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。
一、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，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 hydrogenlysisof benzyl ether
Solvent | Reaction rate(mm H2 / min /0.1g cat) |
THF | 40 |
Hexanol | 25 |
Methanol | 5 |
Toluene | 2 |
Hexane | 6 |
烷基羟基的苄基醚保护示例(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 atroom temperature for 1.5 h. The product was purified by chromatography onsilica gel with toluene-ethanol (20:1) to give 2 (14.0 g, 99%).
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 benzylchloride (36.5 g, 289mmol), KI (1.75 g, 10mmol) and K2CO3 (24.6 g, 178 mmol) with stirring. The resulting mixture was refluxed for 5h. The mixture was allowed to cool toroom temperature and the solvent was removed in vacuo. The residue was added water (100 mL) andextracted with Et2O (80 mL ´ 3). The extract was washed with saturated NaHCO3,water and brine successively. Theorganic layer was dried over Na2SO4 and concentrated invacuo to give the crude product, which was distilled to afford 2 (49.1 g, 79%).
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 1Mhydrochloric acid (0.5 mL) in the presence of 10% palladium on charcoal (50 mg)in an initial hydrogen pressure of 3.4 MPa overnight. The product was purifiedby chromatography on silica gel with toluene-ethanol (3:1) to give 4 (90mg, quant.)
二、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 TMPMethers with DDQ in CH2Cl2/H2O at 20oC
Protective Group | Time (h) | Yield(%) ii iii | ProtectiveGroup | Time (h) | Yield(%) ( ii | ||
3,4-DMPM | <0.33 | 86 | 84 | 2-MPM | 3.5 | 93 | 70 |
4-MPM | 0.33 | 89 | 86 | 3,5-DMPM | 8 | 73 | 92 |
2,3,4-TMPM | 0.5 | 60 | 75 | 2,3-DMPM | 12.5 | 75 | 73 |
3,4,5-TMPM | 1 | 89 | 89 | 3-MPM | 24 | 80 | 94 |
2,5-DMPM | 2.5 | 95 | 16 | 2,6-DMPM | 27.5 | 80 | 95 |
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。
对甲氧基苄基醚保护示例(Tetrahedron Lett.1988, 29, 2459)
To a stirred suspension of NaH (26 mg 1.09 mmol) inDMSO (1 mL) was added dropwise a THF solution (3 mL) of 1 (250 mg, 0.78mmol) 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 intosat. NH4Cl aq. And then extracted with ether. The extract was washedwith sat. NaCl aq., dried over MgSO4, and concentrated in vacuoto leave an oil, which was chromatographed on a short silica gel column elutionwith EtOAc-n-hexane (1:1) gave a colorless oil of 2 296 mg, 86%.
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 (97mg, 0.427 mmol) at room temp. After 2.5 h precipitated DDQH was removed bydecantation and washed with a small amount of CH2Cl2. Thecombined CH2Cl2 solution was washed with sat. NaHCO3aq. And sat. NaCl aq. And dried over Na2SO4. Evaporatedof the solvent in vacuo gave an oil, which was chromatographed on asilica gel column with EtOAc-n-hexane (1:1) as eluant gave a colorless solid of 1 43.8 mg, 84%.
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