进方法碱性条件下季铵盐的Stevens重排，可能会带来一些副反应，如Hofmann消除等。并且，当季铵盐结构中含有 一个以上的酸性质子时，区域选择性也是必须考虑的一个问题。目前，解决方法之一，是利用卡宾和胺反应的方式，来产生叶立德，既避开了使用碱性试剂，又能控制反应的区域性6566在药物合成中的应用4. 立体化学：如迁移基具有手性，重排后构型保持不变。Thomas Stevens Stevens (8 October 1900- 13 November 2000), English organic chemist who will be remem

25、bered in his field for the almost unique distinction of having discoveredthree reactions: the Stevens Rearrangement of quaternary ammonium salts; the McFadyen- Stevens synthesis of aldehydes; and the Bamford- Stevens elimination reaction, which converts ketones to either alkenes or cyclopropanes.68三

26、. Sommelet-Hauser重排定义：在强碱作用下，由苄基季铵盐重排形成邻位烃基取代的苄基叔胺的反应称为Sommelet-Hauser重排。69Proposed Mechanism:70缺点：Stevens 和 Sommelet 重排之间的竞争反应一般来说，极性溶剂（如液氨、HMPA、DMSO等）和较 低的反应温度，有利于Sommelet-Hauser重排；而非极 性溶剂和较高的反应温度则有利于Stevens重排71Modification：72Marcel Sommelet (18771952) was born in Langes, France. He received his P

27、h.D. in 1906 at Paris where he joined the Facult de Pharmacie of Paris University after WWI and became the chair of organic chemistry in 1934.Charles R. Hauser (1900-1970) was born in California but reared and educated in Florida receiving his B.S. and M.S. from the University of Florida in 1923 and

28、 1925 respectively. His Ph.D. was received from the University of Iowa in 1928. He came to Duke as an instructor in Chemistry in 1929. He was appointed to full professor in 1946 and was named a James B. Duke professor of Chemistry in 1961. Hauser was a member of the National Academy of Sciences.735.

29、3 迁移重排（Sigmatropic Rearrangement）概述：邻近共轭体系的一个原子或基团的键迁移至新的位 置，同时共轭体系发生转移，这种分子内非催化的异 构化协同反应(Concerted Reaction)称为-迁移重排。根据反应中迁移起点和终点原子的编号，可用i,j-迁 移来表示重排类型,如1,3-迁移、1,5-迁移、2,3- 迁移、3,3-迁移等，其中3,3-迁移最常见。本节重 点介绍 Claisen 和 Cope 重排。3,3-迁移74X121233X75一. Claisen 重排定义:酚或烯醇的烯丙基醚加热，重排成邻烯丙基 酚或,-不饱和醛、酮的反应，称为Claisen 重

30、排。可分为脂肪族Claisen 重排和芳香族 Claisen重排两类。76Mechanism771. 芳香族Claisen重排芳基烯丙基醚经Claisen重排，一般得邻位重排产物。如两 个邻位均被取代基占据，则得对位重排产物。若邻对位均有 取代基，那么得间位重排产物。78H3COCH3H3COHCH3CH396%CH3BCl793（1）烯丙醇和乙烯醚的反应H2CCHCH2OH + H2CCHOC2H5CHCH2 CHOH2C H2CHg(OAc)2H2CCHCH2CH2CHO96%80通常首先需制备烯丙基乙烯醚类化合物，然后不经分 离直接进行重排。因此， 本反应的关键是如何制备烯 丙基乙烯醚类

31、化合物。下面介绍几种不同的制备烯丙 基乙烯醚类化合物的方法。2. 脂肪族Claisen重排（2）烯丙醇和原酸酯(orthoester)的反应（Johnson-Claisen重排, William S. Johnson, Stanford,1970)81(3) 羧酸烯丙酯和卤硅烷的反应(Ireland-Claisen Rearrangement, Robert E. Ireland, Caltech,1972)OMeOCMe2CBr MeOMeHOMeMe Me Br1. LiHMDS, TBSCl2. rt, H20 75-85%OHOOOOOTMS3Me SiClNLii-Pri-PrOOT

32、MSOOHH+82heat3.硫代和氨基Claisen重排（了解）当烯丙基乙烯醚中的氧原子用S或N取代后也可进行Claisen重排。83在药物合成中的应用84Rainer Ludwig Claisen (January 14, 1851 January 5, 1930) was a famous German chemist best known for his work with condensations of carbonyls (Claisen-SchmidtCondensation, 1881; Claisen Condensation,1887) and sigmatropic r

33、earrangements (1912). He was born in Cologne and studied chemistry at the university of Bonn (1869), where he became a member of K.St.V. Arminia. He served in the army as a nurse in 1870-1871 and continued his studies at Gttingen University. He returned to the University of Bonn in 1872 and started his academic career at the same university in 1874. He died in 1930 in