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   硅醚是最常见的保护羟基的方法之一。随着硅上的取代基的不同,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。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(1)<TES (64)<TBDMS (20,000)<TIPS (700,000)<TBDPS (5,000,000);在碱中稳定性为TMS (1)<TES (100)<TBDMS~TBDPS (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。

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。

1.1 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). Tothis solution at 0oC was added imidazole (874.3 mg, 12.86mmol),followed by TMSCl (1.63 mL, 12.86 mmol). After stirring at 0oC for1.5 h, the 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 0oCwith imidazole (816 mg, 12.00 mmol), followed by chlorodimethylsilane (1.135g, 12.00mmol). The reaction mixturewas stirred for 1h at 0oC 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)

在中,采用硅基化进行羟基保护生成叔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。

2.1 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 with TBDMSCl (1.2 equiv) andimidazole (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 通过TBSOTf进行羟基的叔丁基二甲基硅醚保护示例(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 0oC. 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通过TBAFTBDPS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 22-24oC. 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通过AcOH-THF脱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℃,2h~6h;以及50%三氟乙酸,25℃,15min稳定。

 

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 mL) containing i-Pr2NEt(10 mL) was added t-BDPSiCl (5 mL, 18 mmol) dropwise under N2 at22-24oC. 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%).

 

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 solutionof (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, 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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