硅醚是最常見的保護(hù)羥基的方法之一。隨著硅原子上的取代基的不同，保護(hù)和去保護(hù)的反應(yīng)活性均有較大的變化。當(dāng)分子中有多官能團(tuán)時(shí)，空間效應(yīng)及電子效應(yīng)是影響反應(yīng)的主要因素。在進(jìn)行選擇性去保護(hù)反應(yīng)時(shí)，硅原子周圍的空間效應(yīng)，以及被保護(hù)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(tuán)存在時(shí)，斷裂DEIPS( 二乙基異丙基硅基) 基團(tuán)是較容易的，但實(shí)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(yīng)的不同也會(huì)影響反應(yīng)的選擇性。對(duì)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(hù)速率不同，因此可以選擇性去保護(hù)。這一點(diǎn)對(duì)酚基和烷基硅醚特別有效：烷基硅醚在酸中容易去保護(hù)，而酚基醚在堿性條件下更容易去保護(hù)。降低硅的堿性還可以用于改變Lewis酸催化反應(yīng)的結(jié)果，并且有助于選擇性去保護(hù)。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(yīng)的靈敏性，而對(duì)酸的敏感性降低。對(duì)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(duì)于沒有什么位阻的伯醇和仲醇，盡量不要選用TMS作為保護(hù)基團(tuán)，因?yàn)榈玫降漠a(chǎn)物一般在硅膠這樣弱的酸性條件下也會(huì)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(duì)氟原子的親和性遠(yuǎn)遠(yuǎn)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(shí)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(qiáng)有時(shí)會(huì)干擾質(zhì)譜，因此這時(shí)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(hù)的另一個(gè)好處是可以在分子中游離伯胺或仲胺基的存在下，對(duì)羥基進(jìn)行保護(hù)，其主要由于硅-氮鍵的結(jié)合遠(yuǎn)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(hù)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。

1 三甲基硅醚的保護(hù)(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(shí)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(tuán)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。

1.1 三甲基硅醚羥基保護(hù)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). The reaction mixturewas stirred for 1h at 0^oC and then diluted with EtOAc (200mL). Theorganic 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 wascarried out under aprotic condition-anhydrous tetrabutylammonium fluoride inTHF solution.

2 t-Butyldimethylsilyl ether(TBDMS-OR)

在化學(xué)合成中，采用硅基化進(jìn)行羥基保護(hù)生成叔丁基甲基硅基醚是應(yīng)用較多的方法之一。一般來說，在分子中羥基位阻不大時(shí)主要通過TBSCl對(duì)羥基進(jìn)行保護(hù)。  但當(dāng)羥基位阻較大時(shí)則采用較強(qiáng)的硅醚化試劑TBSOTf來實(shí)現(xiàn)。生成的叔丁基二甲基醚在多種有機(jī)反應(yīng)中是相當(dāng)穩(wěn)定的，在一定條件下去保護(hù)時(shí)一般不會(huì)影響其他官能團(tuán)。它在堿性水解時(shí)的穩(wěn)定性約為三甲基硅醚的10⁴倍。它對(duì)堿穩(wěn)定。相對(duì)來說對(duì)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(duì)多官能團(tuán)，位阻不同的分子進(jìn)行選擇性保護(hù)。在伯、仲醇中，TBS基相對(duì)來說較易于與伯醇反應(yīng)。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(dāng)分子內(nèi)沒有對(duì)強(qiáng)酸敏感的官能基存在時(shí)，可用HCl-MeOH, HCl-Dioxane體系去除TBS，若有對(duì)強(qiáng)酸敏感的官能基存在時(shí)，則可選用AcOH-THF體系去除。

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

The hydroxyl lactone 1, upon treatment with TBDMSCl (1.2 equiv) andimidazole (2.5 equiv.) in DMF (2 mL/g of 1) at 35^oC for 10 h,produced the silyl ether-lactone 2 in 96% yield.

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

To an ice-coldsolution of 4.8 gof pyridine (2.0 equiv) and 4.20 g of 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).

2.3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 tetrabutylammoniumfluoride in THF (5 mL, 5 mmol) at 22-24^oC. The solution was stirredfor 2 h and diluted with 100 mL (1:1) of Et₂O/EtOAc solution. Theorganic layer was separated and washed with H₂O (3 ′ 100 mL). The water extract waswashed with 2:1 Et₂O/EtOAc solution (2 ′ 50 mL), and the organic layers were combined and dried over MgSO₄.The solvent was evaporated in vacuo, and the residue was chromatographedover silica gel using (5:1) hexanes/ethyl acetate solution to give 2 (0.75 g, 82%).  

2.4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 in79% yield.

3 t-Butyldiphenylsilyl ether(TBDPS-OR)

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

3.1通過TBDPSCl進(jìn)行羥基的叔丁基二甲基硅醚保護(hù)示例(J.Org. Chem, 1992,57, 1722)

To a solution of 1,4-butanediol (5 g,55 mmol) in CH₂Cl₂ (10 mL) containing i-Pr₂NEt(10 mL) was added t-BDPSiCl (5 mL, 18 mmol) dropwise under N₂ at22-24^oC. The solution was stirred at 22-24^oC for 2 h,concentrated in vacuo and chromatographed, eluting with hexanes/ethyl acetate(10:1) to 2 (clear oil, 5.6 g, 95%).

4三異丙基硅醚保護(hù) (TIPS-OR)

酸性水解時(shí)，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(shí)比TBDMS基或TBDPS基穩(wěn)定。相對(duì)于仲羥基，TIPS基對(duì)伯羥基有更好的選擇性。

2.4.1通過TIPSCl進(jìn)行羥基的三異丙基硅醚保護(hù)示例(J. Org. Chem. 1995, 60, 7796)

To a stirred solutionof (1)(1.5 g) in CH₂Cl₂(53 mL) cooled to 0^oC were successively added 2,6-lutidine (6.2 mL,53.3 mmol) and triisopropylsilyl triflate (7.90 mL, 29.5mmol).  The mixture was allowed to warm to roomtemperature (30 min).  Then excesstriflate was consumed by addition of methanol (10 mL) and a saturated aqueousNH₄Cl solution (60 mL).  Thephase was separated and the aqueous layer was extracted with CH₂Cl₂(4 ′ 50 Ml).  Thecombined organic phases were washed with a saturated NaHCO₃ (100 mL)a, 1M NaHSO₄ (3 ′ 50 mL), and brine(50 mL), dried over Na₂SO₄, filtered, andconcentrated.  Purification by flashchromatography (10% ethyl acetate in hexane) afforded silyl ether (2) (6.90 g, 89%). 

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