藥物合成反應(yīng)第四講縮合反應(yīng)

1、藥物合成反應(yīng)第四講縮合反應(yīng)第一節(jié) a-羥烷基、鹵烷基、氨烷基化反應(yīng)一、a-羥烷基化反應(yīng)1.醇醛縮合反應(yīng)(Aldol縮合)(1)含有a-活潑氫的醛或酮的自身縮合 堿催化機(jī)理: 甲醛與含有a-活潑氫的醛、酮之間的縮合三羥甲基丙烷催化劑的影響以堿催化劑為主，酸催化劑應(yīng)用較少應(yīng)用特點(diǎn)定向醇、醛縮合(a) 烯醇鹽法(b) 烯醇硅醚法（2）芳醛與a-活性氫的醛、酮的縮合應(yīng)用特點(diǎn)制備反式芳丙醛有機(jī)小分子脯氨酸催化 直接 Aldol 反應(yīng)List, B. et al, J. Am. Chem. Soc. 2000, 122, 2395制備手性b-羥基醛（3）分子內(nèi)的羥醛縮合Robinson環(huán)化2. 不飽和烴的

2、a羥烷基化（Prins反應(yīng)）Mechanism3. 安息香縮合影響因素 芳醛結(jié)構(gòu)的影響強(qiáng)吸電子、強(qiáng)供電子對(duì)反應(yīng)都不利；自身縮合、交叉縮合 催化劑的影響NaCN劇毒，可用噻唑鎓鹽、咪唑鎓鹽等代替Example 4.有機(jī)金屬化合物的a-羥烷基化 (1) Reformatsky反應(yīng): 醛或酮與a-鹵代酸酯在金屬鋅粉存在下縮合而得b-羥基酸酯或脫水得a、b-不飽和羧酸酯的反應(yīng)： metal: Zn, Mg, Cd, Ba, In, Ge, Co, Ni, Ce; metal salt: SmI2, CrCl2, TiCl2, CeX3, Na2Te, R3SnLi,R3Sb/I2, Et2AlClmo

3、st often ether solvents are used such as diethyl ether,tetrahydrofuran, 1,4-dioxane and dimethoxyethane, but mixtures of these solvents with aromatic hydrocarbons and more polar solvents such as acetonitrile, dimethyl formamide, dimethyl sulphoxide, and hexamethylphosphoric triamide are also used;催化

4、劑鋅粉必須活化，常用20%鹽酸處理，再用丙酮、乙醚洗滌，真空干燥。亦可用K、Na、Li等還原無(wú)水氯化鋅，此法活性較高。Mg, Cd, Ba, In, Ge, Co, Ni, Ce等。 例如: 加入(CH3O)3B/THF可提高收率(如上)（2）Grignard反應(yīng) 機(jī)理:影響因素1) the reagents are predominantly prepared by reacting alkyl, aryl, or vinyl halides with magnesium metal in aprotic nucleophilic solvents (e.g., ethers, tertia

5、ry amines);2) the reagents are usually thermodynamically stable but air and moisture sensitive and incompatible with acidic functional groups (e.g., alcohols, thiols, phenols, carboxylic acids, 1, 2 amines, terminal alkynes);二、 a-鹵烷基化反應(yīng)(Blanc反應(yīng)) 3.影響因素也可用ZnCl2(干)等Lewis酸。苯環(huán)上供電子基,有利于反應(yīng)進(jìn)行。吸電子基不利于反應(yīng)進(jìn)行。(

6、87%) 引入-CH2Cl后，可進(jìn)一步轉(zhuǎn)化成其他官能團(tuán)并增長(zhǎng)碳鏈。三、a-氨烷基化反應(yīng) Mannich反應(yīng)：有活潑氫的化合物(醛、酮等) 與甲醛、胺進(jìn)行縮合，H原子被a-氨甲基 取代稱(chēng)為 a-氨甲基化反應(yīng)(Mannich反應(yīng))反應(yīng)機(jī)理 如：(90%)抗膽堿藥阿托品的中間體Introduction1. Metal Catalysis 2. Proline Catalysis3. Brnsted Acid-Catalysis4. Protonated Chiral Catalysis 5. ACDC6. H-Bond Catalysis 7. PTCTrost, B. M. J. Am. Chem

7、. Soc.2006, 128, 2778-2779.Proline catalysisBrnsted acid-catalysis 磷原子的四齒結(jié)構(gòu) (2) 磷酸的酸性足以誘捕亞胺(3) 雙功能手性催化劑 4. Protonated Chiral Catalysis J. Am. Chem. Soc. 2004, 126, 3418-3419 Ishihara, K. J. Am. Chem. Soc 2008, 130, 1685816860. H-Bond Catalysis Jacobsen, E. N. Angew. Chem. Int. Ed. 2005, 44, 466468.2

8、. Pictet-Spengler reactionBaldwin環(huán)化規(guī)則Baldwin環(huán)化規(guī)則SP3 = tet；SP2 = trig；SP = digSP3: 5-6- endo 禁阻SP2: 3-5-endo 禁阻SP: 3-4- exo 禁阻其他允許（3）影響因素 only -arylethylamines with electron-donating substituents afford high yields; the reaction is usually carried out with a slight excess of the carbonyl compound (to

9、 ensure the complete consumption of the amine) in either protic or aprotic medium;3. Strecker反應(yīng)（1）反應(yīng)通式（2）反應(yīng)機(jī)理（3）應(yīng)用-Corey，1999 第三節(jié) b-羥烷基、 b-羰烷基化反應(yīng) 一 b-羥烷基化反應(yīng) 1.反應(yīng)通式-F-C反應(yīng)2. 反應(yīng)機(jī)理苯環(huán)連在取代基多的C上3.應(yīng)用特點(diǎn)（1）區(qū)域選擇性（2）立體選擇性構(gòu)型反轉(zhuǎn)（3）制備環(huán)內(nèi)酯二、 b-羰烷基化反應(yīng) Michael加成反應(yīng)反應(yīng)機(jī)理:（3）影響因素1) the nucleophile (Michael donor) can be de

10、rived by the deprotonation of CH-activated compounds such as aldehydes, ketones, nitriles, -dicarbonyl compounds, etc. as well as by the deprotonation of heteroatoms;2) depending on the type and strength of the electron-withdrawing group (negative charge stabilizing group), the use of even relativel

11、y weak bases is possible (e.g., NEt3);（4）應(yīng)用 第四節(jié) 亞甲基化反應(yīng) 一 羰基烯化反應(yīng)（1）反應(yīng)通式及機(jī)理（2）影響因素the ylides are water as well as oxygen-sensitive；the phosphorous ylides chemoselectively react with aldehydes (fast) and ketones (slow), other carbonyl groups (e.g., esters, amides) remain intact during the reaction;the

12、stereoselectivity, E-or Z-selectivity, is influenced by many factors: type of ylide, type of carbonyl compound, nature of solvent；The Wittig reaction has several important variants: HWE Reactionthe phosphonate carbanions are more nucleophilic than the corresponding phosphorous ylides, so they readil

13、y react with practically all aldehydes and ketones under milder reaction conditions；the by-product dialkyl phosphates are water-soluble, so it is much easier to separate them from the alkene products than from the water-insoluble triphenylphosphine oxide. high (E)-selectivity for disubstituted alken

14、es under much milder conditions than normally used in Wittig reactions； the (E)-selectivity is maximized by increasing the size of the alkyl group of the R1 or R2 substituents There are an important modifications of the HWE olefination:in the Still-Gennari modification R1=OCH2CF3 and the reaction af

15、fords (Z)-olefins exclusively；for base-sensitive substrates, the use of a metal salt (LiCl or NaI) and a weak amine base (e.g., DBU) has proven effective to avoid epimerization.（4）應(yīng)用二 羰基a位的亞甲基化反應(yīng)活性亞甲基的亞甲基化 Knoevenagel 反應(yīng)（1）反應(yīng)通式 （2）反應(yīng)機(jī)理（3）影響因素 the nature of the catalyst is important, usually primary,

16、 secondary, and tertiary amines and their corresponding ammonium salts, certain Lewis acids combined with a tertiary amine (e.g., TiCl4/Et3N).the by-product of the reaction is water and its removal from the reaction mixture by means of azeotropic distillation, the addition of molecular sieves, or ot

17、her dehydrating agents shifts the equilibrium toward the formation of the product; the choice of solvent is crucial and the use of dipolar aprotic solvents (e.g., DMF) is advantageous, since protic solvents inhibit the last 1,2-elimination step;2. Stobbe 反應(yīng)（1）反應(yīng)通式（2）反應(yīng)機(jī)理（3）應(yīng)用制備烯酸3. Perkin反應(yīng)(1) 反應(yīng)通式（

18、2）反應(yīng)機(jī)理（3）影響因素芳香醛結(jié)構(gòu)影響吸電子活性增強(qiáng)，給電子相反 碘番酸中間體催化劑的影響相應(yīng)羧酸的鉀鹽、鈉鹽；銫鹽效果更好（4）應(yīng)用第五節(jié) a、b -環(huán)氧烷基化反應(yīng)(Darzens反應(yīng))1. 反應(yīng)通式EWG = CO2R, CN, SO2R, CONR2, C(=O), C(=NR); Y = O, NR;2. 反應(yīng)機(jī)理3. 影響因素Aliphatic aldehydes usually give lower yields；-Chloro esters are preferable to bromo or iodo esters, since they give higher yields

19、；-halo sulfones,nitriles,ketones, ketimines, thiol esters,or amides,can also be used to obtain the corresponding derivatives；4. 應(yīng)用特點(diǎn)醛、酮同系化C+1布洛芬的合成 第六節(jié) 環(huán)加成反應(yīng)EDG (electron-donating group)= alkyl, O-alkyl, N-alkyl, etc.EWG (electron-withdrawing group) = CN, NO2, CHO, COR, COAr, CO2H, CO2R, COCl etc.一、

20、D-A反應(yīng)Mechanism（3）影響因素及應(yīng)用特點(diǎn)共軛二烯雙鍵必需是順型的順式原理 內(nèi)向加成原理加成定位規(guī)則Example二、1,3偶極環(huán)加成1. Azomethine Ylides2. Azomethine Imines3. Nitrones4. Azides5. O3 / Carbonyl Oxides三、碳烯、氮烯對(duì)不飽和鍵的加成Carbene-電中性二價(jià)碳中間體，兩電子自選方向相同為三線態(tài)，相反為單線態(tài)單線態(tài)與烯烴的反應(yīng)有立體定向性三線態(tài)與烯烴的反應(yīng)不具有立體定向性Simmons-Smith cyclopropanation.(1) a wide range of alkenes can be used: simple alkenes, ,-unsaturates ketones and aldehydes, electron rich alkenes ;(2) due to the electrophilic nature of the reagent, the rate of cyclopropanation is faster with more elect