藥物合成講稿重排反應(yīng)藥物合成反應(yīng)講義課件

1、Chapter 5重排反應(yīng)(Rearrangement RXN)MGABMGABMG（Migrating Group）: 遷移基團(tuán)；A及B為遷移的起點(diǎn)和終點(diǎn)原子1By Xioawen XueChina Pharmaceutical University定義：指在同一分子內(nèi)， 某一原子或基團(tuán)從一個原子遷移 至另一個原子而形成新分子的反應(yīng)。2分類：根據(jù)遷移起點(diǎn)及終點(diǎn)原子之間的位置，可分為1, 2遷 移、1, 3遷移根據(jù)遷移起點(diǎn)及終點(diǎn)原子的種類，可分為從碳原子到碳 原子的重排、從碳原子到雜原子的重排以及從雜原子到 碳原子的重排。根據(jù)反應(yīng)機(jī)理， 可分為親核重排、親電重排、自由基 重排及協(xié)同反應(yīng)（遷移重

2、排）。3NucleophilicElectrophilic4CH35CH3PhCCH2 CHOCH3 PhCCH2CH3CH3CCH2Ph CH3CH3HCCH2Ph CH3（tBuO)2Free radical協(xié)同反應(yīng) Concert65.1 親核重排7主要介紹從C原子到C原子的親核重排以及從C原子到N原子的親核重排一. Wagner-Meerwein Rearrangement定義：有機(jī)分子在催化劑作用下生成碳正離子，其結(jié)構(gòu) 中的烷基、芳基或氫從一個碳原子通過過渡態(tài)遷 移至相鄰帶正電荷碳原子的反應(yīng)稱 Wagner- Meerwein Rearrangement。Mechanism8a. 反

3、應(yīng)物結(jié)構(gòu)：凡能生成正碳離子的化合物，如醇、鹵 烴、 烯烴、胺及環(huán)氧化物等反應(yīng)影響因素OH9NHTsOPPh3NHTsNHTs HNHTsArCO2PPh3DEAD 2ArCO - CH3 CH3CH3CH3CH3CH3CH3CH3CH3 CH3H3C TsOH10b. 基團(tuán)遷移：1. 形成更穩(wěn)定的碳正離子（ SN1 ）環(huán)張力 （環(huán)狀體系）反式共平面規(guī)則（環(huán)狀體系，SN2 ）11MeOMeOHHH3COHNH2NaNO2 / HOAc12在藥物合成中的應(yīng)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重排定義：在酸催化下，鄰二叔醇失去一分子水，重排成醛或酮的反應(yīng)稱Pinacol重排。16MechanismNotes: (1). 哪一個羥基脫水通常是由所形成的碳正離子的 穩(wěn)定性所決定；也可使用特定方法有選擇性地將 其中一個脫去形成碳正離子(2). 哪一個基團(tuán)遷移則由基團(tuán)的遷移能力、進(jìn)攻 時的立體化學(xué)及產(chǎn)物穩(wěn)定性多方面因素所決定。 17影響因素a. 反應(yīng)選擇性1819b. 基團(tuán)的遷移順序：一般來說

8、，芳基 烷基，帶給電子 基的芳基 帶吸電子基的芳基MeMe PhCCPhOHOHMeMe PhCCPhOHOMeMeCCPhPhp-MeO-Ph20OHOHPh PhCCPh-OMe-pOPh-OMe-p PhCCPh-OMe-pPhH+OHMeMeOH OH2Me transCOCH3 CH3H+c. 環(huán)狀化合物中，與離去基團(tuán)處于反式的基團(tuán)優(yōu)先遷移。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）定義：二酮（一般為芳基二酮）用強(qiáng)堿處理發(fā)生重排， 生成羥基乙酸鹽的反應(yīng)稱為二苯基乙二酮二 苯基乙醇酸型重排 。后反應(yīng)范圍擴(kuò)展到脂環(huán)二酮。24Mechanism25OOSCOOHS1. KOH2. HCl反應(yīng)影響因素26a. 反應(yīng)物結(jié)構(gòu)以芳二酮和脂環(huán)酮為主，可以是對稱的，也可以 是不對稱的。對稱二酮反應(yīng)， 產(chǎn)物單一。不對稱二 酮反應(yīng)，也可得到單一產(chǎn)物。OHOOOMeMeHHHOMeHHHKOH, MeOHMe COOHOH60-70%27b. 堿及溶劑所用的堿通常為KOH, NaOH等無機(jī)堿，溶劑為水或含水乙 醇。如用醇的堿金屬鹽為堿，反應(yīng)產(chǎn)物為酯。28在藥物合成中的應(yīng)

10、用29抗癲癇藥苯妥英鈉四. Beckmann 重排定義：醛肟（Oxime）或酮肟在酸性催化劑作用下重排 成取代酰胺的反應(yīng)稱Beckmann 重排。30Mechanism31Usually，the group anti to hydroxy group shifts.反應(yīng)影響因素：a. Catalysts (1). 無機(jī)酸（H2SO4、HCl、PPA）有機(jī)酸（三氟磺酸）Lewis acids (BX3、AlCl3 、TiCl4 、ZnCl2) (4). ?；瘎≒OCl3、PCl5、SOCl2、MeSO2ClTsCl etc）無機(jī)酸和有機(jī)酸為質(zhì)子酸，有時會引發(fā)異構(gòu)化。因此， 為避免異構(gòu)化，可選用

11、Lewis acids 或?；瘎﹣泶呋?233另外，當(dāng)肟結(jié)構(gòu)中含有對酸敏感的基團(tuán)時，同樣可選用Lewis 酸或?；瘎﹣泶呋?。OONOHOONHOCH3SO2Cl34TEABF 3110oCb. 溶劑當(dāng)用質(zhì)子酸催化，極性質(zhì)子溶劑常使肟發(fā)生異構(gòu) 化，重排后得混合物。為防止異構(gòu)化的發(fā)生， 可選用非極性或極性小的 非質(zhì)子溶劑，同時用?；瘎榇呋瘎?5c. 溫度溫度對異構(gòu)化的產(chǎn)生具有較大影響，通常較高的溫度 更容易導(dǎo)致異構(gòu)化。36d. 立體化學(xué)那個基團(tuán)遷移？手性遷移基團(tuán)在重排后構(gòu)型保持不變。37在藥物合成中的應(yīng)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 重排定義：伯酰胺用鹵素（溴或氯）及堿處理，脫羧生成比反 應(yīng)物少一個碳的伯胺的反應(yīng)稱為Hofmann重排。40Mechanism41反應(yīng)影響因素a.反應(yīng)所用試劑及溶劑一般使用Br2 / NaOH或NaOCl/NaOH。當(dāng)大于七個碳的脂 肪酰胺反應(yīng)時應(yīng)選用堿性更強(qiáng)的NaOR/ROH，但生成的產(chǎn)物為氨基甲酸酯。42當(dāng)反應(yīng)物對堿敏感時，可用其他氧化劑，如NBS、Pb(OAc)4 或高價碘試劑 PhI(OAc)2 或 PhI(OCOCF3)243RNCO44H2OPhI(CF3CO2)2F3COPhOIOI OPhOCF3ORNH2F3COPhOIOIPhNR

15、 OHRNH2b.反應(yīng)物結(jié)構(gòu)-若酰胺的碳原子為手性碳，那么重排后它的構(gòu)型保留。45-當(dāng)酰胺羰基的 或位具有羥基或氨基時，反應(yīng)產(chǎn)物為環(huán)狀的氨基甲酸酯或脲。46在藥物合成中的應(yīng)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重排簡介Wolff重排：-重氮酮在加熱、光照或過渡金屬催化劑 存在下，重排生成烯酮及其后續(xù)衍生物的 反應(yīng)。初始生成的烯酮與水、醇或胺反應(yīng) 分別轉(zhuǎn)變成羧酸、酯或酰胺。49ExamplesArndt-Eistert Reaction50Curtius重排：酰基疊氮受熱分解生成異氰酸酯的反應(yīng)。 如反應(yīng)是在水、醇或胺中進(jìn)行，那么產(chǎn)物 則分別為胺、氨基甲酸酯和脲。5152在酸存在下，羧酸、酮或醛與疊氮酸 反應(yīng)，生成胺、酰胺或腈的反應(yīng)。盡管Schmidt反應(yīng)的底物范圍較寬，但應(yīng)用最多的是酮，羧 酸與疊氮酸的

18、反應(yīng)因為類似于Curtius重排，應(yīng)用相對較少， 而醛與疊氮酸的反應(yīng)則少之又少。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 親電重排56主要介紹從C原子到C原子的親電重排（Favorskii重排） 以及從N原子到C原子的親電重排（Stevens & Sommelet Rearrangements），這類反應(yīng)涉及碳負(fù)離子的形成。一. Favorskii重排定義：-鹵代酮在堿作用下與親核試劑作用，生成羧酸或其衍生物的反應(yīng)，稱為Favorski

21、i重排。Mechanism57Notesa. -鹵代酮可以是鏈狀的，也可以是環(huán)狀的58b. 當(dāng)-鹵代酮羰基的另一側(cè)沒有-氫時，在堿作用下 亦可得到相應(yīng)的Favorskii重排產(chǎn)物。這個反應(yīng)與 經(jīng)典的Favorskii重排不同，稱為準(zhǔn)Favorskii重排（quasi-Favorskii rearrangement）。c. 除了-鹵代酮外，在-位帶有其它離去基團(tuán)（如- 磺酸酯基和,-環(huán)氧基等）的酮，也能發(fā)生 Favorskii重排。在藥物合成中的應(yīng)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 重排定義：季銨鹽在堿作用下生成葉立德，氮原子上的一個烴 基發(fā)生1,2-遷移，生成叔胺的反應(yīng)稱為Stevens重排63MechanismNotes：EWG(Z): COR, COOR, Ph, 烯烴基及炔烴基等Bases: NaNH2, LDA, RONa, NaOH (KOH) 等區(qū)域選擇性 (Regioselectivity)：當(dāng)反應(yīng)物結(jié)構(gòu)中具有倆個或以上的CH在堿作用下能形成 ylide，那么酸性大的那個優(yōu)先生成ylide。同時，還應(yīng)根 據(jù)基團(tuán)的遷移能力來決定遷移基。一般來說，烯丙基、芐 基或吸電子基取

24、代的烷基要比普通的伯烷基優(yōu)先遷移。644. 改進(jìn)方法堿性條件下季銨鹽的Stevens重排，可能會帶來一些副反應(yīng)，如Hofmann消除等。并且，當(dāng)季銨鹽結(jié)構(gòu)中含有 一個以上的酸性質(zhì)子時，區(qū)域選擇性也是必須考慮的一個問題。目前，解決方法之一，是利用卡賓和胺反應(yīng)的方式，來產(chǎn)生葉立德，既避開了使用堿性試劑，又能控制反應(yīng)的區(qū)域性6566在藥物合成中的應(yīng)用4. 立體化學(xué)：如遷移基具有手性，重排后構(gòu)型保持不變。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重排定義：在強(qiáng)堿作用下，由芐基季銨鹽重排形成鄰位烴基取代的芐基叔胺的反應(yīng)稱為Sommelet-Hauser重排。69Proposed Mechanism:70缺點(diǎn)：Stevens 和 Sommelet 重排之間的競爭反應(yīng)一般來說，極性溶劑（如液氨、HMPA、DMSO等）和較 低的反應(yīng)溫度，有利于Sommelet-Hauser重排；而非極 性溶劑和較高的反應(yīng)溫度則有利于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 遷移重排（Sigmatropic Rearrangement）概述：鄰近共軛體系的一個原子或基團(tuán)的鍵遷移至新的位 置，同時共軛體系發(fā)生轉(zhuǎn)移，這種分子內(nèi)非催化的異 構(gòu)化協(xié)同反應(yīng)(Concerted Reaction)稱為-遷移重排。根據(jù)反應(yīng)中遷移起點(diǎn)和終點(diǎn)原子的編號，可用i,j-遷 移來表示重排類型,如1,3-遷移、1,5-遷移、2,3- 遷移、3,3-遷移等，其中3,3-遷移最常見。本節(jié)重 點(diǎn)介紹 Claisen 和 Cope 重排。3,3-遷移74X121233X75一. Claisen 重排定義:酚或烯醇的烯丙基醚加熱，重排成鄰烯丙基 酚或,-不飽和醛、酮的反應(yīng)，稱為Claisen 重

30、排?？煞譃橹咀錍laisen 重排和芳香族 Claisen重排兩類。76Mechanism771. 芳香族Claisen重排芳基烯丙基醚經(jīng)Claisen重排，一般得鄰位重排產(chǎn)物。如兩 個鄰位均被取代基占據(jù)，則得對位重排產(chǎn)物。若鄰對位均有 取代基，那么得間位重排產(chǎn)物。78H3COCH3H3COHCH3CH396%CH3BCl793（1）烯丙醇和乙烯醚的反應(yīng)H2CCHCH2OH + H2CCHOC2H5CHCH2 CHOH2C H2CHg(OAc)2H2CCHCH2CH2CHO96%80通常首先需制備烯丙基乙烯醚類化合物，然后不經(jīng)分 離直接進(jìn)行重排。因此， 本反應(yīng)的關(guān)鍵是如何制備烯 丙基乙烯醚類

31、化合物。下面介紹幾種不同的制備烯丙 基乙烯醚類化合物的方法。2. 脂肪族Claisen重排（2）烯丙醇和原酸酯(orthoester)的反應(yīng)（Johnson-Claisen重排, William S. Johnson, Stanford,1970)81(3) 羧酸烯丙酯和鹵硅烷的反應(yīng)(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）當(dāng)烯丙基乙烯醚中的氧原子用S或N取代后也可進(jìn)行Claisen重排。83在藥物合成中的應(yīng)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