常见的羟基的保护与脱保护方法.docx

1、常见的羟基的保护与脱保护方法1. 简介22. 硅醚22.1 三甲基硅醚 (TMS-OR) 32.2 叔丁基二甲基硅醚 (TBDMS-OR) 42.3叔丁基二苯基硅醚(TBDPS-OR) 43. 苄醚64. 取代苄醚75. 取代甲基醚86. 四氢吡喃醚97. 烯丙基醚101. 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

2、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

3、。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

4、 (1)TES (64)TBDMS (20,000)TIPS (700,000)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

5、别的强有时会干扰质谱，因此这时需要使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

6、三甲基硅醚羟基保护示例 (J. Org.Chem. 1996, 61, 2065)Compound 1 (3.00g, 4.286mmol) was dissolved in dry DMF (17 mL). To this solution at 0oC 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 diluted with EtOAc (300 mL) a

7、nd washed with water (3 ? 20 mL) and then brine (30 mL). The organic layer was dried and concentrated in vacuo. The resulting material was then dissolved in dry DMF (20 mL) and treated at 0oC with imidazole (816 mg, 12.00 mmol), followed by chlorodimethylsilane (1.135g, 12.00mmol). The reaction mixt

8、ure was stirred for 1h at 0oC and then diluted with EtOAc (200mL). The organic layer was washed with water and brine. Upon silica gel chromatography (10% ethyl acetate in hexane), 3.197 g (90%) of the desired product 2 was obtained.Cleavage (J. Org.Chem. 1996, 61, 2065)Hydrolysis was carried out und

9、er aprotic condition-anhydrous tetrabutylammonium fluoride in THF solution.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

10、对酸敏感些。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)The hydroxyl lactone 1, upon treatment wi

11、th TBDMSCl (1.2 equiv) and imidazole (2.5 equiv.) in DMF (2 mL/g of 1) at 35oC for 10 h, produced the silyl ether-lactone 2 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( 1987, 52, 622)To an ice-cold solution of 4.8 g of pyridine (2.0 equiv) and 4.20 g of 1 in 30 mL of dry acetonitrile was added slo

12、wly 9.6 g of tert-butyldimethylsilyl triflate (36.2 mmol, 1.2 equiv). The reaction mixture was stirred for 5 h at room temperature and then poured into 200 mL of saturated sodium bicarbonate solution at 0oC. The solution was extracted thoroughly with hexane, and the organic extracts were dried over

13、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TBAF脱TBDPS示例 (Can. J. Chem. 1975, 53, 2975)To a solution of THP ether 1 (1.7 g, 3.3 mmol) in THF (10 mL) was added a 1 M solution of tetr

14、abutylammonium fluoride in THF (5 mL, 5 mmol) at 22-24oC. The solution was stirred for 2 h and diluted with 100 mL (1:1) of Et2O/EtOAc solution. The organic layer was separated and washed with H2O (3 ? 100 mL). The water extract was washed with 2:1 Et2O/EtOAc solution (2 ? 50 mL), and the organic la

15、yers were combined and dried over MgSO4. The solvent was evaporated in vacuo, and the residue was chromatographed over silica gel using (5:1) hexanes/ethyl acetate solution to give 2 (0.75 g, 82%). 2.2.4 通过AcOH-THF脱TBS示例(Tetrahedron Lett. 1988, 29, 6331)Selective removal of one of the TBDMS groups o

16、f 1 was accomplished by treatment with acetic acid-water-THF (13:7:3) (30C, 15h) to give the monohydroxy compound 2 in 79% yield.2.3 t-Butyldiphenylsilyl ether (TBDPS-OR)在酸性水解条件下TBDPS保护基比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基团更好的稳定

17、性。TBDMS基团在酸性条件下不易迁移。TBDPS醚对K2CO3 /CH3OH，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%三氟乙酸，25，15min稳定。2.3.1 通过TBDPSCl进行羟基的叔丁基二甲基硅醚保护示例(J.Org. Chem, 1992, 57, 1722)To a solution of 1,4-butanediol (5 g, 55 mmol) in CH2Cl2 (10

18、mL) containing i-Pr2NEt (10 mL) was added t-BDPSiCl (5 mL, 18 mmol) dropwise under N2 at 22-24oC. The solution was stirred at 22-24oC for 2 h, concentrated in vacuo 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

19、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. Chem. 1995, 60, 7796)To a stirred solution of (1)(1.5 g) in CH2Cl2 (53 mL) cooled to 0oC were successively added 2,6-lutidine (6.2 mL, 53.3 mmol) and triisopropylsilyl triflate (7.90 mL

20、, 29.5mmol). The mixture was allowed to warm to room temperature (30 min). Then excess triflate was consumed by addition of methanol (10 mL) and a saturated aqueous NH4Cl solution (60 mL). The phase was separated and the aqueous layer was extracted with CH2Cl2 (4 ? 50 Ml). The combined organic phase

21、s were washed with a saturated NaHCO3 (100 mL) a, 1M NaHSO4 (3 ? 50 mL), and brine (50 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography (10% ethyl acetate in hexane) afforded silyl ether (2) (6.90 g, 89%). 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

22、-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）

23、。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，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 H2 / min /0.1g cat)THF40Hexanol25Methanol5Toluene2Hexane63.1.1烷基羟基的

24、苄基醚保护示例(Bull. Chem. Soc. Jpn. 1987, 60, 1529)Compound 1 (12.1 g) in DMF (200 mL) was treated with 60% NaH (1.32 g), benzyl bromide (6.44 g) and tetrabutylammonium iodide (0.11 g). The reaction mixture was stirred at room temperature for 1.5 h. The product was purified by chromatography on silica gel

25、 with toluene-ethanol (20:1) to give 2 (14.0 g, 99%).3.1.2 酚羟基的苄基醚保护示例 To a solution of 1 (37.65 g, 277 mmol) in EtOH (135 mL) was added benzyl chloride (36.5 g, 289 mmol), KI (1.75 g, 10 mmol) and K2CO3 (24.6 g, 178 mmol) with stirring. The resulting mixture was refluxed for 5 h. The mixture was al

26、lowed to cool to room temperature and the solvent was removed in vacuo. The residue was added water (100 mL) and extracted with Et2O (80 mL ? 3). The extract was washed with saturated NaHCO3, water and brine successively. The organic layer was dried over Na2SO4 and concentrated in vacuo to give the

27、crude product, which was distilled to afford 2 (49.1 g, 79%).3.1.3苄基醚氢解脱保护示例(J. Am. Chem. Soc. 1971, 93, 1746)Compound 3 (105 mg) was hydrogenated in ethanol (10 mL) containing 1M hydrochloric acid (0.5 mL) in the presence of 10% palladium on charcoal (50 mg) in an initial hydrogen pressure of 3.4 M

28、Pa overnight. The product was purified by chromatography on silica gel with toluene-ethanol (3:1) to give 4 (90 mg, quant.)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。Cleavage of MPM, DMPM, and TMPM ethers with DDQ in CH2Cl2/H2O at 20oCProtective

29、GroupTime (h)Yield(%)ii iiiProtectiveGroupTime (h)Yield(%)( ii 3,4-DMPM0.3386842-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.

30、1988, 29, 2459)To a stirred suspension of NaH (26 mg 1.09 mmol) in DMSO (1 mL) was added dropwise a THF solution (3 mL) of 1 (250 mg, 0.78 mmol) under Ar. After 45 min. at room temperature MPM chloride (158 mg, 1.01mmol) was added, and the stirring was continued for 3 h. the mixture was poured into

31、sat. NH4Cl aq. And then extracted with ether. The extract was washed with sat. NaCl aq., dried over MgSO4, and concentrated in vacuo to leave an oil, which was chromatographed on a short silica gel column elution with EtOAc-n-hexane (1:1) gave a colorless oil of 2 296 mg, 86%.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)To a stirred solution of 2 (92 mg, 0.286 mmol) in CH2Cl2 (2.9 mL) and water (0.17 mL) was added DDQ (97 mg, 0.427 mmol) at room temp. After 2.5 h precipitated DDQH was removed by decantation a