常见的羟基的保护与脱保护方法

1、目录1. 22. 22.1( TMS- OR)32.2( T BDMS- OR)42.3( TBDPS- OR)43. 64. 75. 86.97. 1 0。1. 前言羟基广泛存在于许多在生理上和合成上有意义的化合物中，如核苷，碳水化合物、甾族化合物、大环内酯类化合物、聚醚、某些氨基酸的侧链。另外，羟基也是有机合成中一个很重要的官能基，其可转变为卤素、氨基、羰基、酸基等多种官能团。在化合物的氧化、酰基化、用卤代磷或卤化氢的卤化、 脱水的反应或许多官能团的转化过程中，我们常常需要将羟基保护起来。在含有多官能团复杂分子的合成中，如何选择性保护羟基和脱保护往往是许多新化合物开发时的关键所在，如紫杉醇

2、的全合成。羟基保护主要将其转变为相应的醚或酯， 以醚更为常见。一般用于羟基保护醚主要有硅醚、甲基醚、烯丙基醚、苄基醚、烷氧甲基醚、烷巯基甲基醚、三甲基硅乙基甲基醚等等。羟基的酯保护一般用的不多，但在糖及核糖化学中较为多见。2. 羟基硅醚保护及脱除硅醚是最常见的保护羟基的方法之一。随着硅原子上的取代基的不同，保护和去保护的反应活性均有较大的变化。当分子中有多官能团时，空间效应及电子效应是影响反应的主要因素。在进行选择性去保护反应时，硅原子周围的空间效应，以及被保护分子的结构环境均需考虑。例如，一般情况下，在TBDMS基团存在时，断裂DEIPS( 二乙基异丙基硅基 ) 基团是较容易的，但实际得出的

3、一些结果是相反的。在这些例子中，分子结构中空间阻碍是产生相反选择性的原因。电子效应的不同也会影响反应的选择性。对于两种空间结构相似的醇来说，电子云密度不同造成酸催化去保护速率不同，因此可以选择性去保护。这一点对酚基和烷基硅醚特别有效：烷基硅醚在酸中容易去保护，而酚基醚在碱性条件下更容易去保护。 降低硅的碱性还可以用于改变 Lewis 酸催化反应的结果，并且有助于选择性去保护。在硅原子上引入吸电子取代基可以提高碱性条下水解反应的灵敏性，而对酸的敏感性降低。对大多数醚来说，在酸中的稳定性为TMS (1)<TES(64)<TBDMS (20,000)<TIPS(700,000)&l

4、t;TBDPS (5,000,000)；在碱 中稳定性 为 TMS(1)<TES (10-100)<TBDMSTBDPS (20,000)< TIPS (100,000)。一般而言，对于没有什么位阻的伯醇和仲醇，尽量不要选用TMS作为保护基团，因为得到的产物一般在硅胶这样弱的酸性条件下也会被裂解掉。任何羟基硅醚的都可以通过四烷基氟化胺如TBAF脱除，其主要硅原子对氟原子的亲和性远远大于硅 - 氧之间的亲和性。在用TBAF裂解硅醚后，分解产生的四丁铵离子有时通过柱层析或HPLC很难除干净，而季铵盐的质谱丰度(Bu4N+: 242) 又特别的强有时会。1。干扰质谱，因此这时需要使

5、用四甲基氟化铵或四乙基氟化铵来脱除。使用硅醚保护的另一个好处是可以在分子中游离伯胺或仲胺基的存在下， 对羟基进行保护，其主要由于硅 - 氮键的结合远比硅 - 氧键来的弱，硅原子优先与羟基上的氧原子结合，这正是与其他保护基不同之处。顺便提一句，一般而言，决大部分的硅 - 氮键的结合是不稳定的，其很容易被水解掉。2.1三甲基硅醚的保护(TMS-OR)许多硅基化试剂均可用于在各种醇中引入三甲基硅基。一般来说，空间位阻较小的醇最容易硅基化，但同时在酸或碱中也非常不稳定易水解, 三甲基硅基化广泛用于多官能团化合物，生成的衍生物具有较高的挥发度而利于其相色谱和质谱分析。2.1.1三甲基硅醚羟基保护示例(J

6、. Org.Chem.1996,61, 2065)AcOOOTESAcOOOTESHOTMSOHOHOHO BzOOAcMe2 HSiO BzOOAc12Compound1 (3.00g,4.286mmol) was dissolvedindryDMF(17 mL). To thissolutionat 0 oC was added imidazole (874.3 mg, 12.86mmol), followed by TMSCl (1.63 mL,12.86 mmol). After stirring at 0oC for 1.5 h, the reaction mixture was d

7、ilutedwith EtOAc (300 mL) and washed with water (320 mL) and then brine (30 mL).The organic layer was dried and concentratedin vacuo. The resulting materialwas then dissolvedindryDMF(20 mL) and treatedoimidazole(816 mg,at 0 C with12.00 mmol), followedby chlorodimethylsilane(1.135g,12.00mmol). The re

8、actionmixture was stirredowithEtOAc (200mL). The organicfor 1h at 0 C and then dilutedlayerwas washed withwater and brine.Upon silicagelchromatography(10% ethylacetate in hexane), 3.197 g (90%) of the desired product2 was obtained.Cleavage (J. Org.Chem.1996,61, 2065)Hydrolysis was carriedout under a

9、proticcondition-anhydroustetrabutylammoniumfluoride in THF solution.。2。2.2 t-Butyldimethylsilyl ether (TBDMS-OR)在化学合成中， 采用硅基化进行羟基保护生成叔丁基甲基硅基醚是应用较多的方法之一。一般来说，在分子中羟基位阻不大时主要通过TBSCl对羟基进行保护。但当羟基位阻较大时则采用较强的硅醚化试剂TBSOTf来实现。生成的叔丁基二甲基醚在多种有机反应中是相当稳定的，在一定条件下去保护时一般不会影响其他官能团。它在碱性水解时的稳定性约为三甲基硅醚的 104 倍。它对碱稳定。相对来说对酸

10、敏感些。 TBS醚的生成和断裂的难易取决于空间因素，因此常常用于对多官能团，位阻不同的分子进行选择性保护。在伯、仲醇中， TBS 基相对来说较易于与伯醇反应。 TBS 醚的断裂除了常用的四烷基氟化胺外，许多情况下也可用酸来断。当分子内没有对强酸敏感的官能基存在时，可用 HCl-MeOH, HCl-Dioxane 体系去除 TBS，若有对强酸敏感的官能基存在时，则可选用 AcOH-THF体系去除。2.2.1 通过 TBSCl进行羟基的叔丁基二甲基硅醚保护示例( J. Am. Chem. Soc. 1972, 94,6190)OOOOHOCH 2OBnTBDMSOCH 2 OBn21The hyd

11、roxyl lactone1, upon treatment with TBDMSCl (1.2 equiv) and imidazole(2.5 equiv.) in DMF(2 mL/g of 1) at 35oC for10 h, produced the silyl ether-lactone2 in 96% yield.2.2.2通过TBSOTf 进行羟基的叔丁基二甲基硅醚保护示例( J.Org.Chem. 1987,52,622)CH3CH3CNTBSOTfCNHHOHOTBS12To an ice-cold solution of 4.8 g of pyridine (2.0 e

12、quiv) and 4.20 g of 1 in 30mLof dry acetonitrilewas added slowly9.6 g of tert-butyldimethylsilyltriflate(36.2mmol, 1.2equiv).The reactionmixturewas stirredfor5 h atroomtemperatureand then poured into200 mL of saturatedsodium bicarbonatesolution。3。at 0 oC. The solution was extracted thoroughly with h

13、exane, and the organic extracts were dried over anhydrous potassium carbonate and filtered. Removal of the solvent under reduced pressure followed by distillation of the residue gave 6.29 g (82% yield).2.2.3通过示例(Can. J. Chem.53TBAF脱 TBDPS1975, 2975)Ph Si PhBu 4N +F-/THFC C C6H5OC C C6H5HOTHPOTHPO12T

14、o a solution of THP ether 1 (1.7 g, 3.3 mmol) in THF (10 mL) was added a 1 Msolution of tetrabutylammonium fluoride in THF (5 mL, 5 mmol) at 22-24o C. Thesolution was stirredfor 2 h and dilutedwith100 mL(1:1) ofEt O/EtOAc solution.2The organic layerwas separatedand washed with H2O (3100 mL). The wat

15、er extractwas washed with2:1Et 2O/EtOAc solution(250 mL),and theorganiclayers werecombined and dried over MgSO4. The solvent was evaporatedin vacuo, and theresidue was chromatographed over silica gel using (5:1) hexanes/ethyl acetatesolution to give 2 (0.75 g, 82%).示例(Tetrahedron Lett.1988,292.2.4 通

16、过 AcOH-THF脱 TBS, 6331)OOAcOh/H 2O/THFOOTBSOHOTBSONHBocTBSONHBoc12Selectiveremoval of one ofwith aceticacid-water-THF2 in 79% yield.the TBDMSgroups of 1 was accomplished by treatment (13:7:3) (30 °C, 15h) to give the monohydroxy compound2.3 t-Butyldiphenylsilyl ether (TBDPS-OR)在酸性水解条件下TBDPS保护基比

17、TBDMS更加稳定（约 100 倍），而 TBDPS保护基对碱的稳定性比TBDMS要差。 另外，由于该保护基的分子量较大，容易使底物固化而易于分离。TBDPS 保护基对许多与 TBDMS保护基不相容的试剂显出比TBDMS基团更好。4。的稳定性。 TBDMS基团在酸性条件下不易迁移。TBDPS醚对 K2CO3 /CH 3OH，对 9M氨水、60、2h；对 MeONa（cat. ）/CH3OH、25、 24h 均稳定。该醚对 80%乙酸稳定，后者可用于脱除醚中 TBDMS，三苯甲基，四氢吡喃保护基也对 HBr /AcOH，12，2min；对 25%75% 甲酸， 25， 2h6h；以及 50%三氟

18、乙酸， 25， 15min 稳定。2.3.1通过进行羟基的叔丁基二甲基硅醚保护示例(J.Org. Chem, 1992,57TBDPSCl,1722)i-Pr 2 NEt/t-BDPSiCl/CH 2 Cl2HOOHOHt-BDPSiO12To a solution of 1,4-butanediol (5 g, 55 mmol) in CHCl2(10 mL) containingi-Pr2NEt2(10 mL) was added t-BDPSiCl (5 mL, 18 mmol) dropwise under N2 at 22-24o C. Thesolution was stirred

19、 at 22-24 oC for 2 h, concentratedinvacuo and chromatographed,eluting with hexanes/ethyl acetate (10:1) to 2 (clear oil, 5.6 g, 95%).2.4三异丙基硅醚保护(TIPS-OR)酸性水解时，有较大体积的 TIPS 醚比叔丁基二甲基硅醚要更稳定些。但稳定性比叔丁基二苯基硅基差。 TIPS 基碱性水解时比 TBDMS基或 TBDPS基稳定。相对于仲羟基， TIPS 基对伯羟基有更好的选择性。2.4.1通过 TIPSCl 进行羟基的三异丙基硅醚保护示例( J. Org. C

20、hem. 1995,60,7796)OPMBOPMBHOOMOMTIPSOTf/CH2Cl 2MOM2,6-lutidineTIPSOON(OCH 3)CH 3N(OCH )CH3312To astirredsolutionof(1)(1.5 g)inCH2Cl 2 (53 mL)cooledto0oC weresuccessivelyadded2,6-lutidine(6.2mL,53.3mmol) andtriisopropylsilyltriflate(7.90mL,29.5mmol).Themixturewas allowedto warm toroomtemperature(30 m

21、in). Thenexcess triflatewas consumedby additionof methanol(10 mL) and a saturatedaqueous NHCl solution(60 mL). Thephase was separated4and the aqueous layerwas extractedwithCH2Cl 2 (450 Ml). Thecombined organicphases were washed with a saturated NaHCO 3(100 mL) a, 1M NaHSO 4(350 mL),。5。and brine(50 m

22、L), driedover Na2SO, filtered,and concentrated. Purification4by flash chromatography (10% ethyl acetate in hexane) afforded silyl ether (2)(6.90 g, 89%).。6。3. 羟基苄醚保护及脱除一般羟基的苄醚保护主要有苄基，对甲氧苄基及三苯甲基醚。3.1 苄基醚保护羟基(Bn-OR)一般烷基上的羟基在用苄基醚保护时需要用强碱，但酚羟基的苄基醚保护一般只要用碳酸钾在乙腈或丙酮中回流即可，回流情况下，这类烷基化在乙腈中速度比丙酮中要快四倍左右，因此一般用乙腈

23、做溶剂居多。若反应速度慢可用DMF做溶剂，提高反应温度，或加 NaI,KI 催化反应。苄基醚的裂解主要是通过催化加氢的方法，Pd 是理想的催化剂， 用 Pt 时会产生芳环上的氢化作用。 在含色氨酸的肽中氢解苏氨酸常导致色氨酸还原成2，3- 二氢衍生物。非芳性的胺可以使催化剂活性降低，阻碍 O- 脱苄；在氢化体系中加入Na2CO3可以防止苄基被裂解，但可使双键发生还原。孤立烯烃有可能影响苄基醚键的裂解（H2，5% Pd-C，97%产率）。一般而言选择性的大小取决于取代的类型及空间位阻的情况。与酯共扼的三取代的烯烃存在时，苄基的水解也有相当好的选择性。对甲氧苄基基团存在时，苄基的水解（ Pd-C，

24、EtOAc，室温， 18 小时）有非常好的选择性。在反应体系中加入Pyridine可使对甲氧苄基和苄基氢解产生区别。苄基的氢解有溶剂的作用，如下列表：Effect of solvent on the hydrogenlysis of benzyl etherSolventReaction rate(mm H 2 / min /0.1g cat)THF40Hexanol25Methanol5Toluene2Hexane63.1.1烷基羟基的苄基醚保护示例( Bull. Chem. Soc. Jpn.1987,60, 1529)。7。OTrOTrBnBr, NaHHOOOBnOAcHNAcHNOM

25、eOMe12Compound1 (12.1 g) in DMF (200 mL) was treated with 60% NaH (1.32 g), benzylbromide (6.44 g) and tetrabutylammonium iodide (0.11 g). The reaction mixturewas stirredatroomtemperature for 1.5 h.The product was purifiedbychromatographyon silicagel with toluene-ethanol(20:1) to give 2 (14.0 g, 99%

26、).3.1.2酚羟基的苄基醚保护示例OOOHBnClO1K2 CO 3/EtOH2To a solution of 1 (37.65 g,277 mmol) in EtOH (135 mL) was added benzylchloride(36.5g,289 mmol), KI (1.75g, 10 mmol) and K2 CO3 (24.6 g,178 mmol) withstirring.The resulting mixture was refluxed for 5 h. The mixture was allowed to cooltoroom temperature and th

27、e solvent was removed invacuo. Theresiduewas addedwater(100 mL) and extractedwithEt O (80 mL 3). Theextractwas washed with2saturatedNaHCO3, water and brinesuccessively. Theorganic layer was dried overNaSO and concentrated in vacuo to give the crude product, which was distilled24to afford2 (49.1 g, 7

28、9%).3.1.3苄基醚氢解脱保护示例( J. Am. Chem. Soc.1971,93, 1746)CH 3CH 3AcHNH10%Pd/C/HAcHNH2BnOOHOOAcHNAcHNOMeOMe34Compound 3(105mg)was hydrogenatedinethanol (10mL) containing1Mhydrochloricacid(0.5mL) in the presenceof10%palladiumon charcoal (50mg)in an initial hydrogen pressure of 3.4 MPa overnight. The produc

29、t was purifiedby chromatography on silica gel with toluene-ethanol (3:1) to give4 (90 mg,quant.)。8。9。3.2 对甲氧基 苄基醚保护羟基(PMB-OR)各种甲氧基苄醚已经合成得到并被用作保护基。实际上甲氧基取代的苄基醚较未取代的苄基醚更容易通过氧化去保护。下表给出了用二氯二氰苯醌去保护时的相对速率。DDQ(1.2eq.)OH(OMe)n(OMe)nOCH2 Cl2 ,H2O (10:1), 20 o COHCiiiiiiCleavage of MPM, DMPM, and TMPM ethers

30、with DDQ in CH2Cl 2/H 2O at 20 o CProtectiveTime (h)Yield(%)ProtectiveGroupTime (h)Yield(%)Groupiiiii(ii3,4-DMPM<0.3386842-MPM3.593704-MPM0.3389863,5-DMPM873922,3,4-TMPM0.560752,3-DMPM12.575733,4,5-TMPM189893-MPM2480942,5-DMPM2.595162,6-DMPM27.58095一般而言，对甲氧基苄醚在合成中更为常用，羟基上对甲氧基 苄基的方法和苄基类似，但脱除除了氢解的方

31、法外，还可以氧化除去。3.2.1 对甲氧基苄基醚保护示例 ( Tetrahedron Lett.1988, 29, 2459)BnNaH, DMFBnOOHOOMPMHHOClH 2COMeHH12To a stirredsuspensionof NaH(26 mg1.09 mmol) in DMSO(1 mL) was added dropwisea THF solution (3 mL) of1 (250 mg, 0.78 mmol) under Ar. After 45 min. at roomtemperature MPM chloride (158 mg, 1.01mmol) was

32、 added, and the stirring wascontinued for 3 h. themixturewas poured intosat. NH4Claq. And then extractedwith ether. The extract was washed with sat. NaCl aq., dried over MgSO4, andconcentratedinvacuo to leavean oil, which was chromatographedon a short silicagel column elution with EtOAc-n-hexane (1:

33、1) gave a colorless oil of2 296 mg,86%.。10。3.2.2在苄氧基存在下选择性脱去对甲氧基苄基示例( Tetrahedron Lett.1988,29,2459)BnOODDQBnHMPMOOHHCH2Cl 2-H2OOHH21To a stirredsolutionof 2 (92 mg, 0.286 mmol) inCH2Cl 2 (2.9mL) and water(0.17mL) was added DDQ (97 mg, 0.427 mmol) at room temp. After 2.5 h precipitatedDDQH was remov

34、ed by decantation and washed with a small amount of CH2Cl 2 . Thecombined CH Cl2solution was washed with sat. NaHCO3aq. And sat. NaCl aq. And2dried over Na24in vacuogave an oil, which wasSO. Evaporated of the solventchromatographedon a silicagel column with EtOAc-n-hexane (1:1) as eluantgavea colorl

35、ess solid of1 43.8 mg, 84%.4. 烷氧基甲基醚或烷氧基取代甲基醚烷氧基甲基醚或烷氧基取代甲基醚在羟基保护中也是较为多用的一类，常用的有THP (2- 四氢吡喃 ) ，MOM（甲氧基甲机基），EE（2- 乙氧基乙基），这类保护基都对酸不稳定，因此一般都是脱保护。它们对酸的稳定性是MOM>EE>THP。4.1 THP (2-四氢吡喃 ) 保护羟基THP 醚引入到一个手性分子的结果是形成了一个非对映体，因为在四氢吡喃环上新增了一个手性中心。（有时它会使NMR谱的表达有点困难） 。尽管如此，它仍是有机合成中一个非常有用的保护基团，它的成本低，易于分离，对大多数非质

36、子酸试剂有一定的稳定性，易于被出去。通常，几乎任何酸性试剂或任何可以在原位产生酸的试剂都可被用来引入 THP基团。4.1.1 THP (2-四氢吡喃 )保护羟基示例(J.Org.Chem.1977,42,3772)DHP/PPTSt-BDPSiOC C C6H5t-BDPSiOC C C6H5HOTHPO12。11。To a solution of1 (1.5 g, 3.5mmol) in CH2 Cl 2 (10 mL) at 22-24oC was added 3,4-dihydro-2H-pyran (0.479 mL, 0.442 g, 5.25mmol) and PPTs (20 m

37、g, 0.08mmol). Thesolution was stirred at 22-24oC for 1 h and diluted with a 100-mL solution of(1:1) diethyl ether and ethyl acetate. The organic layer was separated, washedwithH2 O (3100mL),and theresiduewas chromatographed,elutingwithhexane/ethyl acetate(20:1) to givethe THP ether2 as clear oil(1.7

38、5 g, 97%).4.1.2 THP (2-四氢吡喃 ) 脱保护示例 ( J.Org.Chem. 1977, 42,3772)PPTS/EtOH/50o CRCCCCC6H5RCCCCC6H5OHOTHPOHOH12To an ethanol solution (30 mL) of THP ether1 (1.87 g, 5mmol) was added PPTS(20 mg, 0.08mmol) in one portion. The solution was refluxed for 1 h, cooled to22-24 oC, and diluted with a mixture o

39、f diethyl ether (100 mL) and H2O (200 mL).The organiclayer was washed with H O (2100mL), dried overNaSOand224concentratedin vacuoby chromatography on silicagel,. The residue was purifiedeluting with hexane/ethyl acetate (3:1) to give2 (1.36 g, 94%) as clear oil.4.2 MOM 保护羟基MOM是一般是通过MOMCl-DIEA引入；其对酸还

40、是较为稳定的，一般它的脱除需要在强酸条件下进行。4.2.1 MOM (CH3OCH2-OR)羟基保护示例 ( J. Org. Chem.1995, 60,7796)OPMBMOMCl,DIEA, CH 2Cl 2OPMBTBDPSOTBDPSOOHMOM12To a stirred solution of (1) (51.0 g,99 mmol) in CHCl2(1.0 L) at room temperature2were successivelyadded DIEA (51.5mL, 0.297 mol) and MOMCl(15.0mL, 0.198 mol)over a 10 min

41、 period. The solution was stirred 11 h at room temperature afterwhich a saturatedaqueous NHCl solution (200 mL) was added. Theaqueous phase4was segregated, and the organic one was washed with water (100 mL), brine (100 mL0, dried with anhydrous MgSO4, filtered, and concentrated to give pure MOM。12。e

42、ther (2) (55.3 g, 100%) (slightly yellowish oil).4.2.2MOM脱保护示例 (ibid)OPMBOPMBOMOMHCl(gas)/iPrOH,55o COHTIPSOCO 2CH 3TIPSOCO 2CH 3O2O1To a stirred solution (1) (1.00 g, 1.45 mmol) in dry isopropyl alcohol (10.0mL) were added two drops (0.06 mL) of concentrated aqueous hydrochloric acid.The solution w

43、as stirred at 55o C for 10 h and although incomplete as indicatedby TLC analysis, was allowed to cool to room temperature (prolonged reactiontimes tend to give substantial decomposition). A saturated aqueous NaHCO3 (20mL) and diethyl ether(50 mL) were added to the mixture. Thephase was separatedand

44、the aqueous layerwas extracted with diethylether (550 mL). Thecombinedorganic layer was washed with brine (10 mL), dried over MgSO4, filtered, andconcentrated. The crude product was purified by flash chromatography to give(2) (0.63 g, 65%).4.3 EE （CH3 CH2OCH3CH-OR）保护羟基EE的性质和 THP差的不是很多。4.3.1EE（ CH3 CH2OCH3CH-OR）羟基保护示例 ( J.Am.Chem.Soc. 1981, 103,2427)OOOOEEOHOH 2CCHOEtTsOHHOHOOTBDMSOTBDMS12Selective reaction of the primary hydroxyl group in1 with ethyl vinyl etherat 22oC