《有机合成化学》课件6分子的拆开-本科

1、第五章 分子的拆开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: 带有两个相同取代基的叔醇 = 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用醇脱水不行，介绍wittg选择性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不保护，炔碳负离子会和羰基加成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 反应是以美国化学家A. Michael (1853 1942) 的名字命名的,整个反应由两部分构成,一是碳负离子亲核试剂,一是带有吸电子活化基Z 的不饱和共轭体系。前者对后者进行共轭亲核加成直接生成C C 键,例如下式:上述的不饱和共轭体系通常称为Michael 受体,它由不饱和键及与不饱和键相连的不饱和活化基Z 组成,典型的有C=C-Z 和 C C-Z , 其中Z为CHO、COR、COOH、COOR、CONR2 、CN、NO2 、SOR等。这些基团能够活化亲核试剂对烯或炔的

11、共轭加成,其活化能力的相对大小基本上和它们稳定碳负离子的能力一致,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 (苯偶姻反应)ExampleThe ether forms spontaneously from the tertiary alcohols in acid. 2) 1,2-DiolExamplesor OsO4Wittig 反应Analysis: Synthesis orPhEndo-内型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实际可行吗？得到

14、 ,环氧酸酯the Darzens reaction Darzens反应是醛或酮在强碱（如氨基钠、醇钠）作用下与-卤代羧酸酯反应，生成,-环氧酸酯的反应。产物,-环氧羧酸酯也称作“缩水甘油酸酯”，经水解可以得到醛和酮。必须采用某些方法使得酮在起始的缩合反应中扮演亲核试剂的角色。One effective way is to convert it into an enamine.是烯胺进攻活泼的羰基卤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但实际上，这两个试剂结合并不产生原来的化合物，而是一个内酯instead the lactone ：ExampleHomeworkCO2H synthon 3) OTHER ILLOGICAL SYNTHONS -BrCH2CCH CH3COCH2BrCH2(CO2Et)2这个“切断”实际上是把两个羰基连结起来a disconnection which actually links up the two carbonyl groups 环已烯衍生物可以用 Diels -Alder反应制得，反应可用臭氧或它的等价物来完成。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 还原 芳香化合物用碱金属(钠、钾或锂)在液氨与醇(乙醇、异丙醇或仲丁醇)的混合液中还原,苯环可被还原成非共轭的1,4-环己二烯化合物. 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 辅酶A合成中的一个中间体。到此为止，所有简单的含氧二基团都讨论过了，你应该能合理的设计大多数小分子的合成。合成：为避免发生Cannizzaro反应，必须用弱碱。羟基化合物A不被分离，而能自动闭环：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? 环状化合物合成环状化合物既要考虑环状化合物的热力学因素，又要考虑其动力学因素。三员环：从热力学因素考虑，不稳定易开环；从动力学考虑，易成环。五、六、七员环：从热力学因素考虑，都相当稳定；从动力学考虑，易成环。四员环：从热力学因素考虑，不稳定；从动力学考虑，不易成环。环的修饰单边环化双边环化扩环/缩环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