1.    前言

羥基廣泛存在于許多在生理上和合成上有意義的化合物中，如核苷，碳水化合物、甾族化合物、大環(huán)內(nèi)酯類化合物、聚醚、某些氨基酸的側(cè)鏈。。另外，羥基也是有機合成中一個很重要的官能基，其可轉(zhuǎn)變?yōu)辂u素、氨基、羰基、酸基等多種官能團。在化合物的氧化、酰基化、用鹵代磷或鹵化氫的鹵化、脫水的反應或許多官能團的轉(zhuǎn)化過程中，我們常常需要將羥基保護起來。在含有多官能團復雜分子的合成中，如何選擇性保護羥基和脫保護往往是許多新化合物開發(fā)時的關鍵所在，如紫杉醇的全合成。羥基保護主要將其轉(zhuǎn)變?yōu)橄鄳拿鸦蝓?，以醚更為常見。一般用于羥基保護醚主要有硅醚、甲基醚、烯丙基醚、芐基醚、烷氧甲基醚、烷巰基甲基醚、三甲基硅乙基甲基醚等等。羥基的酯保護一般用的不多，但在糖及核糖化學中較為多見。

2.    羥基硅醚保護及脫除

硅醚是最常見的保護羥基的方法之一。隨著硅原子上的取代基的不同，保護和去保護的反應活性均有較大的變化。當分子中有多官能團時，空間效應及電子效應是影響反應的主要因素。在進行選擇性去保護反應時，硅原子周圍的空間效應，以及被保護分子的結(jié)構(gòu)環(huán)境均需考慮。例如，一般情況下，在TBDMS基團存在時，斷裂DEIPS( 二乙基異丙基硅基) 基團是較容易的，但實際得出的一些結(jié)果是相反的。在這些例子中，分子結(jié)構(gòu)中空間阻礙是產(chǎn)生相反選擇性的原因。電子效應的不同也會影響反應的選擇性。對于兩種空間結(jié)構(gòu)相似的醇來說，電子云密度不同造成酸催化去保護速率不同，因此可以選擇性去保護。這一點對酚基和烷基硅醚特別有效：烷基硅醚在酸中容易去保護，而酚基醚在堿性條件下更容易去保護。降低硅的堿性還可以用于改變Lewis酸催化反應的結(jié)果，并且有助于選擇性去保護。在硅原子上引入吸電子取代基可以提高堿性條下水解反應的靈敏性，而對酸的敏感性降低。對大多數(shù)醚來說，在酸中的穩(wěn)定性為TMS(1)<TES (64)<TBDMS (20,000)<TIPS (700,000)<TBDPS (5,000,000)；在堿中穩(wěn)定性為TMS (1)<TES (10-100)<TBDMS~TBDPS (20,000)< TIPS (100,000)。一般而言，對于沒有什么位阻的伯醇和仲醇，盡量不要選用TMS作為保護基團，因為得到的產(chǎn)物一般在硅膠這樣弱的酸性條件下也會被裂解掉。

任何羥基硅醚的都可以通過四烷基氟化胺如TBAF脫除，其主要硅原子對氟原子的親和性遠遠大于硅-氧之間的親和性。在用TBAF裂解硅醚后，分解產(chǎn)生的四丁銨離子有時通過柱層析或HPLC很難除干凈，而季銨鹽的質(zhì)譜豐度(Bu₄N⁺: 242)又特別的強有時會干擾質(zhì)譜，因此這時需要使用四甲基氟化銨或四乙基氟化銨來脫除。

使用硅醚保護的另一個好處是可以在分子中游離伯胺或仲胺基的存在下，對羥基進行保護，其主要由于硅-氮鍵的結(jié)合遠比硅-氧鍵來的弱，硅原子優(yōu)先與羥基上的氧原子結(jié)合，這正是與其他保護基不同之處。順便提一句，一般而言，決大部分的硅-氮鍵的結(jié)合是不穩(wěn)定的，其很容易被水解掉。

2.1 三甲基硅醚的保護 (TMS-OR)

許多硅基化試劑均可用于在各種醇中引入三甲基硅基。一般來說，空間位阻較小的醇最容易硅基化，但同時在酸或堿中也非常不穩(wěn)定易水解,三甲基硅基化廣泛用于多官能團化合物，生成的衍生物具有較高的揮發(fā)度而利于其相色譜和質(zhì)譜分析。

三甲基硅醚羥基保護示例 (J.Org.Chem. 1996, 61, 2065)

Compound 1 (3.00g, 4.286mmol) was dissolved in dry DMF (17 mL). Tothis solution at 0^oC was added imidazole (874.3 mg, 12.86mmol),followed by TMSCl (1.63 mL, 12.86 mmol). After stirring at 0^oC for1.5 h, the reaction mixture was diluted with EtOAc (300 mL) and washed withwater (3 ′ 20 mL) and then brine (30mL). The organic layer was dried and concentrated in vacuo. Theresulting material was then dissolved in dry DMF (20 mL) and treated at 0^oCwith imidazole (816 mg, 12.00 mmol), followed by chlorodimethylsilane (1.135g, 12.00mmol). Thereaction mixture was stirred for 1h at 0^oC and then diluted withEtOAc (200mL). The organic layer was washed with water and brine. Upon silicagel chromatography (10% ethyl acetate in hexane), 3.197 g (90%) of the desired product 2 wasobtained。

Cleavage (J. Org.Chem. 1996, 61, 2065)

Hydrolysis was carried out under aproticcondition-anhydrous tetrabutylammonium fluoride in THF solution.

2.2 t-Butyldimethylsilyl ether(TBDMS-OR)

在化學合成中，采用硅基化進行羥基保護生成叔丁基甲基硅基醚是應用較多的方法之一。一般來說，在分子中羥基位阻不大時主要通過TBSCl對羥基進行保護。  但當羥基位阻較大時則采用較強的硅醚化試劑TBSOTf來實現(xiàn)。生成的叔丁基二甲基醚在多種有機反應中是相當穩(wěn)定的，在一定條件下去保護時一般不會影響其他官能團。它在堿性水解時的穩(wěn)定性約為三甲基硅醚的10⁴倍。它對堿穩(wěn)定。相對來說對酸敏感些。TBS醚的生成和斷裂的難易取決于空間因素，因此常常用于對多官能團，位阻不同的分子進行選擇性保護。在伯、仲醇中，TBS基相對來說較易于與伯醇反應。TBS醚的斷裂除了常用的四烷基氟化胺外，許多情況下也可用酸來斷。當分子內(nèi)沒有對強酸敏感的官能基存在時，可用HCl-MeOH, HCl-Dioxane體系去除TBS，若有對強酸敏感的官能基存在時，則可選用AcOH-THF體系去除。

通過TBSCl進行羥基的叔丁基二甲基硅醚保護示例 (J. Am. Chem. Soc.1972, 94, 6190)

The hydroxyllactone 1, upon treatment with TBDMSCl (1.2 equiv) and imidazole (2.5 equiv.) inDMF (2 mL/g of 1) at 35^oC for 10 h, produced the silylether-lactone 2 in 96% yield.

通過TBSOTf進行羥基的叔丁基二甲基硅醚保護示例(J.Org.Chem. 1987, 52,622)

To an ice-coldsolution of 4.8 g ofpyridine (2.0 equiv) and 4.20 gof 1 in 30 mL of dry acetonitrile was added slowly 9.6 g of tert-butyldimethylsilyl triflate(36.2 mmol, 1.2 equiv). The reaction mixture was stirred for 5 h at roomtemperature and then poured into 200 mL of saturated sodium bicarbonate solutionat 0^oC. The solution was extracted thoroughly with hexane, and theorganic extracts were dried over anhydrous potassium carbonate and filtered.Removal of the solvent under reduced pressure followed by distillation of the residuegave 6.29 g (82%yield).

通過TBAF脫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 tetrabutylammonium fluoridein THF (5 mL, 5 mmol) at 22-24^oC. The solution was stirred for 2 hand diluted with 100 mL (1:1) of Et₂O/EtOAc solution. The organiclayer was separated and washed with H₂O (3 ′ 100 mL). The water extract was washed with 2:1 Et₂O/EtOAcsolution (2 ′ 50 mL), and the organiclayers were combined and dried over MgSO₄. The solvent wasevaporated in vacuo, and the residue was chromatographed over silica gelusing (5:1) hexanes/ethyl acetate solution to give 2 (0.75 g, 82%).

通過AcOH-THF脫TBS示例(Tetrahedron Lett.1988, 29, 6331)

Selectiveremoval of one of the TBDMS groups of 1 was accomplished by treatment withacetic acid-water-THF (13:7:3) (30°C,15h) to give the monohydroxy compound 2 in 79% yield.

2.3  t-Butyldiphenylsilyl ether (TBDPS-OR)

在酸性水解條件下TBDPS保護基比TBDMS更加穩(wěn)定（約100倍），而TBDPS保護基對堿的穩(wěn)定性比TBDMS要差。另外，由于該保護基的分子量較大，容易使底物固化而易于分離。  TBDPS保護基對許多與TBDMS保護基不相容的試劑顯出比TBDMS基團更好的穩(wěn)定性。TBDMS基團在酸性條件下不易遷移。TBDPS醚對K₂CO₃ /CH₃OH，對9M氨水、60℃、2h；對MeONa（cat.）/CH₃OH、25℃、24h均穩(wěn)定。該醚對80%乙酸穩(wěn)定，后者可用于脫除醚中TBDMS，三苯甲基，四氫吡喃保護基也對HBr /AcOH，12℃，2min；對25%~75%甲酸，25℃，2h~6h；以及50%三氟乙酸，25℃，15min穩(wěn)定。

通過TBDPSCl進行羥基的叔丁基二甲基硅醚保護示例(J.Org. Chem, 1992,57, 1722)

To a solution of 1,4-butanediol (5 g, 55 mmol) in CH₂Cl₂ (10 mL) containingi-Pr₂NEt (10 mL) was added t-BDPSiCl (5 mL, 18 mmol) dropwise underN₂ at 22-24^oC. The solution was stirred at 22-24^oCfor 2 h, concentrated in vacuo and chromatographed, eluting with hexanes/ethylacetate (10:1) to 2 (clear oil, 5.6 g, 95%).

2.4三異丙基硅醚保護 (TIPS-OR)

酸性水解時，有較大體積的TIPS醚比叔丁基二甲基硅醚要更穩(wěn)定些。但穩(wěn)定性比叔丁基二苯基硅基差。TIPS基堿性水解時比TBDMS基或TBDPS基穩(wěn)定。相對于仲羥基，TIPS基對伯羥基有更好的選擇性。

通過TIPSCl進行羥基的三異丙基硅醚保護示例(J. Org.Chem. 1995, 60, 7796)

To a stirred solution of (1)(1.5 g) in CH₂Cl₂ (53 mL) cooledto 0^oC were successively added 2,6-lutidine (6.2 mL, 53.3 mmol) andtriisopropylsilyl triflate (7.90 mL, 29.5mmol). The mixture was allowed to warm to room temperature (30 min).  Then excess triflate was consumed by additionof methanol (10 mL) and a saturated aqueous NH₄Cl solution (60mL).  The phase was separated and theaqueous layer was extracted with CH₂Cl₂ (4 ′ 50 Ml).  The combined organic phases were washed witha saturated NaHCO₃ (100 mL) a, 1M NaHSO₄ (3 ′ 50 mL), and brine (50 mL), dried over Na₂SO₄,filtered, and concentrated.  Purificationby flash chromatography (10% ethyl acetate in hexane) afforded silyl ether (2)(6.90 g, 89%).  

3.羥基芐醚保護及脫除

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。

3.1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。若反應速度慢可用DMF做溶劑，提高反應溫度，或加NaI,KI催化反應。

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

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.)

3.2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 20^oC

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 of1 43.8 mg, 84%.

資料來源于網(wǎng)絡：藥明康德寶典