一般羥基的芐醚保護主要有芐基，對甲氧芐基及三苯甲基醚。
一、芐基醚保護羥基 (Bn-OR)
一般烷基上的羥基在用芐基醚保護時需要用強堿，但酚羥基的芐基醚保護一般只要用碳酸鉀在乙腈或丙酮中回流即可，回流情況下，這類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劑居多。若反應(yīng)速度慢可用DMF做溶劑，提高反應(yīng)溫度，或加NaI,KI催化反應(yīng)。
芐基醚的裂解主要是通過催化加氫的方法，Pd是理想的催化劑，用Pt時會產(chǎn)生芳環(huán)上的氫化作用。在含色氨酸的肽中氫解蘇氨酸常導(dǎo)致色氨酸還原成2，3-二氫衍生物。非芳性的胺可以使催化劑活性降低，阻礙O-脫芐；在氫化體系中加入Na2CO3可以防止芐基被裂解，但可使雙鍵發(fā)生還原。孤立烯烴有可能影響芐基醚鍵的裂解（H2，5% Pd-C，97%產(chǎn)率）。一般而言選擇性的大小取決于取代的類型及空間位阻的情況。與酯共扼的三取代的烯烴存在時，芐基的水解也有相當(dāng)好的選擇性。對甲氧芐基基團存在時，芐基的水解（Pd-C，EtOAc，室溫，18小時）有非常好的選擇性。在反應(yīng)體系中加入Pyridine 可使對甲氧芐基和芐基氫解產(chǎn)生區(qū)別。芐基的氫解有溶劑的作用，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 |
烷基羥基的芐基醚保護示例(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%).
酚羥基的芐基醚保護示例
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%).
芐基醚氫解脫保護示例(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、對甲氧基芐基醚保護羥基 (PMB-OR)
各種甲氧基芐醚已經(jīng)合成得到并被用作保護基。實際上甲氧基取代的芐基醚較未取代的芐基醚更容易通過氧化去保護。下表給出了用二氯二氰苯醌去保護時的相對速率。
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，對甲氧基芐醚在合成中更為常用，羥基上對甲氧基芐基的方法和芐基類似，但脫除除了氫解的方法外，還可以氧化除去。
對甲氧基芐基醚保護示例(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%.
在芐氧基存在下選擇性脫去對甲氧基芐基示例(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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