《有機(jī)合成化學(xué)》課件6分子的拆開(kāi)-本科

1、第五章 分子的拆開(kāi)DISCONNECTIONS5.1 ONE-GROUP DISCONNECTIONS5.2 TWO-GROUP DISCONNECTIONS 5.3 SPECIAL TWO-GROUP DISCONNECTIONS 5.4 COMPOUNDS CONTAINING HETEROATOMS5.5 SPECIAL METHODS FOR SMALL RINGS Disconnection: An analytical operation, which breaks a bond and converts a molecule into a possible starting ma

2、terial. The reverse of a chemical reaction. Symbol and a curved line drawn through the bond being broken. Synthon: A generalised fragment, usually an ion, produced by a disconnection. (Some people also use synthon for a synthetic equivalent).Synthetic Equivalent: A reagent carrying out the function

3、of a synthon which cannot itself be used, often because it is too unstable.+SynthonEquivalent-C6H5 C6H6 C6H5MgBr-CH2COX CH3COX(X=R,OR,NR2) R- RM, R2CuLi-CH2COCH3 CH3COCH2CO2Et-CH2COOH CH2(CO2Et)2SynthonSynthetic EquivalentR+ RX+CH2CH2OH Ethene oxideRC+=O RCOXRC+HOH RCHO+CH2OH CH2O+CH2CHCOR CH2=CHCOR

4、FGI: Functional Group Interconversion The operation of writing one functional group for another so that disconnection becomes possible. Again the reverse of a chemical reaction. Symbol with FGI written over it.Example5.1 ONE-GROUP DISCONNECTIONS-+-Analysis: Synthesis: 帶有兩個(gè)相同取代基的叔醇 = Ester + 2Grignar

5、dHow would you make TM 18? Analysis:If one of the groups in the alcohol carbon atom is H, then another disconnection is: The equivalents of the synthon H- are NaBH4, and LiAIH4. How might you make TM 21 using this disconnection? Analysis:Synthesis: Derivatives of alcohol:How would you make TM 25?Ana

6、lysis: Synthesis: an intermediate in the synthesis of maytansine(美登木素), an antitumour compound. 2. Disconnection of simple alkeneDehydration of alcohols How might you make TM40 ?+TM40TM40用醇脫水不行，介紹wittg選擇性3. Disconnection of Aromatic KetoneThe first was the disconnection of alcohols to carbonyl compo

7、unds and Grignard reagents. The Wittig reaction is important enough to be our second major one group disconnection. Our third major one disconnects the bond joining an aromatic ring to an aliphatic side chain. We would make ArCOR by the Friedel-Crafts reaction using acetyl chloride and aluminium chl

8、oride to attack the benzene ring Disconnection b will not do as the nitro group is meta-directing and in any case nitro ben-zene will not react under Friedel-Crafts conditions. Disconnection a is fine as the MeO group is more powerfully ortho-directing than the Me group 4. ControllingProtection!+Act

9、ivation! OH- H+, -CO2 TM+Homework:I不保護(hù)，炔碳負(fù)離子會(huì)和羰基加成5. Disconnection of Simple ketone and Acid+SOCl2SUMMARY HomeworkBrufen 5.2 TWO-GROUP DISCONNECTIONS1. 1,3-oxidized skeleton(1) 3-hydroxycarbonyls+ Analysis: Synthesis: (2) 2,3-Unsaturated carbonyl compound(CH3CO)2OCH2(CO2H)2(3) 1,3-Dicarbonyl compoun

10、dHomework2. 1,5-Dicarbonyl compoundMichael Reaction：Michael 反應(yīng)是以美國(guó)化學(xué)家A. Michael (1853 1942) 的名字命名的,整個(gè)反應(yīng)由兩部分構(gòu)成,一是碳負(fù)離子親核試劑,一是帶有吸電子活化基Z 的不飽和共軛體系。前者對(duì)后者進(jìn)行共軛親核加成直接生成C C 鍵,例如下式:上述的不飽和共軛體系通常稱為Michael 受體,它由不飽和鍵及與不飽和鍵相連的不飽和活化基Z 組成,典型的有C=C-Z 和 C C-Z , 其中Z為CHO、COR、COOH、COOR、CONR2 、CN、NO2 、SOR等。這些基團(tuán)能夠活化親核試劑對(duì)烯或炔的

11、共軛加成,其活化能力的相對(duì)大小基本上和它們穩(wěn)定碳負(fù)離子的能力一致,如NO2 COR CO2R CN CONR2 。How would you make ?Robinson annelation HomrworkoKey:5.3 Disconnection of Special Two-Group1. 1,2-oxidized skeleton1) 2-hydroxy carbonyl compoundsa) 2-hydroxy-acid +-2) HWork: How would you make it?Analysis:SynthesisWe can either protect the t

12、wo hydroxyl groups in A as a cyclic acetal or use four mols of PhMgBr and waste two of them. b) 2-hydroxy-ketoneBenzoin reaction (苯偶姻反應(yīng))ExampleThe ether forms spontaneously from the tertiary alcohols in acid. 2) 1,2-DiolExamplesor OsO4Wittig 反應(yīng)Analysis: Synthesis orPhEndo-內(nèi)型Exo-外型Symmetrical diols c

13、an be made by a radical reaction. Pinacol Rearrangementpinacol reduction Examplebenzene Analysis: Synthesis: the acyloin reaction How could you make TM156? (J. Org. Chem., 1966, 31, 2017) Homework2. 1,4-Oxidized Skeleton1) 1,4-Dicarbonyl Compoundsthe normal polarity is inverted OH-CO2EtO+BrO實(shí)際可行嗎？得到

14、 ,環(huán)氧酸酯the Darzens reaction Darzens反應(yīng)是醛或酮在強(qiáng)堿（如氨基鈉、醇鈉）作用下與-鹵代羧酸酯反應(yīng)，生成,-環(huán)氧酸酯的反應(yīng)。產(chǎn)物,-環(huán)氧羧酸酯也稱作“縮水甘油酸酯”，經(jīng)水解可以得到醛和酮。必須采用某些方法使得酮在起始的縮合反應(yīng)中扮演親核試劑的角色。One effective way is to convert it into an enamine.是烯胺進(jìn)攻活潑的羰基鹵代物而不是羰基本身。The enamine attacks the reactive -carbonyl halide ExampleAnalysis: Synthesis: OH-Br2) 4-H

15、ydroxy Carbonyl CompoundsExample但實(shí)際上，這兩個(gè)試劑結(jié)合并不產(chǎn)生原來(lái)的化合物，而是一個(gè)內(nèi)酯instead the lactone ：ExampleHomeworkCO2H synthon 3) OTHER ILLOGICAL SYNTHONS -BrCH2CCH CH3COCH2BrCH2(CO2Et)2這個(gè)“切斷”實(shí)際上是把兩個(gè)羰基連結(jié)起來(lái)a disconnection which actually links up the two carbonyl groups 環(huán)已烯衍生物可以用 Diels -Alder反應(yīng)制得，反應(yīng)可用臭氧或它的等價(jià)物來(lái)完成。3. 1,

16、6-Dicarbonyl Compoundreconnection+Another way to make cyclohexenes is by the Birch reduction. With that clue, how would you make TM?Birch 還原 芳香化合物用堿金屬(鈉、鉀或鋰)在液氨與醇(乙醇、異丙醇或仲丁醇)的混合液中還原,苯環(huán)可被還原成非共軛的1,4-環(huán)己二烯化合物. The 1,4-reduction of aromatic rings to the corresponding unconjugated cyclohexadienes and hete

17、rocycles by alkalimetals (Li, Na, K) dissolved in liquid ammonia in the presence of an alcohol is called the Birch reduction.Birch ReductionMechanism:CO2HO3 attacks the most electron-rich bondthe sterochemistry of the remaining double bondAnalysis: E.J.Corey et al., J. Amer. Chem. Soc., 1968, 80, 56

18、18 Comprehensive Exercise Khorana 輔酶A合成中的一個(gè)中間體。到此為止，所有簡(jiǎn)單的含氧二基團(tuán)都討論過(guò)了，你應(yīng)該能合理的設(shè)計(jì)大多數(shù)小分子的合成。合成：為避免發(fā)生Cannizzaro反應(yīng)，必須用弱堿。羥基化合物A不被分離，而能自動(dòng)閉環(huán)：5.4 COMPOUNDS CONTAINING HETEROATOMS1 Ether and ester (C-O) ExampleAnalysisSynthesis2 Amine， CN bondExampleWhy is it no good? +Synthesis: NH2OH,H+Using the idea of redu

19、cing a nitra compound and a double bond at the same time, how might we make TM 245? Synthesis3. HeterocycyleIntramolecular reactions are faster and cleaner than intermolecular reactions. How then would you make TM 254? enamineSynthesis: (As carried out in J. Amer. Chem. Soc. 1976, 98, 6650). How wou

20、ld you make TM 256? 環(huán)狀化合物合成環(huán)狀化合物既要考慮環(huán)狀化合物的熱力學(xué)因素，又要考慮其動(dòng)力學(xué)因素。三員環(huán)：從熱力學(xué)因素考慮，不穩(wěn)定易開(kāi)環(huán)；從動(dòng)力學(xué)考慮，易成環(huán)。五、六、七員環(huán)：從熱力學(xué)因素考慮，都相當(dāng)穩(wěn)定；從動(dòng)力學(xué)考慮，易成環(huán)。四員環(huán)：從熱力學(xué)因素考慮，不穩(wěn)定；從動(dòng)力學(xué)考慮，不易成環(huán)。環(huán)的修飾單邊環(huán)化雙邊環(huán)化擴(kuò)環(huán)/縮環(huán)5.5 SPECIAL METHODS FOR SMALL RINGS 1. Three member ring1) Intramolecular Nucleophilic Substitution2) the removal of an atom，Carbon, X=C,N,OA) A reagent for the synthon is a peracid RCO3H How t